Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:30]=[C:31]([NH2:44])[C:32]([C:37]5[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH:42]=5)=[CH:33][C:34]=4[O:35][CH3:36])[N:22]=3)=[CH:13]2)(=O)=O)C=CC=CC=1.C(=O)=O>CO>[Cl:27][C:26]1[C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][CH:13]=2)=[N:22][C:23]([NH:28][C:29]2[CH:30]=[C:31]([NH2:44])[C:32]([C:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH:42]=3)=[CH:33][C:34]=2[O:35][CH3:36])=[N:24][CH:25]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)n1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Yield: 47.1 %

Procedure:
NaOH (2M, 1.488 mL, 2.98 mmol) was added in one portion to a mixture of N′-{4-[1-(benzenesulfonyl)indol-3-yl]-5-chloropyrimidin-2-yl}-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 8, 283 mg, 0.47 mmol) in CH3OH (6 mL) at r.t. under N2. The resulting solution was stirred at reflux for 0.5 h. Dry ice was then added and the resulting mixture was concentrated in vacuo. The resulting residue was triturated with CH2Cl2/CH3OH (4:1, 20 mL), filtered and the filtrate was concentrated in vacuo to give a residue. Purification by FCC, eluting with 2-10% methanolic ammonia in CH2Cl2 gave the title compound (102 mg, 47%) as a pale yellow powder; 1H NMR: 2.30 (3H, s), 2.41 (2H, s), 2.60 (2H, t), 3.02 (2H, d), 3.70 (3H, s), 4.27 (2H, s), 5.73 (1H, s), 6.65 (1H, s), 7.08 (1H, t), 7.17-7.23 (1H, m), 7.26 (1H, s), 7.48 (1H, d), 8.18 (1H, s), 8.38 (1H, s), 8.41 (1H, d), 8.49 (1H, s), 11.85 (1H, s); m/z: ES+ MH+ 460.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C=O)CC1
Yield: 95.7 %

Procedure:
In a manner similar to the method described in example 4a, 5-bromosalicylaldehyde (5.65 g, 28 mmol) (Aldrich) reacted with 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 14 mmol, ASTATECH) and K2CO3 in N,N-dimethylformamide to give 4-(4-bromo-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellow gum (Yield 5.15 g, 51%).
Reaction SMILES: [C:1]1([C:7](=[O:21])[C:8](=[CH:17][N:18]([CH3:20])C)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:22][C:23]1[CH:29]=[CH:28]C(N)=[CH:25][CH:24]=1>CO>[C:1]1([C:7](=[O:21])[C:8](=[CH:17][NH:18][C:20]2[CH:28]=[CH:29][C:23]([I:22])=[CH:24][CH:25]=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(I)cc1
Reactant: CN(C)C=C(C(=O)c1ccccc1)C(=O)c1ccccc1
Solvent: CO
Product: O=C(C(=CNc1ccc(I)cc1)C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,3-diphenyl-2-[(dimethylamino)methylene]-1,3-propanedione (317 mg, 1.13 mmol) in 5.5 mL of MeOH was treated with solid 4-iodoaniline (245 mg, 1.12 mmol). The resulting solution was stirred at rt overnight. The resulting precipitate was isolated by filtration and washed with MeOH. The title compound was isolated as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCN(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.6 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid methyl ester (563 mg, 1.80 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (862 mg, 20.5 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=5 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×40 mL) and chloroform/methanol (3:2, 1×50 mL). The combined organic extracts were then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid (456 mg, 84%) as a brown foam: EI-HRMS m/e calcd for C19H25NO2 (M+) 299.1885, found 299.1885.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:18])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:20][O:19][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:18][CH3:21])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1
Reactant: COC(=O)c1cc(O)cc2cnn(CC(OC)OC)c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)cc2cnn(CC(OC)OC)c12
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of methyl 1-(2,2-dimethoxyethyl)-5-hydroxy-1H-indazole-7-carboxylate (180 mg, 0.6 mmol) from Step F above in DMF (10 ml) was added cesium carbonate (313 mg, 1.0 mmol) followed by iodomethane (40 μL, 0.64 mmol) and the reaction was stirred overnight. The reaction mixture was extracted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated in vacuo to afford methyl 1-(2,2-dimethoxyethyl)-5-methoxy-1H-indazole-7-carboxylate (180 mg, 96%): 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 4.90 (d, J=5.0 Hz, 2H), 4.51 (d, J=5.0 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.27 (s, 6H); MS (ESI+) m/z 295 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].O1CCCC1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([O:6][CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=3)[N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Reactant: OCc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(OCc3cc(F)cc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
3,5-Difluorobenzyl alcohol (227.5 μL, 2.01 mmol) was dissolved into 15 mL of anhydrous tetrahydrofuran and treated with sodium hydride (80.3 mg, 60% dispersion in mineral oil, 2.01 mmol). This was stirred under nitrogen for 15 minutes at ambient temperature, then the reaction was treated with 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-1a) (500 mg, 1.67 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes) to afford 605.2 mg of the title product (I-1b).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)(=O)=O)=CC=1)([O-])=O.[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH:40]3[CH2:41][CH2:36][CH2:37][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Dimethylformamide (23 ml) was added to 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline, tert-butyl 3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate (1.93 g) and cesium fluoride (2.28 g). The reaction mixture was then stirred at room temperature for 4 days. The reaction mixture was evaporated under vacuum and partitioned between methylene chloride and water. The solutions were filtered to remove insoluble solids and the methylene chloride was washed with water and saturated brine and adsorbed onto silica. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the required product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonylpiperidin-3-yloxy)-7-methoxyquinazoline as a yellow gum (0.67 g); Mass Spectrum: (M+H)+ 503.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:21])[CH3:20].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH2:8][CH:2]([NH:1][C:27]([C:26]2[CH:30]=[CH:31][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[CH:24][CH:25]=2)=[O:28])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C(N)Cc1ccc(OC)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)NC(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-amino-3-(3,4-dimethoxyphenyl)propionate (the compound obtained in Example 1-(1)) (15.2 g), 4-isopropyloxybenzoic acid (10.8 g), and 1-hydroxybenzotriazole monohydrate (9.2 g) are dissolved in methylene chloride (120 ml), and thereto is added 1,3-dicyclohexylcarbodiimide (12.4 g) under ice-cooling, and the mixture is stirred at room temperature overnight. The insoluble materials are removed by filtration, and the filtrate is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration with diethyl ether to give ethyl 3-(3,4-dimethoxyphenyl)-2-{[4-(isopropyloxy)-phenyl]carbonylamino}propionate (24.2 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.IC1C=CC=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:5]1([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Ic1ccccc1
Product: O=C1Nc2ccc(C#Cc3ccccc3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (90 mg, 0.38 mmol) (from Example 82) was coupled with iodobenzene (219 mg, 1.07 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 2 mL triethylamine at 70° C. for 15 hours to give (Z)-1,3-dihydro-5-phenylethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 92 mg, 78%)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].[Br:12]Br.C(=O)([O-])O.[Na+]>ClCCl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([OH:11])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:10]=1
Reactant: BrBr
Reactant: CC(C)Oc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Oc1cc(Br)ccc1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To 200 ml of dichloromethane solution containing 27.2 g (0.179 mol) of 2-isopropoxyphenol was added dropwise 50 ml of dichloromethane solution containing 28.4 g (0.177 mol) of bromine at −70° C. or lower. After completion of the dropwise addition, the mixture was stirred at the same temperature 1 hour, and gradually raised to −10° C. After completion of the reaction, the reaction mixture was poured into ice-water, the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and then extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 38.8 g of the title compound as a colorless oil. (Yield: 94%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]1.[OH-:16].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]([NH2:14])=[O:16])[CH2:9]1
Reactant: [OH-]
Reactant: N#CC1CCN(c2c(Cl)cncc2Cl)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1CCN(c2c(Cl)cncc2Cl)C1
Yield: 73 %

Procedure:
A solution of 1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carbonitrile 14 (83 mg, 0.34 mmol) in sulphuric acid (3 mL) was stirred for 90 min and then poured onto ice/water (100 g). The mixture was made basic by the addition of a 2 M solution of sodium hydroxide and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure, to furnish the title compound as a white solid (65 mg, 73%), m.p. 161-163° C.; umax (CHCl3)/cm−1 3053, 2985, 1689, 1558, 1465; m/z (ESI) C10H12Cl2N3O requires 260.0352 found [M+H]+ 260.0355.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:29][CH:30]([CH3:32])[CH3:31])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[C:25]([C:21]1[O:22][C:23]([CH3:24])=[C:19]([CH2:18][CH2:17][O:16][C:10]2[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:7]([CH2:6][CH:5]([O:29][CH:30]([CH3:31])[CH3:32])[C:4]([OH:33])=[O:3])=[CH:8][CH:9]=2)[N:20]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(C(C)(C)C)oc2C)c2ccsc12)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(C(C)(C)C)nc1CCOc1ccc(CC(OC(C)C)C(=O)O)c2sccc12
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
0.322 g of the above prepared 3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-isopropoxy-propionic acid ethyl ester (0.680 mmol) was dissolved in 3.4 ml of THF/EtOH=1/1, treated with 1.133 ml of 3N NaOH (5 eq.), and kept at ambient temperature for 1.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/AcOEt afforded finally 0.287 g of the title compound as a white solid of mp. 159–60°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask containing thiazol-2-amine (0.185 g, 1.843 mmol), perfluorophenyl 1-chloroisoquinoline-6-sulfonate (0.719 g, 1.755 mmol), and THF (0.163 mL) was cooled to 0° C. LHMDS (1.0 M in THF) (3.86 ml, 3.86 mmol) was added dropwise and the reaction was stirred for 5 minutes at 0° C. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was triturated in DCM and loaded onto a silica gel cartridge. The tan solid remaining at the top of the cartridge was scraped into a flask and put aside. The remaining material was purified by silica gel chromatography (40 g column, gradient elution 0 to 100% EtOAc:Heptane with a 10% MeOH:DCM flush). The product fractions were combined with the previously isolated material to afford 1-chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a tan solid. m/z (ESI) 326.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:21])[CH2:19][CH3:20]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([CH2:19][CH3:20])=[N:21][N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: CCC#N
Reactant: CCOc1ccc(N/C(C)=C\C(=O)OC)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOc1ccc(-n2nc(CC)c(C(=O)OC)c2C)cc1
Yield: 88 %

Procedure:
According to AVV A, (Z-3-(4-ethoxyphenylamino)-but-2-enoic acid methylester (235.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. The bluish-brown raw product (307.8 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→70:30→0:100), whereby the pure product was obtained in the form of a weak-yellow oil (254.7 mg, 0.88 mmol, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[N:12][OH:13])[NH2:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(N)=NO)cc1
Yield: 20 %

Procedure:
13.32 g (0.1 mol) 4-methoxybenzonitrile, 20.85 g (0.3 mol) of hydroxylamine hydrochloride and 41.40 g (0.3 mol) potassium carbonate was added to 400 mL absolute ethanol and refluxed 21 hours. The product was filtered and recrystallized from methanol to give 3.12 g (0.02 mol) of 4-methoxybenzamide oxime.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[O:17]>ClCCl>[CH3:10][N:11]1[CH:15]=[C:14]([C:5](=[O:8])[CH2:6][CH3:7])[CH:13]=[C:12]1[CH:16]=[O:17]
Reactant: Cn1cccc1C=O
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc(C=O)n(C)c1
Yield: 94.8 %

Procedure:
To a suspension of aluminium chloride (22.9 g, 172 mmol) in anhydrous dichloromethane (100 ml) and propionylchloride (5.3 g, 57.3 mmol)was added a solution of 1-methyl pyrrole-2-carboxaldehyde (5 g, 46 mmol) in anhydrous dichloromethane (20 ml). The mixture was refluxed for 90 min, poured into ice and stirred until melted. The layers were separated and aqueous layer was extracted with dichloromethane (2×100 ml). The organic phase and extracts were combined, dried over sodium sulfate. The solvent was removed in vacuo to give the title compound (7.2 g, 95%), 1H NMR (d6-DMSO) d 9.6 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 3.9 (s, 3H), 2.8 (q, 2H), 1.06 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[NH:14][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([I:22])[CH:24]=1
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: NC(c1ccccn1)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(c1ccccn1)c1ccccn1)c1cccc(I)c1
Reaction time: 1 h
Yield: 39 %

Procedure:
1.5 g of C,C-dipyridin-2-yl-methylamine are suspended in 50 ml of methylene chloride and 1.15 ml of triethylamine and treated dropwise at 0° with a solution of 3-iodo-benzoyl chloride. After 1 hr. at 0° the reddish suspension is concentrated, the residue is poured into water and extracted three times with methylene chloride. Chromatography on silica gel with methylene chloride/methanol 9:1 yields 1.31 g of brownish N-(di-pyridin-2-yl-methyl)-3-iodo-benzamide. Yield: 39%. Mass spectrum: peaks inter alia at m/e: 415 (M+, 8%), 320 (44%), 231 (36%), 184 (100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:38][C:39]([F:44])([F:43])[CH:40]1[CH2:42][O:41]1.O>CN(C=O)C>[F:38][C:39]([F:44])([F:43])[CH:40]([OH:41])[CH2:42][N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[CH:7]=3)[CH:21]=[N:22]2)[CH2:27][CH2:28]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: FC(F)(F)C1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CC(O)C(F)(F)F)CC3)c2)c2ccc(F)cc21
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 111 mg; 0.25 mmol), K2CO3 (35 mg; 0.25 mmol) and 2-(trifluoromethyl)oxirane (142 mg; 1.27 mmol) in DMF (10 mL) was stirred overnight under nitrogen. The reaction mixture was added water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase flash chromatograph to afford 65 mg (47%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:20][CH3:21])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]([Br:1])[CH3:21])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(Br)cc1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1C(C)Br
Temperature: 25 °C
Yield: 104.4 %

Procedure:
Add N-bromosuccinimide (1090 g, 6.12 mol) and 2,2′-azo-bis-isobutyronitrile (11.4 g, 0.069 mol) to a 20° C. solution of methyl 5-bromo-2-ethylbenzoate (1296 g, 5.33 mol) in carbon tetrachloride (7 L). Heat to reflux for 4 hours, cool to 20-30° C. and wash with water (10 L), extract the aqueous phase with dichloromethane (5 L), combine the organic layers, and wash with water (10 L), Na2SO3 (5 L) and saturated aqueous sodium chloride. Dry with sodium sulfate, filter, and evaporate under reduced pressure to give the title compound as a pale yellow solid (1791 g, 104% crude). ES/MS m/z: 241 (M−HBr).