Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:15]1[CH2:20][CH:19]=[C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:15]3[CH2:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CCCOc2cccc3[nH]ccc23)C1
Temperature: 100 °C
Yield: 52.2 %

Procedure:
The above 1-(4-indolyloxy)-3-chloropropane (0.629 g, 3 mmol), 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.595 g, 3 mmol) and sodium carbonate (0.795 g, 7.5 mmol) were mixed together in 15 mL dimethylformamide. This mixture was heated at 100° C. for 18 h. Evaporation of dimethylformamide, dilution with water and crystallization of the resulting precipitate from ethanol provided 0.582 g of yellow crystals. Mp 192°-194° C. Mass spectrum, m+ =371. Anal (C24H25N3O) theory C, 77.60; H, 6.78; N, 11.31; found C, 77.49; H, 6.53; N, 11.29.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][C:28]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>C(N(CC)CC)C>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:28]=4[CH3:27])=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cccc(N)c1C
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
As described for Example 123, a mixture of 0.361 g of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)-carbonyl]benzoyl chloride, 0.101 g of triethylamine and 0.145 g of 2,3-dimethylaniline is stirred for 1.5 hr. and worked up to give 0.44 g of crystals, m.p. 248°-251° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)#[N:30]>>[C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:33][CH:32]=1)#[N:30]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: N#Cc1ccc(OCc2ccc(-c3nccnc3NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)cc1
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-cyanophenol, the title compound was isolated as a yellow solid in 73% yield (93% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-carboxylate and benzyl bromide in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as a light yellow solid. Mass spectrum (ESI, [M+H]+) m/z 358. 1HNMR (300 MHz, DMSO-d6): δ 7.94 (s, 1H), 7.55 (d, 1H, J=9.01 Hz), 7.42 (d, 1H, J=8.85 Hz), 7.34 (s, 1H), 7.30-7.21 (m, 3H), 6.99 (d, 2H, J=7.94 Hz), 5.85 (s, 2H), 4.28 (q, 2H), and 1.28 ppm (t, 3H). Elemental Analysis for C18H16BrNO2: Calculated: C, 60.35; H, 4.50; N, 3.91. Found: C, 69.19; H, 4.51; N, 3.75.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[Pd].CO>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([CH2:23][NH2:24])=[CH:21][CH:22]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C#N)nc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CN)nc1
Reaction time: 3.5 h
Yield: 87.2 %

Procedure:
In a flask, 2920 mg (8.72 mmol) {2-[(6-Cyano-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester and 1000 mg Pd (10% on carbon) were placed under nitrogen and 10 ml THF and 120 ml methanol were added. The starting material was hydrogenated under atmospheric pressure and at rt for 3.5 h. The catalyst was filtered off. The solvent was evaporated and the residue was subjected to silica gel chromatography (toluene/isopropanol/NH3 (conc.) 16:20:1) to yield 2600 mg (7.6 mmol) {2-[(6-Aminomethyl-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester; exact MW [M+H] calc'd: 343.18; MW found [M+H]: 343.2.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].F[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ccc(NCCO)cc1
Temperature: 90 °C
Yield: 20 %

Procedure:
A mixture of ethanolamine (2.29 g, 37.5 mmol) and 1-fluoro-4-nitrobenzene (3.53 g, 25.0 mmol) in dimethylsulphoxide (25 ml) was treated with potassium carbonate (6.9 g, 50 mmol) and heated at 90° C. overnight. The mixture was cooled and poured onto water (250 ml), the precipitated solid filtered off, dried, dissolved in ethanol (50 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature . The catalyst was removed by filtration, the ethanol evaporated and the residue purified by column chromatography using EtOAc to yield the title compound (740 mg, 5.0 mmol). NMR: 2.95 (t, 2H), 3.5 (t, 2H), 4.1 (s, 2H), 4.4 (s, 1H), 4.55 (t, 1H), 6.4 (m, 4H); MS: 153 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])[C:4]=1[OH:14].[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C.C(O)C>[C:15]([O:14][C:4]1[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(C=C[N+](=O)[O-])c1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture of 2-methoxy-6-(2-nitrovinyl)phenol (29.0 grams, 0.15 mole) and sodium acetate (12.4 grams, 0.15 mole) in acetic anhydride (100 ml.) was refluxed for four hours and then poured into ice water. The resulting semi-solid precipitate was dissolved in hot 95% ethanol. Cooling the solution precipitated the crude product which was purified for analysis by chromatography on silica gel with methylene chloride as elutant. The purified 2-methoxy-6-(2-nitrovinyl)phenyl acetate melted at 128° C.-129° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[C:35](SC)[S:36][CH3:37])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:42][NH2:43]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:42][NH:43][C:35]([S:36][CH3:37])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NN
Reactant: CSC(SC)=C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Solvent: CCO
Solvent: O
Product: CSc1[nH]nc2c1CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 80 °C
Yield: 28.1 %

Procedure:
To a solution of tert-butyl(1-(4-(6-(bis(methylthio)methylene)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.35 mmol) in anhydrous ethanol (1.7 mL) was added hydrazine monohydrate (25 μL, 0.52 mmol). The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 2 hours. After cooling to room temperature the reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 90:10 to 80:20) to give the desired product as a yellow solid (53 mg, 28% yield). 1H-NMR (500 MHz, CDCl3) δ 7.94 (1H, s), 7.16-7.24 (4H, m), 7.11-7.16 (3H, m), 7.06-7.10 (2H, m), 3.16 (2H, t), 2.83 (2H, t), 2.35 (3H, s), 2.15-2.45 (4H, br m), 1.88-2.01 (1H, m), 1.64-1.77 (1H, m), 1.00-1.35 (9H, br m). LCMS (Method A) RT=6.94 min, M+H+=539.15.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])[O:8][C:9](=O)[C:2]=12.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])[O:8][CH2:9][C:2]=12
Reactant: O=C1OC(=O)c2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1OCc2ncccc21
Temperature: 15 °C
Reaction time: 4 h
Yield: 13.3 %

Procedure:
A solution of furo[3,4-b]pyridine-5,7-dione (3.0 g, 20 mmol) in THF (20 mL) is treated with sodium borohydride (0.75 g, 20 mmol). The reaction mixture is placed under an argon atmosphere and the temperature is maintained at 15° C. with a water bath. Acetic acid (2.4 g, 39 mmol) is added dropwise at 15° C. The reaction mixture is stirred for 4 h and is then concentrated on a rotary evaporator. The crude residue is then treated with acetic acid (8 mL.) and acetic anhydride (8.0 mL) and heated at 100° C. overnight. The reaction mixture is cooled and concentrated. The residue is purified by chromatography (silica gel, gradient elution 30% EtOAc/hexane to 50% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a white solid (360 mg, 27%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([N:23]1[CH:27]([CH3:28])[C:26](=[O:29])[O:25][CH:24]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Br[CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48]>C1COCC1>[C:15]([N:23]1[C:27]([CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])([CH3:28])[C:26](=[O:29])[O:25][CH:24]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: CC1C(=O)OC(c2ccccc2)N1C(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(CN2C(=O)c3ccccc3C2=O)C(=O)OC(c2ccccc2)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
Into a solution of hexamethyldisilazane (17.5 g, 106 mmol) in THF (100 mL) was added n-butyllithium (1.58 M in hexane, 50 mL, 78.5 mmol) at −78° C. After 5 min at −78° C., the solution was allowed to warm to 0° C. for 30 min and then cooled to −78° C. again. A solution of 3-benzoyl-4-methyl-2-phenyl-1,3-oxazolidin-5-one (dried overnight in vacuo before using, 20 g, 71 mmol) in THF (250 mL) was added slowly under argon, and the dark red brown solution was stirred at this temperature for 3 h. A solution of N-(bromomethyl)phthalimide (22.2 g, 92.5 mmol) in THF (200 mL) was then added dropwise. The reaction mixture was allowed to warm to 20° C. in 4 h and stirred at this temperature overnight. The solvent was evaporated. The residue was dissolved in 10% NH4Cl (250 mL) and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and evaporated. Recrystallization from CH2Cl2 and ether (1:4) gave white crystals of 2-((3-benzoyl-4-methyl-5-oxo-2-phenyloxazolidin-4-yl)methyl)isoindoline-1,3-dione (23 g, 74%). LC-MS (ES, m/z): 441 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C(N(CC)CC)C.[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)#[CH:19]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]#[C:18][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
Dissolve 1-fluoro-4-iodo-2-methoxybenzene, (prepared as described in PREPARATION 47), (1.0 g, 4.0 mmol) in triethylamine (15 mL, 108 mmol) and add 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (500 mg, 3.8 mmol) followed by bis(triphenylphosphine)palladium (II) dichloride (100 mg, 0.14 mmol) and copper (I) iodide (60 mg, 0.32 mmol). Stir for 18 h at room temperature, concentrate and purify by silica gel chromatography, eluting with 3:1 hexanes:ethyl acetate. Further purify on silica gel, eluting with 9:1 dichloromethane:ethyl acetate, to give the title compound as a white solid (650 mg, 65%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9](=[O:51])[CH2:10][C:11]1[CH:50]=[CH:49][CH:48]=[CH:47][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:45][CH3:46])[N:16]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:46][O:45][C:27]1[CH:28]=[C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:30]=[CH:31][C:26]=1[NH:25][C:17]1[N:16]=[C:15]([CH2:14][CH2:13][C:12]2[CH:47]=[CH:48][CH:49]=[CH:50][C:11]=2[CH2:10][C:9]([NH2:8])=[O:51])[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][N:18]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a stirred solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I23) (185 mg, 0.301 mmol) in DCM (10 mL) and the resulting solution was stirred at room temperature for 2 hours. DCM (20 mL) and 10% NaHCO3 solution (10 mL) were added then the organic layer was dried (MgSO4) and evaporated to dryness under reduced pressure to give the title compound (2) (125 mg, 81%) as a colourless solid; 1H NMR (400 MHz, CD2Cl2) δ 8.49 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.28-7.12 (m, 3H), 6.94 (bs, 2H), 6.85 (d, J=8.2 Hz, 1H), 6.78 (dd, J=11.8, 3.1 Hz, 1H), 6.35 (s, 1H), 5.94 (s, 1H), 3.88 (s, 3H), 3.65 (s, 2H), 3.42 (d, J=12.3 Hz, 2H), 3.24-3.02 (m, 4H), 2.91 (t, J=11.3 Hz, 2H), 2.75-2.61 (m, 1H), 2.10-1.83 (m, 4H). LCMS Method C: rt 4.92 min; m/z 514.1 [M+1]+, 521.1 [M−1]+.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[N:5][CH:4]=1.[CH3:22][NH:23][CH3:24]>C1COCC1>[CH:16]1([C:8]([C:6]2[O:7][C:3]([CH2:2][N:23]([CH3:24])[CH3:22])=[CH:4][N:5]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC(c1ccccc1)(c1ncc(CBr)o1)C1CCCCC1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1cnc(C(O)(c2ccccc2)C2CCCCC2)o1
Reaction time: 8 h

Procedure:
A solution of (5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol (Intermediate 4) (3.2 g, 9.2 mmol) in THF (40 mL) was treated with a 2 M solution of dimethylamine in THF (40 mL, 80 mmol). A suspension formed after stirring for a few minutes. The reaction mixture was left at RT overnight and then the solid was filtered off and discarded. The filtrate was concentrated under reduced pressure and the residue was partitioned between DCM and satd. sodium hydrogen carbonate solution (aq.). The organic layer was dried (Na2SO4) and evaporated to afford the title compound as a solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:36][CH3:37])=[C:7]2[C:12](=[C:13]([C:15]3[C:16]([O:23]C)=[N:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[CH:14]=1)[N:11]=[CH:10][C:9]([N:25]1[CH2:29][CH2:28][C@H:27]([CH2:30][NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]1)=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Br>CC(O)=O>[C:1]([C:5]1[C:6]([O:36][CH3:37])=[C:7]2[C:12](=[C:13]([C:15]3[C:16](=[O:23])[NH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[CH:14]=1)[N:11]=[CH:10][C:9]([N:25]1[CH2:29][CH2:28][C@H:27]([CH2:30][NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]1)=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nc(=O)n(C)cc1-c1cc(C(C)(C)C)c(OC)c2cc(N3CC[C@H](CNS(C)(=O)=O)C3)cnc12
Agent: Br
Solvent: CC(=O)O
Product: COc1c(C(C)(C)C)cc(-c2cn(C)c(=O)[nH]c2=O)c2ncc(N3CC[C@H](CNS(C)(=O)=O)C3)cc12

Procedure:
step 3—A 10 mL screw-capped tube was charged with 122 (0.021 g, 39.6 μmol), HBr (16.0 mg, 10.8 μL, 198 μmol) and HOAc. After 4 h the reaction mixture was poured into satd. aq. NaHCO3 (50 mL) and extracted with EtOAc (3×20 mL). The organic extract was dried (Na2SO4), filtered and evaporated to 0.020 g (98%) of I-40 as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Product: CCC(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and propionyl chloride
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)=[CH:2]1.[S:19]1[CH:23]=[CH:22][C:21]([C:24]2C=C(CC=O)C=C[CH:29]=2)=[CH:20]1>>[S:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:2]=[C:3]([C:6]3[S:10][C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)=[N:8][CH:7]=3)[CH:4]=[CH:5][CH:29]=2)=[CH:20]1
Reactant: O=CCc1cccc(-c2ccsc2)c1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Product: Oc1ccc(Nc2ncc(-c3cccc(-c4ccsc4)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-thiophen-3-yl-phenyl)-acetaldehyde (Example 25). The title compound: ES-MS: 350.9 [M+H]+; single peak at tR=4.16 min (System 2).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:7][CH2:8][C:9]#[CH:10].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([OH:24])[C:10]#[C:9][CH2:8][CH2:7][CH2:6][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C#CCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(C#CCCCOC1CCCCO1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 68.4 %

Procedure:
61.5 ml of 1.6M solution of n-butyllithium (98,4 mmol) in hexane are added dropwise to a solution, cooled to −78° C. under argon, of 13.25 g (78.8 mmol) of 2-(pent-4-yn-1-yloxy)tetrahydro-2H-pyran in 130 ml of anhydrous tetrahydrofuran. Stirring is continued at −78° C. for 1 hour and then a solution of 12.18 g (86.6 mmol) of 4-chlorobenzaldehyde in 40 ml of tetrahydrofuran is added dropwise. Stirring is continued at −78° C. for 2 hours and then the solution is reheated to 0° C. and is poured onto 300 ml of a saturated aqueous ammonium chloride solution. Extraction is carried out with 450 ml of ethyl acetate. The organic phase is washed with 50 ml of water and then with 50 ml of a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 70/30 mixture of n-hexane and of ethyl acetate, to produce 16.64 g (53.88 mmol) of product in the form of a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)([O-])=O>[Fe].C(O)(=O)C>[NH2:1][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccsc1-c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
To 20 ml of acetic acid, 1 g of 3-nitro-2-(4-chlorophenyl)thiophene and 0.93 g of iron powder were added and heated for 2 hours at 60° C. The reaction mixture was filtered through a diatomaceous earth (Celite) layer. Ethyl acetate was added to the filtrate and extracted 5 times with a 5% aqueous hydrogen chloride solution. The aqueous layer was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.54 g of the product as an yellow brown crystal. The yield was 62%. 1H-NMR(CDCl3, δ value):3.82(2H, brs), 6.64(1H, d, J=5.1), 7.12(1H, d, J=5.1), 7.34-7.39(2H, m), 7.43-7.48(2H, m)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:9][CH:10]=1)=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][CH2:12][CH2:13][NH:14][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:9][CH:10]=1)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CCCN)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCNS(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of 5-(3-amino-propyl)-furan-2-carboxylic acid methyl ester hydrochloride salt (see Preparation DD2) (150 mg, 0.683 mmol), and triethylamine (0.313 mL, 2.25 mmol) in CH2Cl2 (15 mL) at 0° C. was added methanesulfonyl chloride (86 mg, 0.75 mmol). The reaction was stirred at room temperature for 18 h. The organic solution was washed consecutively with dilute HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title sulfonamide (156 mg). MS 262 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)=[O:3].[CH3:12][Mg]I.C(OCC)C>>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([C:2]([OH:3])([CH3:12])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: C[Mg]I
Solvent: CCOCC
Product: COc1cccc(C(C)(C)O)c1
Temperature: 0 °C

Procedure:
A flame-dried 25 mL R.B. flask equipped with a reflux condenser was charged, under argon, with 3-methoxyacetophenone (1 g, 6.66 mmol) at 0° C. Methylmagnesium iodide in diethylether (4.4 mL, 13.3 mmol, 3M) was then added. The reaction mixture was brought to reflux for 60 min and then cool down to 0° C. and quenched with successive addition of water (5 mL) and saturated ammonium chloride (25 mL). The mixture was extracted with diethyl ether (3×20 mL), the organic extracts were washed successively with 20% sodium bisulfite and saturated sodium bicarbonate, dried, filtered and concentrated. Purification by flash chromatography, using 15% acetone in hexanes, yields propan-2-ol (0.832 g, 75%). 1H NMR (400 MHz, acetone-d6) δ: 1.51 (s, 6H), 3.79 (s, 3H), 6.77 (d, 1H, J=8.1 Hz), 7.07 (d, 1H, J=7.7 Hz), 7.13 (s, 1H), 7.22 (t, 1H, J=7.9 Hz).