Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[CH3:13][C:14]1([CH3:27])[C:18]2([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19]([CH2:21][CH:15]1[CH2:16][CH2:17]2)=[O:20]>C(Cl)Cl.C(N(CC)CC)C>[CH:4]1([CH2:3][CH2:2][NH:1][S:23]([CH2:22][C:18]23[C:14]([CH3:13])([CH3:27])[CH:15]([CH2:16][CH2:17]2)[CH2:21][C:19]3=[O:20])(=[O:25])=[O:24])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCC1CCc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CCC1(CS(=O)(=O)NCCC1CCc3ccccc31)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indene (2 ml), 1.99 g, 17.2 mmol) was dissolved in dry THF (2 ml) and stirred at -78° under nitrogen. n-Butyllithium (6.87 ml of a 2.5M solution in hexane: 17.2 mmol) was added, and the solution was then warmed to ambient temperature, stirred for 15 minutes, recooled to -78°, and added via syringe to a solution of chloroacetonitrile (1.09 ml, 1.30 g, 17.2 mmol) in THF (2 ml) stirred at -78°. After completion of the addition, the solution was diluted with ether (200 ml) and washed with 1M HCl followed by saturated sodium bicarbonate solution. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 10% EtOAc in hexane and the product fractions evaporated in vacuo to give 3-cyanomethylindene. 3-Cyanomethylindene (310 mg, 2.0 mmol) was dissolved in a 10% solution of conc. ammonium hydroxide in absolute ethanol. 5% Rhodium/alumina catalyst (60 mg) was added and the mixture was shaken under an atmosphere of hydrogen (40 psi) overnight. The mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 93:7:0.7 CH2Cl2 :MeOH:NH4OH, and the product fractions were combined and evaporated to dryness in vacuo to provide 1-(2-aminoethyl)indane. 1-(2-Aminoethyl)indane (47 mg, 0.292 mmol) and (+)-10-camphorsulfonyl chloride (73 mg, 0.29 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (2 drops), and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue chromatographed on a silica gel column eluted in with 20% EtOAc in hexane. The product fractions were combined and evaporated to dryness in vacuo. The resulting oil was dried in vacuo at ambient temperature for 3 hours to provide the title compound as a solid: (mp 52°-70°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][CH:14]2[CH3:19].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:29][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9]2[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]3[C:17]=2[C:16](=[O:18])[NH:15][CH:14]3[CH3:19])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A mixture of 7-(2-chlorophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (68 mg, 0.22 mmol, prepared by the procedures described in Example 1) and NBS (46 mg, 0.26 mmol) in DMF (2 mL) was stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% hexanes to 25% EtOAc in hexanes) to afford 7-(4-bromo-2-chlorophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (40 mg, 47%). MS APCI (−) m/z 385, 387 (M-, Br, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.54 (d, 1H), 7.31 (dd, 1H), 6.89 (t, 1H), 6.75 (dd, 1H), 6.05 (s, 1H), 4.63 (q, 1H), 1.49 (d, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:39]=2)/[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1S(C)(=O)=O
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (190 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (250 mg, 2.5 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide (42 mg, 18%) as an amorphous white solid: EI-HRMS m/e calcd for C20H22N6O3S2 (M+) 458.1195, found 458.1192.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=O.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([NH2:17])=[C:12]([NH2:18])[CH:11]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[NH:18][C:12]2[CH:11]=[C:10]([Cl:9])[C:15]([Cl:16])=[CH:14][C:13]=2[N:17]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cn1cccc1C=O
Product: Cn1cccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
2-(1-Methylpyrrol-2-yl)-5,6-dichlorobenzimidazole was prepared from 1-methyl-2-pyrrolecarboxaldehyde and 4,5-dichloro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[OH:9])=[O:2].[Br:13]N1C(=O)CCC1=O>>[Br:13][C:7]1[CH:6]=[C:5]([CH2:10][C:11]#[N:12])[CH:4]=[C:3]([CH:1]=[O:2])[C:8]=1[OH:9]
Reactant: N#CCc1ccc(O)c(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Product: N#CCc1cc(Br)c(O)c(C=O)c1
Yield: 80.6 %

Procedure:
Proceeding as in Reference 9, but substituting 3-formyl-4-hydroxyphenylacetonitrile (1 g, 6.2 mmol) and N-bromosuccinimide (1.7 g, 9.3 mmol), gave 3-bromo-5-formyl-4-hydroxyphenylacetonitrile (1.2 g).
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[C:5]([O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[CH2:32]([S:39][CH:40]([CH:43]([O:46][CH3:47])[O:44][CH3:45])[CH2:41][NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:32]([S:39][CH:40]([CH:43]([O:44][CH3:45])[O:46][CH3:47])[CH2:41][NH:42][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:3]=2[N:2]([CH3:1])[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:24])=[O:25])=[O:13])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)C(CNC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
A mixture of 7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxylic acid (2.10 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (1.30 g), 1H-1,2,3-benzotriazol-1-ol (730 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.04 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:4-1:9, volume ratio) to give the title compound (2.70 g, yield 87%) as a colorless amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[NH:5][CH:6]=[N:7]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:30]([O:36][CH2:37][N:5]1[C:4](=[O:14])[C:3]2[C:8](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[OH:1])[N:7]=[CH:6]1)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cc(O)c2c(=O)[nH]cnc2c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a suspension of 5-hydroxy-7-methoxyquinazolin-4(3H)-one (4.395 g, 22.9 mmol) in DMF (50 mL) at 0° C. was added 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (55 mL, 55 mmol). After it was stirred at room temperature for 1 hour, it was cooled again with an ice-water bath and to it was added chloromethyl pivalate (4.14 g, 27.5 mmol). After it was stirred at room temperature for another hour, it was quenched with a solution of AcOH (10 mL) in water (150 mL) and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated to afford the (5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate solid (5.674 g, 81%). 1H NMR (300 MHz, CDCl3) δ 11.36 (s, 1H), 8.16 (s, 1H), 6.69 (d, 1H), 6.51 (d, 1H), 5.88 (s, 2H), 3.89 (s, 3H), 1.21 (s, 9H); LC-MS (ESI) m/z 307 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[IH:11].CS[C:14]1[NH:15][CH2:16][CH2:17][N:18]=1>CO>[IH:11].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:14]1[NH:18][CH2:17][CH2:16][N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CSC1=NCCN1
Agent: I
Solvent: CO
Product: Clc1ccc(CNC2=NCCN2)cc1Cl
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
To a solution of 3,4-dichlorobenzylamine (0.352 g, 2.0 mmol) in methanol (5 ml) was added 2-methylthio-2-imidazoline hydroiodide (0.488 g, 2.0 mmol) and the mixture was heated to reflux for 4 h. The solvent was partly removed by evaporation (to approx. 1 ml) and ether (5 ml) was added. After stirring for 15 min the precipitating white solid was removed by filtration and washed with ether. It was obtained 130 mg (18%) of a white solid; MS (ISP): 244.1; 246.0 ([M+H]+.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([OH:13])[CH:12]=1.Br[CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([CH:12]=1)[O:13][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (0.4 g) in DMF (5 ml) was dropwise added, under ice-cooling, a DMF (5 ml) solution of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenol (3.3 g), and the mixture was stirred for 10 minutes. To the solution was added diethyl bromomalonate (2.1 ml), and the mixture stirred at 70° C. for 30 minutes. Then, to the reaction mixture was added water (10 ml), and the mixture extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under a reduced pressure, and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=5/1) to give 3.0 g of the title compound (colorless oil). Also, 0.7 g of the phenol derivative of the starting material was recovered.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30]Br)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(I)cc2C=O)CC1
Temperature: 60 °C
Yield: 63 %

Procedure:
To a solution of 5-iodosalicylaldehyde (2 g, 8.2 mmol) (Aldrich) in N,N-dimethylformamide (20 mL) was added anhydrous K2CO3 (1.15 g, 8.2 mmol), and 4-bromomethyl-piperidine -1-carboxylic acid tert-butyl ester (2.3 g, 8.2 mmol, Pharmacore). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 4-(2-formyl-4-iodo-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (Yield 2.3 g, 63%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10]([CH3:23])=[C:11]([C:14]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12]Cl.[CH3:24][NH:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[OH:8][C:9]1[C:10]([CH3:23])=[C:11]([C:14]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12][N:25]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH:36]([CH3:38])[CH3:37])[CH3:24]
Reactant: CNCCOc1cc(C)ccc1C(C)C
Reactant: Cc1c(C)c(OCCO)c(CCl)c(C)c1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C)C)c(OCCN(C)Cc2c(C)c(O)c(C)c(C)c2OCCO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
Triethylamine (2.1 ml) was added dropwise to a solution of 3-hydroxy-6-(2-hydroxyethoxy)-2,4,5-trimethylbenzyl chloride (2.45 g) and N-methyl-2-(2-isopropyl-5-methylphenoxy)ethylamine (2.07 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured on ice water and extracted with ethyl acetate. The obtained extract was purified by silica gel column chromatography (eluent; ethyl acetate/benzene=1/1) and recrystallized from methanol-water to give 2.51 g of the title compound (colorless needle crystals).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]4[N:15]([N:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:27][CH2:26]5)=[O:24])[CH:21]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14]4[N:15]([N:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:26][CH2:27]5)=[O:24])[CH:21]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)[CH2:2]1)(=[O:38])=[O:37]
Reactant: O=C(Nc1cc2c(-c3ccc(O[C@@H]4CCNC4)cc3)cccn2n1)C1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC[C@@H](Oc2ccc(-c3cccn4nc(NC(=O)C5CC5)cc34)cc2)C1
Temperature: 0 °C
Yield: 30 %

Procedure:
(R)—N-(4-(4-(pyrrolidin-3-yloxy)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (340 mg, 0.94 mmol) and triethylamine (0.16 ml, 1.13 mmol) were suspended in DCM (10 ml) and stirred at 0° C. under N2. Methane sulfonylchloride (77 μL, 0.99 mmol) was added slowly and the resulting solution was allowed to warm to room temperature over 4 h. The reaction mixture was washed with sat. NaHCO3 solution (aq.) and the aqueous phase extracted with DCM. The combined organics were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative HPLC to give (R)—N-(4-(4-((1-(methylsulfonyl)pyrrolidin-3-yl)oxy)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide. (126 mg, 30% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 1-benzyl-piperidin-4-ol (25 g, 130.7 mmol) and triethylamine (36.1 ml, 261.4 mmol) in 250 ml of THF is treated with 2,2-dimethyl-propionyl chloride (32.2 ml, 261.4 mmol). The suspension is heated under reflux over night. The solvent is evaporated, the residue taken up in DCM and washed with saturated sodium bicarbonate solution and brine. Drying and evaporation gave an orange oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[C:28]([CH:40]=O)[NH:27][C:26]=1[CH3:42])=[O:24])[CH3:21].N1CCCCC1.Cl>C(O)C>[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)=[C:28]([CH:40]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:11]3[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=3)[C:16]([OH:18])=[O:17])[NH:3][C:2]2=[O:1])[NH:27][C:26]=1[CH3:42])=[O:24])[CH3:21]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c1CCCN1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (51 mg, 0.2 mmol), 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64 mg, 0.2 mmol) and piperidine (0.2 mL) in ethanol (1 mL) was heated in a sealed tube at 60° C. for 5 hours. The reaction was acidified with 1N HCl and the resulted precipitate was collected by vacuum filtration, washed with water and dried to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:36])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25]([NH:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:34][CH3:35])=[CH:13][CH:12]=1)=[O:10].[OH-].[K+]>O.CO>[Cl:36][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:34][CH3:35])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)CNC(=O)Nc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(=O)NCC(=O)O)cc12
Yield: 35.5 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino carbonylamino)-dibenzo[b,d]furan-1-carboxamide (Example 50) (150 mg, 0.28 mmol) was hydrolysed using potassium hydroxide (2 eq.) in 3 ml water and 3 ml methanol for 30 min. at room temperature. The solid precipitated was filtered and washed with methanol to obtain the product as white solid (50 mg).mp: >250° C.
Reaction SMILES: [CH:1]([CH:5]1[CH:9]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]([CH3:18])[C:6]1=[O:19])=[CH:2][CH2:3]C.[O:20]=[O+][O-].CSC>[Cl-].CO>[CH:3]([CH2:2][CH2:1][CH:5]1[CH:9]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]([CH3:18])[C:6]1=[O:19])=[O:20]
Reactant: O=[O+][O-]
Reactant: CCC=CC1C(=O)N(C)CC1COC1CCCCO1
Agent: [Cl-]
Solvent: CO
Solvent: CSC
Product: CN1CC(COC2CCCCO2)C(CCC=O)C1=O

Procedure:
11.0 g (41 m mols) of 3-(butenyl)-1-methyl-4-(2-tetrahydropyranyl-oxy-methyl)-pyrrolidone were dissolved in a mixture of 60 ml of absolute methyle chloride and 30 ml of absolute methanol. At -70° C ozone was introduced into this solution, while stirring, until the solution had a blue color. The reduction of the ozonide with dimethyl sulfide and the isolation of the aldehyde was effected in analogy to Example (5).
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:24]([C:23]1[C:22]([N:19]([CH2:13][CH2:14][CH2:16][CH2:17][CH2:18][CH2:31][CH3:32])[CH2:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=2)=[N:29][CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-{[4-(3-aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 33 and 2-chloronicotinonitrile as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][C:13](=[O:21])[C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)=[CH:11][C:6]=2[N:5]([CH2:22][CH3:23])[C:4]1=[O:24])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:30]>CN(C)C(=O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([CH2:28][C:29]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:30])[C:13]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)=[O:21])=[CH:11][C:6]=2[N:5]([CH2:22][CH3:23])[C:4]1=[O:24])[CH3:2]
Reactant: O=C(CBr)c1cccnc1
Reactant: CCn1c(=O)n(CC)c2cc(CC(=O)c3cccc(C)c3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(CC)c2cc(C(CC(=O)c3cccnc3)C(=O)c3cccc(C)c3)ccc21
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of 1,3-diethyl-5-(2-oxo-2-m-tolyl-ethyl)-1,3-dihydro-benzoimidazol-2-one (prepared as described previously, 500 mg, 1.55 mmol) in N,N-dimethylacetamide (DMA, 2.35 mL) was added NaH (124 mg of a 60% dispersion in mineral oil, 3.1 mmol). The slurry was stirred for 10 minutes, then a solution of 3-(Bromoacetyl)pyridine (310 mg, 1.55 mmol) in DMA (0.470 mL) was added. After 1 hour, the reaction was quenched with 3 mL of acetic acid and diluted with water. The aqueous was extracted with EtOAc (3×10 mL), the organics combined and washed with water, saturated sodium bicarbonate, then again with water. The organics were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 600 mg of the title compound.