Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.FC1C=C(C=CC=1)C[C@H]1CCN(C(OC(C)(C)C)=O)C1>>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: Fc1cccc(C[C@@H]2CCNC2)c1
Agent: CC(C)(C)OC(=O)N1CC[C@H](Cc2cccc(F)c2)C1
Product: Fc1cccc(C[C@H]2CCNC2)c1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 98 starting with tert-butyl (S)-3-(3-fluorobenzyl)-pyrrolidine-1-carboxylate (intermediate 117).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:23]([CH3:24])[C:13]3=[N:14][CH:15]=[C:16]([S:18][C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[C:5]([C:10]2[N:23]([CH3:24])[C:13]3=[N:14][CH:15]=[C:16]([S:18][C:19]([F:22])([F:20])[F:21])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:33])[CH3:2]
Reactant: CCSc1cccnc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cccnc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Yield: 42.7 %

Procedure:
A mixture of 2-(3-ethylsulfanyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (200 mg), m-chloroperbenzoic acid (purity: not less than 65%) (230 mg) and chloroform (10 ml) was stirred while ice-cooling for 5 hours. To the reaction mixture was poured saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfinyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (89 mg), which is hereinafter referred to as “the present compound 14”, and 2-(3-ethylsulfonyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (130 mg), which is hereinafter referred to as “the present compound 15”.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](CC#N)[C:12]=3[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:22][C:21]([OH:24])=[O:23])[C:12]=3[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#CCc1cccc2c(-c3ccc(Br)cc3)nccc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1cccc2c(-c3ccc(Br)cc3)nccc12
Reaction time: 3 h

Procedure:
A mixture of 7.5 g of 1-(4-bromophenyl)isoquinoline-5-acetonitrile, 70 ml of acetic acid and 35 ml of 50% sulfuric acid was heated with stirring for 3 hours. After the reaction, water was added, and the pH of the reaction mixture was adjusted to 2 with an aqueous solution of sodium hydroxide. The crystals that precipitated were collected by filtration, and recrystallized from tetrahydrofuran-acetone to afford 7.0 g of 1-(4-bromophenyl)isoquinoline-5-acetic acid having a melting point of 230.5° to 232.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4.30 g (11.2 mmol) of t-butyl 4-(4-methoxycarbonylbenzenesulfonyl)-piperazine-1-carboxylate was stirred in 15 ml of methanol and 15 ml of THF. 17 ml of 1 N aqueous sodium hydroxide solution was added to the resultant mixture, and they were stirred at 60° C. overnight. The reaction liquid was evaporated under reduced pressure, and 1 N hydrochloric acid was added to the residue. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: C([O:4][CH2:5][CH2:6][S:7][C:8]1[CH:9]=[N:10][C:11]([NH:22][C:23]2[S:27][N:26]=[C:25]([C:28]3([CH3:37])[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]3)[N:24]=2)=[C:12]([O:14][C:15]2[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([NH:22][C:23]2[S:27][N:26]=[C:25]([C:28]3([CH3:37])[CH2:29][CH2:30][N:31]([C:34](=[O:36])[CH3:35])[CH2:32][CH2:33]3)[N:24]=2)=[N:10][CH:9]=1
Reactant: CC(=O)OCCSc1cnc(Nc2nc(C3(C)CCN(C(C)=O)CC3)ns2)c(Oc2cccnc2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)N1CCC(C)(c2nsc(Nc3ncc(SCCO)cc3Oc3cccnc3C)n2)CC1
Yield: 44.8 %

Procedure:
A mixture of 2-(6-(3-(1-acetyl-4-methylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)ethyl acetate (89 mg, 0.164 mmol) and potassium carbonate (113 mg, 0.820 mmol) in ethanol (25 mL) was heated at reflux for 2 hr. The reaction was filtered and concentrated, and the residue was purified by reverse phase with 0.1% TFA buffer. The purified fractions were poured into saturated sodium bicarbonate and extracted with methylene chloride to afford 1-(4-(5-(5-(2-hydroxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-4-methylpiperidin-1-yl)ethanone (36.8 mg, 0.0735 mmol, 44.8% yield). 1H NMR (d6-DMSO) δ 12.18 (s, 1H), 8.28 (d, 1H), 8.26 (dd, 1H), 7.44 (d, 1H), 7.25-7.15 (m, 2H), (4.89 (m, 1H), 3.89 (m, 1H), 3.60 (m, 1H), 3.52 (m, 2H), 3.18 (t, 1H), 3.00-2.88 (m, 3H), 2.53 (m, 3H), 2.31 (m, 2H), 1.97 (s, 3H), 1.62-1.40 (m, 2H), 1.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[NH:5][C:6]=1[C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:19]([O:23][C:24]([O-:26])=O)(=O)OC>>[CH3:15][O:14][C:12]([N:5]1[C:6]([C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]([CH3:1])[N:3]([C:24]([O:23][CH3:19])=[O:26])[C:4]1=[O:18])=[O:13]
Reactant: COC(=O)OC(=O)[O-]
Reactant: CCOC(=O)CCCCC(=O)c1[nH]c(=O)[nH]c1C
Product: CCOC(=O)CCCCC(=O)c1c(C)n(C(=O)OC)c(=O)n1C(=O)OC
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
A mixture of 1.88 g (7.4 mmol) of 4-methyl-5-(5-ethoxycarbonylpentanoyl)-4-imidazolin-2-one and 20 ml methyl pyrocarbonate was heated to 90° C., and stirred for 1.5 hours whereupon a complete solution was obtained. After removal of the volatiles in vacuo, the oily residue was treated with 20 ml hexanes to give a white solid which was collected by filtration and washed with two 5 ml portions of hexanes. Recrystallization from 100 ml ethyl ether gave 2.1 g (76.6%) of the title compound; m.p. 74°-76° C.; 1H-NMR (CDCl3): 1.27 (t, 3, OCH2CH3), 1.58-1.76 (m, 4, 2CH2 's), 2.33 (t, 2, CH2), 2.38 (s, 3, CH3), 2.57 (t, 2, CH2), 3.98 (s, 3, NCOOCH3), 4.01 (s, 3, NCOOCH3) and 4.14 ppm (q, 2, OCH2CH3); 13C-NMR δ (CDCl3) 11.9, 14.2, 23.1, 24.3, 34.0, 41.8, 54.8, 55.1, 60.3, 120.9, 126.5, 146.4, 149.9, 150.2, 173.2, and 192.6 ppm.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[NH:35]1[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C:37]([CH:44]=O)=[CH:36]1>N1C=CC=CC=1>[CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[C:15](=[CH:44][C:37]2[C:38]3[C:39](=[N:40][CH:41]=[CH:42][CH:43]=3)[NH:35][CH:36]=2)[C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ncccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Yield: 47.1 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide (Preparation 7(A)) (500 mg, 1.10 mmol) was condensed with 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (160 mg, 1.16 mmol) in pyridine (5 mL). Purification by medium pressure chromatography eluting with a solvent gradient (5% acetone in CH2Cl2 to 50% acetone in CH2Cl2 to 10% MeOH in CH2Cl2) yielded 300 mg of N-isopropyl-2-[5-oxo-1-phenyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-phenyl-acetamide. 1H NMR (CDCl3) δ 8.31 (d, 1H), 8.05 (d) and 7.96 (d, total 1H), 7.71 (m, 1H), 7.59 (m, 2H), 7.33-7.51 (m, 9H), 7.17 (m, 2H), 7.01 (m, 1H), 6.80 (t, 1H), 5.09 (m, 1H), 4.50 (d) and 4.30 (d, total 1H), 4.15 (m, 1H), 3.92 (d, 1H), 1.14 (m, 6H); MS 580.6 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:17][C:16]=1[C:28](=[O:30])[CH3:29].[OH-].[K+].Cl>CCO>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:17][C:16]=1[C:28](=[O:30])/[CH:29]=[CH:1]/[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1cc(N2CCN(C)CC2)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(Cl)c(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)c2)CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
A mixture of 4-formylcinnamic acid (250 mg, 1.42 mmol), 1-[2-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (obtained as described in Preparation 13, 358 mg, 1.42 mmol) and 1.7 M KOH (1.67 ml) in EtOH (10 ml) was stirred at 0° C. for 6 h and then acidified with 10% HCl until reaching a pH value of 6. The resulting yellow precipitate was filtered and rinsed with EtOH and Et2O to give 519 mg of (E)-3-(4-{(E)-3-[2-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid. The reaction product was used in the next step without any further purification.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12](C2C(O)=CC=CC=2)[C:13](O)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:24]([O-:27])(O)=[O:25]>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][C:5]([N+:24]([O-:27])=[O:25])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(O)c(-c2ccccc2O)c1)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C(Oc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Temperature: 85 °C

Procedure:
4-Benzoyloxybiphenol (40 g) is mixed with 310 ml of glacial acetic acid and heated to 85° C. Fuming nitric acid (100 ml) is added slowly while maintaining the reaction medium temperature between 85°-90° C. After complete addition, the reaction is cooled to room temperature.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][NH:7][C:8]1[N:9]=[N:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:12]([CH3:14])[N:13]=1)(=[O:5])[CH3:4]>CO>[C:3]([NH:6][NH:7][C:8]1[NH:9][N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]([CH3:14])[N:13]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NNC1=NC(C)C(c2ccccc2)=NN1
Reaction time: 1 h
Yield: 41.9 %

Procedure:
Sodium borohydride (1.11 g) was added to a stirred solution of 3-(2-acetylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (3.29 g) in methanol (30 ml) at room temperature and then the stirring was continued for 1 hour. The precipitates were collected by filtration, washed successively with water, methanol, and diisopropyl ether, and then recrystallized from a mixture of methanol and water to give colorless crystals of 3-(2-acetylhydrazino)-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (1.39 g), m.p. 204.5°~205° C. (decomp.).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([OH:21])=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33]I)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH3:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([O:21][CH2:33][CH2:32][CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:10][CH:9]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: ICCCCc1ccccc1
Reactant: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(OCCCCc3ccccc3)ccc2c1=O

Procedure:
A solution of 3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one (50 mg), 4-phenyl-1-iodobutane (100 mg) and cesium carbonate (100 mg) in DMF (2.5 mL) was heated at 80 C for 6 h. The reaction was partitioned between water and EtOAc. The organic solution was dried (Na2SO4) and concentrated, then purified by flash chromatography (20% EtOAc in hexanes) to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=O)=[C:10]2[N:9]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])=[C:10]2[N:9]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cnn2ccc(-c3ccccc3F)nc12
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (33 mg, 0.137 mmol) in 3 mL ETOH was added thiazolidine-2,4-dione (16 mg, 0.137 mmol) and piperidine (14 μL). The mixture was stirred at R.T. overnight. The solid formed was isolated by filtration and washed with EtOH to give 5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][OH:24])[CH:17]=[C:16]([Cl:26])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:26])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]([NH:21][CH2:22][CH2:23][OH:24])=[O:25]
Reactant: O=C(NCCO)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: c1cc2[nH]ccc2cn1
Product: O=C(NCCO)c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-N-(2-hydroxyethyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzamide (Compound No. 75) was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-[(2-hydroxyethyl)carbamoyl]benzoic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23].O>C1(C)C=CC=CC=1.C1COCC1>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[S:22]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)(=[O:24])=[O:23])=[O:11]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
40 g (220 mmol) of L-hydroxyproline methylester hydrochloride (twice suspended in toluene and evaporated under reduced pressure to remove water) was suspended in 600 ml hexamethyldisilazane and refluxed for 2 h. The solution was evaporated under reduced pressure and dissolved in 100 ml THF. 49.9 g (220 mmol) of 2-naphthalene-sulphonyl chloride in 200 ml of THF were added slowly and stirred for 16 h at room temperature. 150 ml H2O were added and after 1 h the solvents were evaporated. The residue was partitioned between water/EtOAc (3×), the organic phases were washed with 10% NaCl and dried over Na2SO4 to give 60.4 g (82%) of (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester, MS: 335 (M+).
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10](Br)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:18][N:19]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:1]1([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:18]#[N:19])=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)c1cc(Br)cnc1N1CCOCC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cnc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 160 mg (0.63 mmol) of 2-(morpholin-4-yl)-3-trifluoromethyl-5-bromopyridine (from Step C), 117 mg (1.0 mmol) of zinc cyanide, 20.1 mg (0.22 mmol) of tris(dibenzylideneacetone)dipalladium(0) and 48.7 mg (0.088) mmol of 1,1′-bis(diphenylphosphino)ferrocene in 2 mL of N-methylpyrrolidinone under argon was stirred at 100° C. for 1 h. The mixture was cooled and partitioned between ether and water. The organic layer was dried and concentrated. Chromatography on a Biotage 40S cartridge using 9:1 v/v hexanes/ether then 17:3 v/v hexanes/ether as the eluant afforded 87 mg of the title compound: ESI-MS (m/z) 258.2; HPLC A: 3.04 min.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][N:27]1[CH2:31][CH2:30][C@@H:29]([C:32]2[N:36]3[CH:37]=[C:38]([O:41][C@H:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C@@H:45]([NH2:52])[CH2:44][CH2:43]4)[CH:39]=[CH:40][C:35]3=[N:34][N:33]=2)[CH2:28]1.CCN(C(C)C)C(C)C.N>O1CCOCC1.CO.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:42]([O:41][C:38]3[CH:39]=[CH:40][C:35]4[N:36]([C:32]([C@@H:29]5[CH2:30][CH2:31][N:27]([CH3:26])[CH2:28]5)=[N:33][N:34]=4)[CH:37]=3)[CH2:43][CH2:44]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CC[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCN(C)C5)n4c3)c3ccccc32)cc1

Procedure:
A brown solution of (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 227 mg, 0.560 mmol), Intermediate 90e (145 mg, 0.400 mmol) and DIPEA (0.111 mL, 0.640 mmol) in dry dioxane (5 mL) was stirred at 65° C. for 15 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (30 mL); concentration in vacuo gave a brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave a pale brown solid (195 mg). Further purification by MDAP (Method 8) gave the title compound as a white powder after freeze-drying (10.0 mg, 4%). LCMS (Method 5): Rt 3.62 min, m/z 619 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.83-1.98 (2H, m), 2.08-2.20 (3H, m), 2.32 (3H, s), 2.33-2.40 (1H, m), 2.36 (3H, s), 2.59-2.70 (2H, m), 2.75 (1H, dd, J 9.2, 6.1), 2.96 (1H, t, J 8.7), 3.93-4.01 (1H, m), 4.83 (1H, td, J 8.4, 5.4), 5.46 (1H, t, J 4.6), 6.32 (1H, s), 7.10 (1H, d, J 8.5), 7.18 (1H, dd, J 9.9, 2.1), 7.27-7.40 (8H, m), 7.69 (1H, dd, J 9.9, 0.8), 8.04 (1H, s), 8.44 (1H, d, J 2.0).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.O.C(O)C>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[C:5]5[CH:19]=[CH:18][CH:17]=[CH:16][C:6]5=[C:7]5[CH:15]=[CH:14][CH:13]=[CH:12][C:8]5=4)[N:3]=3)[CH:36]=[CH:37][CH:38]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(-c2cccc3c2sc2ccccc23)c1
Reactant: Clc1ccc2c3ccccc3c3ccccc3c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: c1cc(-c2ccc3c4ccccc4c4ccccc4c3n2)cc(-c2cccc3c2sc2ccccc23)c1
Yield: 82 %

Procedure:
In a 100-mL three-neck flask, 0.46 g (1.7 mmol) of 2-chlorodibenzo[f,h]quinoline, 0.62 g (2.0 mmol) of 3-(dibenzothiophen-4-yl)phenylboronic acid, 20 mL of toluene, 2 mL of ethanol, and 2 mL of a 2M aqueous solution of potassium carbonate were put. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 65 mg (56 μmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 80° C. for 7 hours. After a predetermined time, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extract combined with the organic layer was washed with a saturated aqueous solution of sodium carbonate and a saturated solution of sodium chloride, and the resulting organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give an oily substance. The obtained oily substance was purified by silica gel column chromatography (toluene:hexane=1:1), so that a solid was obtained. The solid was purified by high performance liquid column chromatography. The high performance liquid column chromatography was performed using chloroform as a developing solvent. The obtained fraction was condensed to obtain a solid. A methanol suspension of the obtained solid was irradiated with ultrasonic waves, and a solid was collected by suction filtration, so that the objective substance was obtained as 0.68 g of white powder in 79% yield.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[C:14](#[N:17])[CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:16][CH:15]([C:1](=[O:9])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:14]#[N:17]
Reactant: CCC#N
Reactant: CCOC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C#N)C(=O)c1cccnc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under a N2 atmosphere ethyl nicotinate (3 g, 0.02 mol) and NaH (1.6 g, 0.04 mol) were suspended in toluene (30 mL) and heated to 90° C. Propiononitrile (2.2 g, 0.04 mol) was added dropwise and the reaction was stirred at 90° C. overnight. After cooling to room temperature, the solid was filtered and collected. The solid was dissolved in water (50 mL) and washed with ethyl acetate (30 mL). The aqueous layer was adjusted to pH=6 with 2M HCl and extracted again with ethyl acetate (30 mL×2). The combined ethyl acetate extracts were combined and dried over Na2SO4, filtered and concentrated in vacuo to give the desired product: 1HNMR (400 MHz, CDCl3) δ 9.25 (d, 1 H, J=1.2 Hz), 8.90 (d, 1 H, J=4.8 Hz), 8.33 (d, 1 H, J=8.0 Hz), 7.54 (dd, 1 H, J=1.2 Hz, J=8.0 Hz), 4.37-4.39 (m, 1 H), 1.71 (d, 3 H, J=7.2 Hz).