Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1C=O.[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.[CH3:24]O>>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH:24]=[N:23][CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: NC1CCCc2ccccc21
Reactant: CO
Reactant: CC1Cc2ccccc2N1C=O
Product: CC1Cc2cccc(C=NC3CCCc4ccccc43)c2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.68 g of 2-methylindolino aldehyde was dissolved in 35 ml of methanol and then 1.58 ml of 1,2,3,4-tetrahydro naphthyl amine was slowly added thereto. The mixture was stirred at room temperature overnight before some precipitates were slowly formed, and then was filtered while being washed with methanol to provide ivory solids as a clean product (2.3 g). (Yield: 75%) This compound was a mixture of two stereoisomers at a ratio of 1:0.6.
Reaction SMILES: [NH2:1][C:2](=[O:34])[C@@H:3]([NH:12][C:13](=[O:33])[C@@H:14]([NH:16][C:17](=[O:32])[C@@H:18]([NH:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[S:25][C:26]([CH:29]=[O:30])=[CH:27][N:28]=1)[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:34])[C@@H:3]([NH:12][C:13](=[O:33])[C@@H:14]([NH:16][C:17](=[O:32])[C@@H:18]([NH:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[S:25][C:26]([CH2:29][OH:30])=[CH:27][N:28]=1)[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)CNc1ncc(CO)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of material from Example 7 (13.2 mg, 0.022 mmol) in EtOH/H2O (4:1) (1.5 mL) is added solid sodium borohydride (7.8 mg, 0.206 mmol) in 2 equal portions over 1 b. After the addition is complete, the reaction is stirred at room temp for 1.5 h and evaporated to dryness to give the title compound (quantitative yield) as a white solid that is used crude in the next step. LC/MS (Condition A): ret. T=0.94-1.16 min, (M+Na) 515.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1.[CH:48]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH2:49]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][N:43]([CH2:49][CH2:48][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1cc(OC2CCNCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
To N-(2,6-difluorophenyl)-3-[3-(2-{[2-methyl-4-(4-piperidinyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide (Example 6) (0.10 g, 0.16 mmol) in THF (5 mL) was added methyl vinyl sulfone (0.028 mL, 0.32 mmol) in one portion. The reaction was stirred at rt until complete by MS. Purification by flash chromatography provided the title compound (0.048 g, 0.065 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.66 (m, 2H), 1.89-1.97 (m, 2H), 2.19 (s, 3H), 2.22-2.33 (m, 2H), 2.68-2.77 (m, 4H), 3.02 (s, 3H), 3.23-3.28 (m, 2H), 4.34-4.39 (m, 1H), 6.45 (d, J=4.9 Hz, 1H), 6.76-6.85 (m, 1H), 6.88 (s, 2H), 7.22 (dt, J=16.3, 8.2 Hz, 3H), 7.36-7.48 (m, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.78-7.89 (m, 1H), 8.06 (d, J=7.3 Hz, 1H), 8.18 (d, J=5.1 Hz, 1H), 8.31 (s, 1H), 8.89 (s, 1H), 9.30-9.36 (m, 1H), 10.24 (s, 1H). MS (M+H, ES+) 738.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 36 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and piperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 36%; MS: m/z=277 (M+H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)Oc1ccc(C(=O)O)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(OS(C)(=O)=O)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-methylsulfonyloxybenzoic acid (0.60 g, 2.8 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (15 mL) was heated at reflux for 30 min (the mixture became homogeneous). The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (110 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (94 μL, 0.68 mmol) in methylene chloride (20 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 160 mg (78%) of the title compound as white crystals: mp 199-200° C.; [α]21D -20° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (3, M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-:16].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1C=CC(C=C)=CN=1.[OH2:30]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:20]([OH:30])([C:19]([F:29])([F:28])[F:18])=[O:16]
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: O
Reactant: [OH-]
Agent: Cc1cccc2c3c([nH]c12)CCN(C)C3
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (2.5 ml), powdered KOH (561 mg, 10 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(tri fluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added slowly to the above solution and stirred for 16 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethyl acetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 40 mg (8.2%) of 54246-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole as TFA salt.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=O)[CH3:2].[N:12]1[NH:13][C:14](=[O:18])[CH:15]=CC=1>>[O:18]=[C:14]1[NH:13][N:12]=[C:1]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])[CH:2]=[CH:15]1
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: O=c1cccn[nH]1
Product: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
7.3 g of 3-acetylbenzonitrile are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCN(Cc1ccccc1)C2
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
A mixture of 25 mg (0.049 mmol) of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide, 0.0152 mL (0.15 mmol) of benzaldehyde and 0.6 mL of DMF was stirred for 10 min. 67 mg (0.3 mmol) of sodium triacetoxyborohydride was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and dried over sodium sulfate. Purification by column chromatography on silica gel gave 11.7 mg (49%) of 2-benzyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 492 (M+1)+.
Reaction SMILES: [OH:1][CH:2]([CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[H-].[Na+].S(OC)(O[CH3:39])(=O)=O.Cl>CN(C=O)C>[CH3:39][O:1][CH:2]([CH2:21][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: CCCN(CC(O)COC(Cc1ccccc1)C(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CC(COC(Cc1ccccc1)C(=O)c1ccccc1)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
5 g. (11.3 mMol) 2-[2-hydroxy-3-(tert.-butyloxycarbonyl-propylamino)-propoxy]-3-phenyl-propiophenone are dissolved in 50 ml. abs. DMF and mixed at 0° C. with 0.30 g. (12.5 mMol) sodium hydride. Thereafter, it is stirred for 70 minutes at room temperature. Subsequently, the reaction mixture is cooled to 0° C. and a solution of 1.60 g. (12.5 mMol) dimethyl sulphate in 5 ml. absolute DMF added dropwise thereto. After 40 minutes at 0° to 5° C., the reaction mixture is emptied into 2N HCl. The phases are separated and the H2O phase extracted three times with CH2Cl2. The combined organic phases are after drying over Na2SO4, evaporated. There are obtained 4.5 g. of an orange oil which is purified column chromatographically. Column chromatography: silica gel, Bz:EE=14:1. The purified oil crystallises in a low-cooling cabinet.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33]Cl)[CH3:29]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:33][CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:28][CH3:29])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(Cc2ccccc2)oc2ccc(Br)cc12
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(Cc3ccccc3)oc3ccc(Br)cc23)cc1

Procedure:
Reaction of 2-benzyl-5-bromo-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride as previously described gives the title compound.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:32])([F:33])[F:34])=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccccc3C(F)(F)F)(CC1)CC2
Yield: 39.4 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-aminobenzotrifluoride (55.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-trifluoromethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (28.4 mg).
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][C:9]=1[OH:10]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][C:9]=1[O:10][CH3:1]
Reactant: CCOC(=O)c1ccc(Cl)c(O)n1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)c(OC)n1
Temperature: 70 °C
Reaction time: 7 h
Yield: 80 %

Procedure:
Silver carbonate (142.4 g) and methyl iodide (25 mL) were added to a solution of ethyl 5-chloro-6-hydroxypyridine-2-carboxylate (26.0 g) in chloroform (500 mL), and the mixture was stirred at 70° C. for seven hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) and purified again by silica gel column chromatography (hexane:ethyl acetate=20:1) to give ethyl 5-chloro-6-methoxypyridine-2-carboxylate as a white solid (22.3 g, 80%).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=C[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[N:37]1C=CN=CC=1C(O)=O>>[C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[N:37][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: O=C(O)c1cnccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2C#N)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cccnc2C#N)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyanopyridin-3-yloxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 245 and pyrazine-2-carboxylic acid.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].O>C(Cl)(Cl)Cl>[C:45]([N:31]([CH:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1)[C:25]1[CH:24]=[C:23]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][C:11]([C:13]4[CH:14]=[N:15][C:16]5[C:21]([CH:22]=4)=[CH:20][CH:19]=[CH:18][CH:17]=5)=[C:12]3[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28])(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1cc(-n2nc(C(C)C)c3c(-c4cnc5ccccc5c4)ccnc32)ccc1C#N)C1CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
Compound (77a) (0.050 g) and triethylamine (0.017 mL) were dissolved in chloroform (1.0 mL), and acetyl chloride (0.017 mL) was added to the resulting mixture, followed by stirring at room temperature for 15 hr. The reaction solution was distributed between chloroform and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away to obtain 2-(acetylpiperidin-4-ylamino)-4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. According to Example 1(7), compound (77) (the second stage yield: 68%) was prepared as a white solid using 2-(acetylpiperidin-4-ylamino)-4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[N:12]=[C:11]([S:23][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH3:25])[N:10]=1)(C(C)(C)C)(C)C.[ClH:32]>O1CCCC1>[ClH:32].[OH:15][C:13]1[CH:14]=[C:9]([OH:8])[N:10]=[C:11]([S:23][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH3:25])[N:12]=1
Reactant: CC(Sc1nc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)n1)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: CC(Sc1nc(O)cc(O)n1)c1ccccn1
Reaction time: 0.5 h
Yield: 111.1 %

Procedure:
A solution of 4,6-di-(tert-butyldimethylsilyloxy)-2-(1-(2-pyridyl)ethyl)thio-pyrimidine (1.23 g, 2.58 mmol) in 8 ml of tetrahydrofuran is treated with 2 N HCl (5.2 ml, 10.31 mmol, 4.0 equiv.) at room temperature. After 30 min, the reaction mixture is concentrated directly at reduced pressure, diluted with toluene and reconcentrated again. The resulting white solid is triturated with methylene chloride, collected and dried to obtain 0.819 g of crude 4,6-dihydroxy-2-(1-(2-pyridyl)ethyl)thio-pyrimidine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13]1COCC1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
6-Bromoindole (10.4 g, 53.1 mmol) (prepared according to Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106.) was added in small portions over 30 min to a stirred suspension of sodium hydride (2.96 g, 61.7 mmol, 50% in mineral oil) in dry THF (120 mL) at 0° C. Stirring was continued for another 30 min. lodomethane (4.5 ml, 71.6 mmol) was added dropwise. After 1 h, the mixture was poured into ice-water and extracted with ether (3×200 mL). The combined organic extracts were washed with brine and dried (MgSO4). Evaporation of the solvents and chromatography of the residue over silica gel using hexane gave 6-bromo-1-methyl-1H-indole (10.8 g, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][O:27][CH3:28])=[CH:21][C:20]=2[OH:29])=[O:18])=[CH:11][C:10]=1[O:30][CH2:31][O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:34].[Na+].OO>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:29][C:20]3[C:19]([C:17](=[O:18])[C:16]=2[OH:34])=[CH:24][CH:23]=[C:22]([O:25][CH2:26][O:27][CH3:28])[CH:21]=3)=[CH:11][C:10]=1[O:30][CH2:31][O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(OCOC)c2)c(O)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc2c(=O)c(O)c(-c3ccc(OCc4ccccc4)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To (E)-3-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-1-(2-hydroxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one (450 mg, 1 mmol) in 1.5 mL MeOH was added 4 mL of a 15% NaOH solution, followed by hydrogen peroxide (113 mg, 30% solution). The mixture was stirred at rt for 2 h and additional 226 mg of hydrogen peroxide was added. The reaction was stirred for 15 and quenched onto NaH2PO4 (sat. 50 mL). It was extracted with EtOAc (3×50 mL) and the combined organic phase was dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford 2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3-hydroxy-7-(methoxymethoxy)-4H-chromen-4-one as a off-white solid (55 mg, 12%). MS (ESI) m/z 465 (M+H+).
Reaction SMILES: CN(C)C=O.[CH2:6]([N:8]([CH2:22][CH3:23])[C:9]1[C:10]2S[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:11]=2[N:12]=[CH:13][N:14]=1)[CH3:7].O.[ClH:25]>[Ni].C(OCC)C>[ClH:25].[CH2:22]([N:8]([CH2:6][CH3:7])[C:9]1[CH:10]=[C:11]([C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:16]=2)[N:12]=[CH:13][N:14]=1)[CH3:23]
Reactant: CCN(CC)c1ncnc2c1sc1ccccc12
Agent: [Ni]
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(-c2ccccc2)ncn1
Reaction time: 48 h

Procedure:
To a solution of 1.5 ml. of dimethylformamide containing 4-diethylaminobenzothieno[3,2-d]pyrimidine (2.0 g.) is added a large excess of Raney nickel and the resulting mixture heated to reflux. Water is allowed to distill from the reaction mixture until the temperature reaches 150° C. where refluxing is continued with rapid stirring for 48 hours. The solids are filtered and the filtrate concentrated in vacuo to an oil. The residual oil is partitioned between water and chloroform and the organic layer separated and dried over sodium sulfate. Removal of the solvent under reduced pressure provides an oil which when dissolved in ethyl ether and treated with gaseous hydrogen chloride provides 1.4 g. of the hydrochloride salt of the desired product, which is identical in every respect to that synthesized via Method A.
Reaction SMILES: [I:1]I.C([O-])(=O)C.[Tl+].[CH3:8][N:9]([CH3:17])[C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[CH3:8][N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][C:13]([I:1])=[C:12]([OH:16])[CH:11]=1
Reactant: II
Reactant: CN(C)c1cccc(O)c1
Agent: CC(=O)[O-]
Agent: [Tl+]
Solvent: ClCCl
Product: CN(C)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.7 %

Procedure:
Iodine (6.35 g, 25 mmol) in methylene chloride (300 mL) was added dropwise over 3 h to a stirred suspension of thallium(I) acetate (7.90 g, 30 mmol) and 3-dimethylaminophenol (3.43 g, 25 mmol) in methylene chloride (300 mL). The resulting mixture was stirred at room temperature for 24 h and filtered. Evaporation of the solvents and chromatography of the residue over silica gel using 0-5% diethyl ether in hexanes gave 5-dimethylamino-2-iodophenol (2.35 g, 36%).