Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The 2-(2-phenylethoxy)ethanol obtained according to the preceding paragraph was dissolved in 100 ml of pyridine. The solution was treated with 4.48 g of methanesulfonyl chloride and the mixture was stirred at room temperature for 0.5 hour. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and 2N hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to give 8.1 g (85%) of 2-(2-phenylethoxy)ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:13]=[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][N:7]3[N:6]=2)[CH2:4][CH2:3]1.[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24]([N:10]1[CH2:11][CH2:12][N:7]2[N:6]=[C:5]([CH:2]3[CH2:4][CH2:3]3)[N:13]=[C:8]2[CH2:9]1)=[O:25])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C1Cn2nc(C3CC3)nc2CN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C3CC3)nc2C1)Cc1cc(F)c(F)cc1F

Procedure:
A 54 mg portion of 2-cyclopropyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D. Purification by two sequential preparative TLC columns (silica gel, 10% methanol/dichloromethane) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccn4)CC3)nc2c1
Yield: 84 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH:15]1[CH2:17][O:16]1)[C:10]([O:12]C)=O.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[NH:19][NH2:20]>CC(O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:15]([OH:16])[CH2:17][N:20]([NH:19][C:18](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]1=[O:12]
Reactant: COC(=O)C(CC1CO1)c1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O

Procedure:
To a solution of methyl 2-(2-chloro-4-fluorophenyl)-3-(oxiran-2-yl)propanoate (4.56 g, 17.6 mmol) in 2-propanol (20 mL) was added tert-butyl carbazate (2.3 g, 17.6 mmol) and the reaction heated to reflux for 16 hours. The reaction was then concentrated to dryness, redissolved in toluene (20 mL) and 1,5,7-triazobicylo(4.4.0)dec-5-ene (0.6 g, 4.4 mmol) was added and the mixture heated to reflux for 3 hours. The reaction was then diluted with ethylacetate, washed with 1 N HCl, dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was recystallised from hot ethyl acetate to afford the title compound was obtained as a colourless solid (1.7 g, 26%). The mother liquor contained the trans isomer.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:3]([OH:5])=[O:4].[CH3:15][C:16]([CH3:18])=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[O:4][C:16]([CH3:18])([CH3:15])[O:1]1)([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCC(O)C(=O)O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=O)C(CCCCCCC(=O)O)O1

Procedure:
A stirred mixture of 10.2 g. of 2-hydroxynonanedioic acid, 50 ml. of acetone, 75 ml. of petroleum ether (b.p. 30°-55° C.), and 0.25 ml. of sulfuric acid is heated at reflux for 7 hours with azeotropic removal of water. The stirred mixture is treated with 0.59 g. of sodium carbonate and diluted with petroleum ether. The solution is decanted from solid and concentrated to give 9.4 g. of oil; pmr (CDCl3) δ1.58 and 1.63 (gem-dimethyl group).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>CC#N>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=Cc1ccncc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2ccncc2)cc1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a CH3CN solution of 1-iodo-4-nitrobenzene (498 mg, 2 mmol) and 4-vinylpyridine (262 mg, 2.5 mmol) was added TEA (350 μL, 2.5 mmol) and Pd(OAc), (0.45 mg, 0.2 mmol). The mixture was heated to 100° C. for 48 hr in a capped Pyrex tube. It was then cooled to room temperature, quenched with 1N HCl (20 mL) and concentrated under reduced pressure. The mixture was filtered and the solid was taken up in EtOAc (30 mL) and washed with 1N NaOH (30 mL). The organic layer was concentrated, dried over Na2SO4 and concentrated to give 4-[2-(4-nitro-phenyl)-vinyl]-pyridine as yellow solid (160 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:41]1[CH:46]=[CH:45][C:44]([C:47]2[C:52]([N:53]=[C:54]=[O:55])=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1>C1COCC1>[C:47]1([C:44]2[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=2)[CH:48]=[CH:49][CH:50]=[CH:51][C:52]=1[NH:53][C:54](=[O:55])[N:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:12]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:40])(=[O:11])=[O:10])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a solution of 3,5-dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxy-N-(3-((isobutyl amino)methyl)benzyl)benzene sulfonamide (Compound E of Example 184, 0.04 g, 0.0667 mmol, 1.0 eq) in a 5 mL of THF at 0° C. was added 2-biphenyl isocyanate (0.013 g, 0.0667 mmol, 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 min and concentrated to remove the volatiles. The residue was purified by preparative HPLC to afford the title compound (0.03 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ 0.66-0.68 (d, 6H), 1.7 (m, 1H), 2.82-2.84 (d, 2H), 4.30 (s, 2H), 4.43 (d, 4H), 6.84-6.89 (t, 2H), 6.99 (d, 1H), 7.14-7.20 (m, 4H), 7.23 (m, 4H), 7.25-7.34 (m, 5H), 7.44-7.46 (d, 3H), 7.57-7.62 (m, 4H), 7.80 (s, 1H). MS (HD: 796.1 (M−H)−.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:16][CH2:15]2)[C:7]1=[O:17])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[N+:18]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7](=[O:17])[C:8]12[CH2:16][CH2:15]1)([O-:20])=[O:19]
Reactant: CCCCCN1C(=O)C2(CC2)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Reaction time: 3 h

Procedure:
1′-Pentyl-spiro[cyclopropane-1,3′-indoline]-2′-one (24.8 g) is suspended in acetic acid (250 ml) and nitric acid (fuming, 11.9 ml) is added over a period of 15 min at 15° C. The mixture is stirred for 3 h, diluted with water and extracted with Et2O (3×300 ml). The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated to give the compound (29.3 g).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8](CC=C)[CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][N:32](C=O)C>C1COCC1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:31]#[N:32])=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20]
Reactant: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]c(C#N)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To 1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.05 g, 3.6 mmol) in THF (15 ml) at −78° C. was added LiHMDS (4 ml, 1M in hexane, 4 mmol) over 10 min and the solution stirred for 0.5 h. DMF (0.5 ml) was added and the solution stirred at −78° C. for a further 0.5 h then allowed to warm to ambient temperature with the cooling bath over 2 h. The reaction was quenched with 2N hydrochloric acid (3 ml) and partioned between ethyl acetate and brine. The organics were isolated, dried and concentrated. The crude product was chromatographed over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) to afford the title compound as a white solid (0.35 g, 30%). m/z 305 [MH+]
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:20])[CH:11]=[N:12][C:13]=3[CH:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>CC#N>[O:20]=[C:10]1[CH:11]=[N:12][C:13]2=[C:18]3[N:9]1[CH2:8][C@@H:7]([CH2:6][N:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]1)[N:17]3[C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: CS(=O)(=O)OC[C@@H]1Cn2c(=O)cnc3ccc(=O)n1c32
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of [(1S)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl]methyl methanesulfonate (1.05 g, 3.53 mmol) in dry CH3CN (50 ml) at room temperature under argon was treated with pyridine (0.343 ml, 4.24 mmol), followed by 1,1-dimethylethyl 4-piperidinylcarbamate (0.884 g, 4.24 mmol). The mixture was heated at 70° C. for 1.5 h and then at 90° C. for 3 h. LCMS showed ˜25% of product. So 0.5 eq of pyridine and 0.5 eq of 1,1-dimethylethyl 4-piperidinylcarbamate were added and the reaction was heated at 90° C. overnight and then stirred at room temperature for 2 days. The reaction was complete. The solvent was evaporated and the residue partitioned between sat NaHCO3 and 20% MeOH/DCM (100 ml/100 ml). The layers were separated and the aqueous layer was extracted with 20% MeOH/DCM again (2×100 ml). The combined organic extracts were dried over MgSO4, filtered and evaporated to afford 1.7 g of crude which was purified by silica chromatography using a 0-5% MeOH/DCM gradient to afford the product as a yellow solid (0.57 g, 40.2%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][C:22]=1[Cl:23].C1COCC1.O>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2([OH:1])[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOCC(=O)C1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(O)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (418 mg) prepared by the method described in WO2004/074291 in THF (12 mL) was added 0.5 M 3,4-dichlorophenylmagnesium bromide-THF (4.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (455 mg).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[N:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17].O[C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]=[N:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([O:33][C:37]3[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=3)=[O:32])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(OC(=O)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
0.6 g of N,N'-dicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 1.0 g of 4-(4-nitrophenylazo)benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichlormethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases are combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which are pure according to thin-layer chromatography gives 0.9 g of 4-[4-(4-nitrophenylazo)benzoyloxy]benzaldehyde.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([C@H:13]3[CH2:15][C@H:14]3[C:16](O)=[O:17])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:22][NH2:23]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]3[CH:13]4[CH:14]([C:16](=[O:17])[NH:22][N:23]=3)[CH2:15]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(c1ccc(C2CCCCC2)cc1)[C@H]1C[C@H]1C(=O)O
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2ccc(C3CCCCC3)cc2)C2CC12
Yield: 92.5 %

Procedure:
8.0 g (29.4 millimoles) of cis-2-(p-cyclohexylbenzoyl)-cyclopropanecarboxylic acid, 1.6 g (32.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 8 hours. The product is filtered off at 0° C. and dried under reduced pressure at 50° C. 7.3 g (93% of theory) of 2-(p-cyclohexylphenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 211°-212° C. after recrystallization from isopropanol.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[C:30]([C:32]2[N:36]=[C:35]([CH3:37])[N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:33]=2)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O.O>[Cl:22][C:23]1[CH:31]=[C:30]([C:32]2[N:36]=[C:35]([CH3:37])[N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:33]=2)[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: COc1ccc(Cn2nc(-c3ccc(C(=O)Cl)c(Cl)c3)nc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4Cc5cccnc5Nc5ccccc54)c(Cl)c3)nc2C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (0.55 g, 2.8 mmol) in dimethylformamide (10 mL) under nitrogen was added solid potassium carbonate (0.39 g, 2.8 mmol). The mixture was treated dropwise with a solution of the crude acid chloride (2.8 mmol) of Step F in dimethylformamide (10 mL). After stirring at room temperature for 90 minutes, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined and washed with 1N aqueous sodium hydroxide, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed on a column of flash silica Merck-60. Less polar impurities were eluted with 1:1 ethyl acetate-hexane. Further elution with 2% methanol in dichloromethane provided the title compound as a white solid (0.57 g), m.p. 218-221° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:13])=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)[nH]c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 51.5 %

Procedure:
To a solution of 2-methyl-1H-indole-3-carboxylic acid (3.3 g, 18.85 mmol), 1-hydroxybenzotriozole (4.69 g, 37.7 mmol, 2 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.24 g, 37.7 mmol, 2 eq), triethylamine (20.0 mL) in dichloromethane (100 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (5.77 g, 37.7 mmol, 2 eq). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:2) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (3.00 g, 9.7 mmol, 51%). LRMS (M+H+) m/z: calcd 309.36. found 310. HPLC Purity (214 nm): >95%. 1H NMR (300 MHz, d6-DMSO): δ 11.61 (s, 1H), 11.43 (s, 1H) 7.74 (d, J=5.1 Hz, 1H), 7.58-7.54 (m, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.04 (t, J=6 Hz, 3H), 5.89 (s, 1H), 4.32 (d, J=4.5 Hz, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH:25][C:43]([C:40]5[C:41](=[O:42])[N:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)[N:37]=[CH:38][CH:39]=5)=[O:44])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (100.0 mg, 0.256 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 70.53 mg, 0.301 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (144.3 mg, 0.753 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (101.7 mg, 0.753 mmol), N-ethyl-N-isopropylpropan-2-amine (162.2 mg, 1.255 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (103 mg, 66.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 615 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.41 (m, 2H), 8.23 (d, 1H), 7.98 (d, 1H), 7.60 (m, 2H), 7.39 (m, 2H), 7.24 (m, 3H), 6.46 (d, 1H), 6.28 (m, 1H), 4.04 (s, 4H), 2.78 (m, 2H), 2.52 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH3:22])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH:16]4[CH2:21][CH2:20][N:19]([C:30](=[O:32])[CH3:31])[CH2:18][CH2:17]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH3:22])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1[nH]n(C2CCCC2)c2nc(C3CCNCC3)nc(=O)c1-2
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nc3n(C4CCCC4)[nH]c(C)c-3c(=O)n2)CC1
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-methyl-6-(4-piperidinyl)pyrazolo[3,4-d]pyrimidin-4-one (0.79 g, 2.6 mmol), triethylamine (2.0 ml), and chloroform (25 ml) was added acetic anhydride (2.0 ml, 0.02 mol). The mixture was stirred for 3 hours and the solvent was removed in vacuo. The residue was treated with water and the product was collected by filtration to afford 0.8 g (90%) of 1-cyclopentyl-3-methyl-6-(1-acetyl-4-piperidinyl)pyrazolo[3,4-d]pyrimidin-4-one as white needles, m.p. 176°-178° C. when recrystallized from cyclohexane.
Reaction SMILES: I.CS[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCOCC>C(O)C>[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][N:5]=2)=[CH:17][CH:16]=1
Reactant: NCc1ccc(O)cc1
Reactant: CSC1=NCCc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: Oc1ccc(CNC2=NCCc3ccccc32)cc1
Yield: 22.4 %

Procedure:
1-Methylthio-3,4-dihydroisoquinoline hydroiodide (0.6 g, 0.00197 mol) and 4-hydroxybenzylamine (0.24 g, 0.00195 mol) were heated together at reflux temperature in ethanol (25 ml) for five hours. Effluent gases were passed through a CHLOROS trap. The mixture was then cooled and the ethanol evaporated off at reduced pressure. The tacky residue was dissolved in dilute HCl and the solution extracted with ethyl acetate. The clear aqueous solution was basified with 6N. NaOH and re-extracted with ethyl acetate. The latter organic extract was washed with water, dried and evaporated to dryness to give a white sticky solid. This was treated with ether and the ether decanted off. The residual solid was crystallised from absolute ethanol to give the title compound (0.11 g) as white crystals, m.p. 177°-179°.