Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:14]2[CH:9]([C:10](O)([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH2:1]([O:3][C:4]([N:6]1[CH:14]2[C:9](=[C:10]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2C1CCCC2(O)C#Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC2=C(C#Cc3ccccc3)CCCC21
Temperature: 0 °C
Yield: 1.1 %

Procedure:
A solution of 4-hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid ethyl ester (1.0 g, 3.19 mmol), triethylamine (2.2 ml, 16 mmol) and phosphorous oxychloride 0.877 ml, 10 mmol) is heated to 40° C. for 4 hours. The dark mixture is cooled to 0° C. and treated with 1M sodium hydroxide (5 ml) and then acidified with a 10% aqueous citric acid solution. The mixture is extracted with dichloromethane, the organic extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica with hexane and diethyl ether (4:1 v/v). The first product containing fractions afforded (±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (10 mg, 1%) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.44 (m, 2H), 7.32 (m, 3H), 4.24-3.97 (m, 3H), 3.8 (m, 1H), 3.25 (m, 1 H), 2.93 (m, 1H), 2.56 (m, 1H), 2.28 (m, 2H), 1.90 (m, 1H), 1.60 (m, 2H), 1.28 (t, J=7 Hz, 3H), 1.14 (m,1H). ES-MS (+): 296.1. After collecting a mixture of the two products (475 mg, 50%), the third product containing fractions yielded (±)-(3RS,7aRS)-4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (64 mg, 7%) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.43 (m, 2H), 7.31 (m, 3H), 6.27 (m, 1H), 4.15 (m, 2H), 4.01-3.83 (m, 1H), 3.46(m, 2H), 2.82 (m, 1H), 2.37-1.82 (m, 5H), 1.57 (m, 1H), 1.27 (t, J=7 Hz, 3H). ES-MS (±): 296.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:13][C:14]1[N:19]=[C:18]([O:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)nc(N)n2)cc2oc(=O)[nH]c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.20 g (1.15 mmol) 6-hydroxy-4-methylbenzo[d]oxazol-2(3H)-one and 0.19 g (1.16 mmol) 2-amino-4,6-dichloropyrimidine in 3.0 mL DMF were combined with 0.22 g (1.59 mmol) potassium carbonate and stirred overnight at 60° C. Then water was added and the precipitate formed was suction filtered, washed and dried. The substance was purified by preparative HPLC-MS. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.Cl[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5]2)=[N:1]1
Reactant: COCCCCl
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Product: COCCCn1cc2ccc(C(=O)OC)cc2n1

Procedure:
Analogously to Example 8c, 1.0 g of methyl 1H-indazole-6-carboxylate and 1.16 g of 1-chloro-3-methoxypropane are reacted. The title compounds are obtained as yellowish oils.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]1[CH2:19][C:18]([OH:21])([CH3:20])[C:17]2[C:12](=[CH:13][C:14]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:15][CH:16]=2)[O:11]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.FC(F)(F)C([O-])=O>C(Cl)Cl>[C:25]1([S:22]([C:14]2[CH:13]=[C:12]3[C:17]([C:18]([CH3:20])([OH:21])[CH2:19][CH:10]([CH2:9][NH:7][CH3:6])[O:11]3)=[CH:16][CH:15]=2)(=[O:23])=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(CC1CC(C)(O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC1CC(C)(O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
To a solution of (7-benzenesulfonyl-4-hydroxy-4-methyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (212 mg, 0.474 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction was stirred for 3 hours at room temperature, then concentrated in vacuo. The residue was purified via flash chromatography (DCM/MeOH/TEA) to give 7-benzenesulfonyl-4-methyl-2-methylaminomethyl-chroman-4-ol (63 mg, 38% yield) as a trifluoroacetate salt: Mp 163.9-165.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.[CH3:21][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:12])[CH3:21])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(C=O)c2n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (0.88 g, 2.83 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −78° C. and treated with methylmagnesium bromide (3.0 M in diethyl ether, 0.9 mL, 2.83 mmol) over several minutes. After 1 h, cooling was removed and stirring continued for 1 h at room temperature. The reaction was cooled to 0° C., treated with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated. The organic layer was washed with water (2×), brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 540 mg (58%) as a light brown oil. 1H-NMR (CDCl3, 300 MHz) δ 8.00 (s, 1H), 8.21 (s, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.13 (m, 1H), 5.65 (s, 2H), 5.28 (q, J=6.2 Hz, 1H), 3.57-3.62 (m, 2H), 1.64 (d, J=6.2 Hz, 3H), 0.86-0.92 (m, 2H), 0.07 (s, 9H). Mass spec.: 327.04 (MH)+.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH3:32].C(OCC)(=O)C>CN(C)C=O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:31][CH3:32])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
The 1-(1′-acetyl-5-hydroxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (40 mg, 0.122 mmol) obtained in Step 2 of Example 198 was dissolved in N,N-dimethylformamide (0.5 mL). Thereafter, cesium carbonate (52 mg, 0.159 mmol) and iodoethane (23 mg, 0.146 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 18 hours. Thereafter, ethyl acetate was added to the reaction solution, and the reaction mixture was then washed with water and brine. The resultant was dried over anhydrous sodium sulfate. The solvent was distilled away, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate) to obtain 1-(1′-acetyl-5-ethoxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (24 mg, 54%) in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: NC1CCNC1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CC[C@@H](N)C3)ccc2S(C)(=O)=O)c1OC
Yield: 42.4 %

Procedure:
N-(1-(5-Chloro-2,3-dimethoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (100.0 mg, 0.26 mmol), pyrrolidin-3-amine (86.1 mg, 0.51 mmol), N,N-diisopropylethylamine (133.0 mg, 1.03 mmol) were stirred at 100° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (50.0 mg, 42.8% yield). 1H NMR (400 MHz, CDCl3): δ 7.52 (d, 1H), 6.88 (d, 1H), 6.76 (d, 1H), 6.51 (d, 1H), 6.89 (dd, 1H), 4.84 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.64 (m, 1H), 3.46-2.84 (m, 4H), 3.04 (s, 3H), 2.12 (m, 1H), 2.01 (s, 3H), 1.75, (m, 1H), 1.53 (d, 3H); MS (ESI) m/z: 454.1 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.IC.[C:24]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=3)[N:10]([CH3:24])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2cc(F)ccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Br)cccc1-n1c(=O)c2ccc(F)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione (2.70 g, 7.73 mmol), iodomethane (0.580 mL, 9.28 mmol) and Cs2CO3 (3.78 g, 11.6 mmol) in THF (20 mL) was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was diluted with DCM and washed with water. The aqueous phase was extracted with DCM, and the combined organic phases were dried and concentrated to give 3-(3-bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione (2.85 g), used without further purification. Mass spectrum m/z 363, 365 (M+H)+, 385, 387 (M+Na)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](=[N:14]O)[NH2:13]>C(Cl)Cl.O>[Cl:10][CH2:11][C:12]1[N:14]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][N:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(CCl)=NO
Solvent: ClCCl
Solvent: O
Product: ClCc1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
Benzoyl chloride (1.60 ml, 13.8 mmol) was added to a suspension of 2-chloro-N′-hydroxyacetimidamide (I44) (1.0 g, 9.21 mmol) in DCM (25 ml), with stirring at room temperature. After 30 minutes, TEA (1.41 ml, 10.1 mmol) was added to the white suspension, and the mixture was stirred for additional 30 minutes. (UPLC-MS complete conversion). The solution was diluted with DCM (20 ml), and water (30 ml) was added. The aqueous phase was extracted three times with DCM (15 ml), and the combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting residue is suspended in toluene (25 ml), and the mixture is heated to reflux for six hours and then at room temperature for two days. The dark solution was evaporated, and the crude product was purified by flash chromatography eluting with petroleum ether/EtOAc=95/5 to obtain 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (803 mg, 44.8% yield) as a off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>CO>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)([O-:17])=[O:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a mixture of tert-butyl N-(piperidin-4-yl)carbamate (25 g, 125 mmol, 1.0 eq) and 3-nitrobenzaldehyde (19 g, 125 mmol, 1.0 eq) in MeOH (500 mL) were added NaBH(OAc)3 (53 g, 250 mmol, 2.0 eq) and acetic acid (1 mL). Then the resulting mixture was stirred at 30° C. overnight. LC-MS indicated complete conversion. The solvent was removed under vaccum and the residue was purified by column chromatography (DCM:MeOH=15:1), to provide tert-butyl N-{1-(3-nitrobenzyl)piperidin-4-yl}carbamate (32 g, 76%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:18]12CC[CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.[H-].[Na+]>C1(C)C=CC=CC=1>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[C@@H:1]([O:3][C:4]([C:6]1([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH2:2]2
Reactant: CCOC(=O)C1(c2cccs2)CCCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Yield: 86 %

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid ethyl ester (Example 5c) (2.5 g) and (R) -quinuclidin-3-ol (2.08 g) were dissolved in toluene (350 mL) and sodium hydride (0.1 g) added under nitrogen. The mixture was heated to reflux for 20 hours after which the toluene was carefully distilled off to leave ˜100 mL which was cooled and washed with water (100 mL), dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica eluting with ethyl acetate/triethylamine (99/1) to afford the sub-titled compound (2.84 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([O:32][CH3:33])[CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:6]=3[N:21]=2)=[C:27]([O:32][CH3:33])[CH:26]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Yield: 96.5 %

Procedure:
A solution of 0.10 g (0.00032 mole) of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19), 0.060 g (0.00032 mole) of 4-amino-3-methoxy-benzoic acid methyl ester, 0.10 g (0.00049 mole) of p-toluene-sulfonic acid monohydrate and 4 mL of 2-propanol at 150 degrees for 1 hour in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-85:15%), to give 0.14 g of (rac)-4-(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid methyl ester as white powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]2[N:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH2:23]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=4)[CH2:23]3)[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(Cl)cc2)nc1Cl
Agent: Cl
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)c3C#N)C2)nc1

Procedure:
Analogously to the preparation of Example 20, 60 mg (0.19 mmol) of 2-chloro-6-(4-chlorophenyl)-4-(trifluoromethyl)pyridine-3-carbonitrile and 56 mg (0.23 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) were used to obtain, after separation by means of preparative HPLC (method 13), 46 mg (50% of theory) of the product in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[N:27]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[C:28]([CH3:31])=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:36][C:35]3[CH:34]=[CH:33][C:32]([N:27]4[C:28]([CH3:31])=[CH:29][CH:30]=[C:26]4[CH3:25])=[CH:39][CH:38]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1ccc(C)n1-c1ccc(C=O)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-n4c(C)ccc4C)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione to 4-(2,5-Dimethyl-pyrrol-1-yl)-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): δ 1.32-1.66 (br m, 8H), 1.89 (m, 2H), 1.90 (s, 6H), 2.30 (m, 1H), 2.52 (m, 2H), 2.61 (d, 1H, J=17.7 Hz), 2.79 (d, 1H, J=17.7 Hz), 3.57 (d, 1H, J=14.4 Hz), 3.65 (d, 1H, J=14.4 Hz), 3.80 (s, 3H), 5.77 (s, 2H), 7.01 (t, 1H, J=8.6 Hz), 7.10 (t, 1H, J=8.4 Hz), 7.10 (d, 2H, J=8.3 Hz), 7.21 (s, 1H), 7.31 (d, 2H, J=8.1 Hz), 10.91 (s, 1H) Anal. Calcd. For C32H36N0O4Cl.0.5H2O: C, 70.77; H, 6.887; N, 2.58. Found: C, 70.92; H, 6.79; N, 2.54.
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN1C(=O)N(C)CCC1.Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:22][CH:21]=1>O1CCCC1>[CH:3]1([S:9][C:20]2[N:25]=[CH:24][C:23]([C:26]([N:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH2:32][N:31]4[CH:39]=[CH:40][CH:41]=[C:30]4[CH2:29]3)=[O:27])=[CH:22][CH:21]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reactant: SC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(c1ccc(SC2CCCCC2)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 35 mg of sodium hydride (60% in oil) in 3 ml of tetrahydrofuran is added under argon 0.10 g of cyclohexylmercaptan. A white precipitate forms and after 0.5 hour at room temperature, 1 ml of N,N'-dimethylpropyleneurea is added. To the mixture is added 0.13 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, quenched with water and ammonium chloride and concentrated under vacuum. The aqueous suspension is filtered and the solid washed with water and hexane. The solid is purified by chromatography on silica gel prep-plates with ethyl acetate-hexane (1:4) as eluent to give 0.13 g of white solid; mass spectrum (CI): 404 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=2)[CH:27]=[N:26]1>ClCCl>[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[N:35]=[CH:34][C:33]([C:36]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:37])=[CH:32][CH:31]=2)[CH:27]=[N:26]1
Reactant: Cn1cc(-c2ccc(C(=O)Cl)cn2)cn1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cn2)cn1
Reaction time: 18 h

Procedure:
A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.37 g) and diisopropylethylamine (0.61 g) in dichloromethane (25 ml) was cooled to 0° C. and a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl chloride in dichloromethane (25 ml) was added portionwise. After 18 hours at room temperature, the reaction mixture was washed with water and a saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.31 g), m.p. 173-175° C.; MS, m/z: 370.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[CH3:8][C:9]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:37][C:36]3[CH:35]=[N:34][N:33]([CH3:38])[C:32]=3[NH:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)=[O:27])[CH:23]=[CH:22][C:10]=1[CH2:11][NH:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][N:18]1[CH2:17][CH2:16][CH:15]([CH2:14][C:13]([NH:12][CH2:11][C:10]2[CH:22]=[CH:23][C:24]([C:26]([N:28]3[CH2:37][C:36]4[CH:35]=[N:34][N:33]([CH3:38])[C:32]=4[NH:31][C:30]4[CH:39]=[CH:40][CH:41]=[CH:42][C:29]3=4)=[O:27])=[CH:25][C:9]=2[CH3:8])=[O:21])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)CC1CCNCC1
Reactant: CC(C)(C)CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)CC1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
3,3-Dimethylbutyraldehyde (0.048 ml, 0.38 mmol) was added to a solution of N-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-2-piperidin-4-yl-acetamide from Example E91 (130 mg, 0.25 mmol) in methanol/acetic acid (49:1, v/v, 2.5 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (24 mg, 0.38 mmol) was added, and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated Na—HCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 1.5% 35% ammonia:15% methanol:83.5% dichloromethane) to give a white solid identified as the title compound (107 mg, 75%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: CC(=O)c1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-acetylbenzoic acid: MS (ESI): m/z 411 (M+1).