Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:56][CH2:57][CH:58]([CH3:63])[C:59]([O:61][CH3:62])=[O:60]>CN(C)C=O.O>[CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:56][CH2:57][CH:58]([CH3:63])[C:59]([O:61][CH3:62])=[O:60])=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOc1cccc(-n2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(CC)n2)c1
Reactant: COC(=O)C(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(-n2cc(C(Nc3ccc(C(=O)NCC(C)C(=O)OC)cc3)C3CCCCC3)c(CC)n2)c1
Reaction time: 8 h
Yield: 13.6 %

Procedure:
4-({Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)benzoic acid (0.18 g) synthesized in the above-mentioned (2) was dissolved in N,N-dimethylformamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), 1-hydroxybenzotriazole.monohydrate (0.09 g) and methyl 3-amino-2-methylpropanoate (0.07 g) were added at room temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give methyl 3-({[4-({cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)phenyl]carbonyl}amino)-2-methylpropanoate (0.03 g) as a yellow oil. This was dissolved in ethanol (2.0 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (0.5 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.02 g, 9%) as a colorless solid.
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][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH2:17])=S.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:17]
Reactant: NC(=S)Nc1ccccc1-c1ccccc1F
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1ccccc1-c1ccccc1F

Procedure:
A mixture of N-(2'-fluoro-2-biphenylyl)thiourea (6 g), lead acetate trihydrate (9.25 g), potassium hydroxide (13.65 g) and water (180 ml) was heated at 90°-95° C. for 3 hours to give 2'-fluoro-2-biphenylylcyanamide as a colourless solid (m.p. 68°-69° C.).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.Cl>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])=[CH:29][CH:28]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(Cl)cc4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.5 g, 1.4 mmol) and 4-chlorobenzoyl chloride (0.25 g, 1.4 mmol) in DMF (30 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, then, 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.22 g, 40% yield); mp 278-280° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.10 (95.66%); 1H NMR (DMSO-d6) δ 1.97-2.03 (m, 1H), 2.31-2.45 (m, 1H), 2.57-2.62 (m, 1H), 2.85-2.97 (m, 1H), 4.30 (d, 1H, J=17.3 Hz), 4.45 (d, 1H, J=17.3 Hz), 4.59 (d, 2H, J=5.7 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.47 (d, 1H, J=8.1 Hz), 7.54-7.58 (m, 3H), 7.70 (d, 1H, J=7.8 Hz), 7.91-7.96 (m, 2H), 9.23 (t, 1H, J=6.0 Hz). 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 127.1, 128.4, 129.2, 130.4, 132.9, 136.1, 142.4, 143.7, 165.2, 167.9, 170.9, 172.8; LCMS: MH=412, 414; Anal. Calcd for C21H18ClN3O4+0.5 CH2Cl2: C, 56.84; H, 4.22; N, 9.25. Found: C, 56.79; H, 4.30; N, 9.33.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[CH:8][C@H:7]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:4])=[O:3]>C(O)C.[Pd]>[CH3:1][S:2]([O:5][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:19])[CH2:8][C@H:7]1[NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])(=[O:3])=[O:4]
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OS(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OS(C)(=O)=O
Reaction time: 16 h
Yield: 49 %

Procedure:
Degass a solution of (+/−)-(1S,2R,6S)-2-((tert-butoxycarbonyl)amino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-en-1-yl methanesulfonate (1.0 equiv.) in Ethanol (0.20 M). To this solution was added Pd/C (0.2 equiv.) and purge with Ar and H2. The mixture was stirred under H2 for 16 hrs. Filter the mixture over cetlite and wash the cake with MeOH. Concentrate the filtrate to yield (+/−)-(1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl methanesulfonate in 49% yield). LC/MS (m/z)=400.3 (MH+), Rt=0.62 min.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:24][C:23]([CH2:47][C:48]#[N:49])([N:25]4[CH:29]=[C:28]([C:30]5[C:31]6[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=6[N:33]=[CH:34][N:35]=5)[CH:27]=[N:26]4)[CH2:22]3)[CH2:17][CH2:16]2)=[O:14])[CH:4]=1.[CH2:50]([N:52](CC)[CH2:53][CH3:54])[CH3:51].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N1CCCC1.FC(F)(F)C(O)=O>C(Cl)Cl.C(N(CC)CC)C>[N:52]1([CH2:2][C:3]2[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:24][C:23]([CH2:47][C:48]#[N:49])([N:25]5[CH:29]=[C:28]([C:30]6[C:31]7[CH:38]=[CH:37][NH:36][C:32]=7[N:33]=[CH:34][N:35]=6)[CH:27]=[N:26]5)[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:4]=2)[CH2:53][CH2:54][CH2:51][CH2:50]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(CN4CCCC4)nc(C(F)(F)F)n3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-(1-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.030 g, 0.043 mmol, from Step E) and triethylamine (0.015 mL, 0.11 mmol) in methylene chloride (1 mL) at 0° C. was added methanesulfonyl chloride (0.006 mL, 0.08 mmol). The reaction was allowed to warm to room temperature immediately after addition of mesyl chloride (MsCl). When mesylate formation was confirmed to be complete, the solution of mesylate was added to a mixture of pyrrolidine (0.017 mL, 0.20 mmol, Aldrich) and a few drops of triethylamine in DCM (0.2 mL). The displacement reaction was heated to 40° C. for 30 minutes. The reaction was cooled to room temperature and trifluoroacetic acid (1 mL) was added. After stirring for 1 hour, the solvents were removed in vacuo and replaced with methanol (1 mL) and ethylenediamine (0.2 mL). After stirring for 30 minutes, the product was purified by preparative HPLC-MS (Waters SunFire C18, 5 um particle size, 30×100 mm, eluting with a gradient of 5-23% MeCN in H2O containing 0.1% TFA over 12 minutes). Yield: 0.012 g (25%); LC-MS: 620.2 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 9.10 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.01 (s, 1H), 7.83 (d, 1H), 7.29 (d, 1H), 4.95 (d, 2H), 4.85 (s, 2H), 4.77-4.66 (m, 3H), 4.02 (d, 1H), 3.95-3.15 (m, 8H), 3.12-2.99 (m, 1H), 2.31-2.03 (m, 6H), 1.77-1.51 (m, 2H). 19F NMR (300 MHz, CD3OD): δ −72.21 (s, 3F), −77.61 (s, 12F).
Reaction SMILES: [F:1][C:2]1[C:3]([F:43])=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[O:18][C:17]([CH3:23])([CH3:22])[CH:16]([CH2:24][C:25]3[CH:26]=[C:27]([NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])[CH:28]=[CH:29][C:30]=3[O:31][CH3:32])[C:15]4=[O:41])=[N:7][C:6]=2[CH:42]=1.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[C:3]([F:43])=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[O:18][C:17]([CH3:23])([CH3:22])[C@@H:16]([CH2:24][C:25]3[CH:26]=[C:27]([NH:33][S:34]([C:37]([F:38])([F:39])[F:40])(=[O:35])=[O:36])[CH:28]=[CH:29][C:30]=3[O:31][CH3:32])[C@H:15]4[OH:41])=[N:7][C:6]=2[CH:42]=1
Reactant: COc1ccc(NS(=O)(=O)C(F)(F)F)cc1CC1C(=O)c2cc(OCc3nc4cc(F)c(F)cc4s3)ccc2OC1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NS(=O)(=O)C(F)(F)F)cc1C[C@H]1[C@@H](O)c2cc(OCc3nc4cc(F)c(F)cc4s3)ccc2OC1(C)C
Reaction time: 3 h
Yield: 0 %

Procedure:
To a stirred solution of 1.36 g (2.12 mole) of the product of Example 104 in 20 mL tetrahydrofuran at -78° C. was added dropwise 4.7 mL (4.66 mL) 1.0M LiB(C2H5)3H in THF (Super-Hydride [trademark]). The mixture was allowed to come to room temperature over 3 hours, then quenched with 10 mL 10% ammonium chloride. The mixture was poured into water, acidified to ph 1-4 with 1N HCl and then extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes gave 670 mg (48%) of pure product. NMR (CDCl3): δ1.40 (s, 3H); 1.53 (s, 3H); 2.10 (m, 1H); 2.90 (m, 2H); 3.88 (s, 3H); 4.23 (s, br, 1H); 5.29 (s, 2H). MS (LSIMS) m/e: 644 (M+, 12), 627 (32), 268 (100).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: NC(=O)c1c(N)ncn1CCOc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1CCOc1ccccc1
Yield: 93 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22, using 1.00 g (4.06 mmol) of 4-amino-1-(2-phenoxyethyl)-5-imidazolecarboxamide prepared in the same manner as in Example 155 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.39 g of 4-(2-fluorobenzoylamino)-1-(2-phenoxyethyl)-5-imidazolecarboxamide (yield 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 11, 6-amino-4-(3'-trifluoromethylanilino)quinazoline was reacted with acetic anhydride to give 6-acetamido-4-(3'-trifluoromethylanilino)quinazoline in 87% yield as a solid.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19]>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCCCCO
Product: CCCCCOc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and pentanol to provide 2-nitro-6-(pentyloxy)benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([NH2:21])=[N:13]2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:23]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[CH3:24].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([NH:21][CH:29]3[CH2:30][CH2:31][N:26]([C:23](=[O:25])[CH3:24])[CH2:27][CH2:28]3)=[N:13]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2nc(N)c3cccnc32)C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCC(Nc2nn([C@H]3C[C@H](NC(=O)OC(C)(C)C)C3)c3ncccc23)CC1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Tert-butyl(trans-3-(3-amino-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)carbamate (from example 113, step 2, 0.210 g, 0.692 mmol) was dissolved in methanol (4 mL) and acetic acid (3 drops). 1-Acetyl-4-piperidone (0.100 ml, 0.812 mmol) was added and the mixture heated at 60° C. for 1 hour. The solution was cooled and sodium cyanoborohydride (0.065 g, 1.034 mmol) was added. The reaction was stirred for 14 hours at room temperature. Saturated sodium bicarbonate (10 mL), water (50 mL) and ethyl acetate (100 mL) were added and the mixture stirred for 20 minutes. The phases were separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in dichloromethane gradient) gave the desired tert-butyl(trans-3-(3-((1-acetylpiperidin-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)carbamate (0.134 g, 0.313 mmol, 45.2% yield).
Reaction SMILES: O.O.Cl.[F:4][C:5]([F:27])([F:26])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[C:11]2[NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=O.[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][NH:33][CH2:34][CH3:35])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O.C(Cl)(Cl)Cl.O.CCOCC>[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][N:33]([CH2:34][CH3:35])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[NH:16][C:11]1[C:10]2[C:15](=[C:6]([C:5]([F:26])([F:4])[F:27])[CH:7]=[CH:8][CH:9]=2)[N:14]=[CH:13][CH:12]=1)[CH3:29]
Reactant: CCNCCN(CC)CC
Reactant: O=C(O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCN(CC)CCN(CC)C(=O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 1 h
Yield: 46.2 %

Procedure:
12.1 Grams (0.03 mole) of 2-(8-trifluoromethyl-4-quinolylamino)benzoic acid hydrochloride dihydrate were refluxed in 80 milliliters of thionyl chloride for half an hour. A yellow solid precipitated. The thionyl chloride was evaporated off and 50 milliliters of benzene were added and evaporated. The resulting acid chloride hydrochloride was added in portions with stirring to a cooled mixture of 4.32 grams (0.03 mole) of N,N,N'-triethylethylenediamine in 80 milliliters of chloroform and 31.8 grams (0.3 mole) of sodium carbonate in 100 milliliters of water. The mixture was stirred for one hour, and allowed to stand overnight. The chloroform layer was separated and dried and the chloroform evaporated to give an oil, which could not be solidified. The oil was dissolved in ether and purified by chromatography on an alumina (type H) column. Elution with ether/chloroform (50:50) gave a pale yellow oil which was kept under vacuum for four days when it gradually solidified to give 6.35 grams (46% yield) of title compound of melting point 112°-113° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH3:15])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:18][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH3:14])[S:11][C:10]=1[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(O)C2CCCCC2)c(C)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(Cl)C2CCCCC2)c(C)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of cyclohexyl(2,5-dimethylthiophen-3-yl)methanol (643 mg) synthesized above in toluene (10 mL) was added thionyl chloride (314 μL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (653 mg, 94%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH2:9][CH2:8][C:7](=[O:10])[C:6]=1[CH2:11][CH2:12][CH3:13].[H][H]>>[CH2:11]([CH:6]1[C:7](=[O:10])[CH2:8][CH2:9][CH:5]1[CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH2:12][CH3:13]
Reactant: CCCC1=C(CC(=O)OC)CCC1=O
Reactant: [H][H]
Product: CCCC1C(=O)CCC1CC(=O)OC
Temperature: 40 °C
Yield: 73.6 %

Procedure:
Into a 1 liter flask purged with dry nitrogen, there is introduced 210 ml of anhydrous methanol followed by 63.2 g of aluminium triisobutyl over thirty minutes. The resulting solution is refluxed for one hour. After cooling, the solution is introduced into an autoclave with 6.5 g of 5.3% palladium on carbon. 58.8 g (0.30 mole) of methyl[2-n-propyl-3-keto-cyclopent-1-en-1-yl]-acetate is added. The autoclave is closed, shaken to homogenise the mass and heated to 40°C. Hydrogen is then introduced under a pressure of 10 kg/cm2 until no further hydrogen absorption occurs. After cooling, the mass is filtered to separate the catalyst, poured into water and extracted with petroleum ether (3 × 100 ml). The petroleum ether solution is washed to neutrality and distilled. 53 g of crude product are thus obtained which are rectified under reduced pressure. 43.8 g of methyl [2-n-propyl-3-keto-cyclopent-1-yl]-acetate is thus obtained, presenting the following characteristics:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[CH3:19])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>>[CH3:19][N:14]1[C:15]2[C:11](=[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][CH2:26][CH:28]3[CH2:29][O:30]3)=[O:9])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: ClCC1CO1
Reactant: Cn1ccc2c(C(=O)c3ccccc3O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc2c(C(=O)c3ccccc3OCC3CO3)cccc21

Procedure:
Using the procedure of Step A of Example 3, 3 g of the product of Step D, 6.6 of potassium carbonate and 4.7 ml of epichlorhydrin were added in 5 stages. After a total of 48 hours at reflux, filtration was carried out. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed as indicated in Example 2 to obtain 3.7 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#C[Si](C)(C)C)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 3 hours with 1.30 g (12.5 mmol) of ethynyltrimethylsilane, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate/hexane (1:1). After crystallization from ethyl acetate and hexane there was obtained 7-chloro-4,5-dihydro-5-methyl-3-[(trimethylsilyl)ethynyl]-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 186°-187°.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].[OH-].[Na+]>O1CCCC1>[C:11]([C:8]1[CH:9]=[C:10]2[C:2]([NH:1][C:26](=[O:28])[CH3:27])=[N:3][NH:4][C:5]2=[N:6][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc2c(N)n[nH]c2nc1-c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2nc(-c3ccc(O)cc3)c(C#N)cc12
Yield: 36.2 %

Procedure:
To a mixture of 165 mg (0.66 mmol) of 3-amino-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile obtained following general procedure D1 and of 180 μL (2.16 mmol) of pyridine diluted in 1.6 ml of anhydrous tetrahydrofuran, are added dropwise at 0° C. 168 mg (2.16 mmol) of acetyl chloride. The solution is stirred under reflux for 4 h, then 655 μL (5M, 3.28 mmol) of sodium hydroxide solution are added, and the mixture is stirred for 1 h30 at 40° C. The tetrahydrofuran is concentrated and the solution is brought to acid pH (in the order of 3/4). The solid is filtered, washed with water, dried, and triturated in ethanol to yield 70 mg of N-(5-cyano-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)acetamide in the form of a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=[O:37])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[NH:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccnc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccnc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-pyridin-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example G26) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige powder (161 mg).