Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[O:32])=[CH:24][C:23]=3[F:43])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[N-:44]=[N+]=[N-].[Na+]>CN(C=O)C>[NH2:44][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[O:32])=[CH:24][C:23]=3[F:43])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCCCl)c4)sc23)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCCN)c4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a solution of 366 (0.19 g, 0.31 mmol) in DMF (5 mL) was added sodium azide (0.050 g, 0.77 mmol) and the reaction mixture was heated to 100° C. for 1 h. The mixture was then cooled, partitioned between ethyl acetate and water, the organic phase was collected, washed with water, brine, dried (anhydrous MgSO4), filtered, and concentrated. The residue was filtered through a short plug of silica, eluting with ethyl acetate, and the eluate was concentrated. The residue was dissolved in 1:1 ethyl acetate/methanol (30 mL) mixture; to this solution was added palladium (10% on carbon), and the suspension was stirred under an atmosphere of hydrogen for 3 h. It was then filtered through celite and concentrated. The residue was purified by flash chromatography (eluent 95:3:2 chloroform/methanol/NH4OH) to afford 367 (0.097 g, 52% yield): LRMS (M+H): 601.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:12][CH2:13][C:14]1[N:18]([C:19]2[S:20][C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:22][C:23]=2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:17]([CH3:38])=[N:16][N:15]=1>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([C:23]1[CH:22]=[C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[S:20][C:19]=1[N:18]1[C:17]([CH3:38])=[N:16][N:15]=[C:14]1[CH2:13][NH:12][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11])=[O:32]
Reactant: COc1cccc(N=C=O)c1
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(OC)c2)s1

Procedure:
3-Methoxyphenyl isocyanate and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methoxyphenyl)ureidomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[C:21]([Si:18]([O:17][CH2:16][CH2:15][O:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2])([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
tert-Butyl-[2-(2,3-dinitro-phenoxy)-ethoxy]-dimethyl-silane was prepared by a procedure according to example 108 (i) starting from 500 mg (2.72 mmol) 2,3-dinitro-phenol and 1.00 g (4.18 mmol) (2-Bromo-ethoxy)-tert-butyl-dimethyl-silane.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:16]([N:4]1[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1CNCC(C)O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CN(Cc2ccccc2)CC(C)O1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a tetrahydrofuran solution (500 mL) of 2,6-dimethylmorpholine (Aldrich Co.) (mixture of cis/trans isomers) (25.02 g, 217.24 mmol), triethylamine (51.48 mL, 369.31 mmol) was added at room temperature, and the mixture was stirred for 15 minutes. Then, benzyl bromide (43.93 mL, 369.31 mmol) was added dropwise over 30 minutes, and the mixture was stirred for 4 days. A saturated aqueous solution of sodium hydrogen carbonate (200 mL) was added to the reaction liquor, and the mixture was stirred for 30 minutes, and then extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 65i, n-hexane to ethyl acetate/n-hexane 1:1), to obtain the title compound (10.7 g, 24%) as an oily matter.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].N1CCCC1>CO>[C:19]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:2][C:1](=[O:3])[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:11]4[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=4)[C:17]#[N:18])[CH:5]=3)[O:10]2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(-c2cccc(C#N)c2)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 3′-acetyl-4′-hydroxybiphenyl-3-carbonitrile (0.802 g, 3.38 mmol) and 1-acetylpiperidin-4-one (0.477 g, 3.38 mmol) in MeOH (50 mL) was added pyrrolidine (0.4 mL). The resulting solution was heated to reflux for 1.5 h. The reaction mixture was cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with aqueous 1 M HCl, aqueous 1 M NaOH, and brine successively. Solvent was removed under reduced pressure after dried over anhydrous Na2SO4, to yield 0.768 g of 3-(1′-acetyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)benzonitrile as a light brown solid. It was used for next step without further purification. MS ESI +ve m/z 361 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)[CH3:3].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:5]=2)[CH3:3])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(N)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CC(NC(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
N-[4-(1-Aminoethyl)-2-phenylethynylphenyl]methanesulfonamide (440.1 mg, 1.40 mmol) and TEA (390.3 μl, 2.800 mmol, 2 eq) were added in methylene chloride. The reaction mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (248.8%, 1.540 mmol, 1.3 eq.) was added into the mixture. The reaction mixture was stirred for 1 hr. Methylene chloride was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (241.4 mg, 35%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([F:28])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][O:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16](=[O:22])[C:17]([C:18]=1[N+:19]([O-])=O)=[C:5]23>CC(O)=O.[Fe]>[NH2:19][C:18]1[C:17]2[C:16](=[O:22])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][N:6]3[C:7]4([CH2:13][CH2:12][O:11][CH2:10]4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([F:28])[C:2]=1[F:1]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCOC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CCOC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
A mixture of ethyl 9′,10′-difluoro-8′-nitro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (3.15 g, 7.95 mmol) and iron (2.66 mg, 47.7 mmol) in AcOH (40 mL) was stirred at 90° C. for 5 h. After the reaction mixture was concentrated in vacuo, DMF was added and the mixture was filtrated through Celite. The filtrate was poured into water and the resulting precipitate was collected by filtration and dried to yield ethyl 8′-amino-9′,10′-difluoro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (1.54 g, 53%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) 1.25 (3H, t, J=7.3 Hz), 2.29-2.38 (2H, m), 3.72 (1H, d, J=11.0 Hz), 3.90-3.96 (1H, m), 4.06-4.11 (1H, m), 4.15 (1H, d, J=11.0 Hz), 4.19 (2H, q, J=7.3 Hz), 4.32 (1H, d, J=11.0 Hz), 4.41 (1H, d, J=11.0 Hz), 7.42 (2H, brs), 8.34 (1H, s).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[CH:21]=1>>[CH:1]1([NH:4][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N:20]3[CH:21]=[C:17]([C:7]4[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[N:9][O:10][C:6]=4[CH3:5])[N:18]=[CH:19]3)[CH:23]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CC3)c2)cn1
Yield: 47 %

Procedure:
As described for Example 71c, cyclopropylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (53 mg, 47%) which was obtained as an off-white solid. MS: m/e=385.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH3:12])([CH3:11])[C:7](=O)[CH2:8]Br)[CH3:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[S:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH3:12])([C:7]1[N:22]=[C:20]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:25])([F:14])[F:26])=[CH:24][CH:23]=2)[S:21][CH:8]=1)[CH3:11])[CH3:2]
Reactant: CCOC(=O)CC(C)(C)C(=O)CBr
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(C)c1csc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
500 mg (1.99 mmol) of 5-bromo-3,3-dimethyl-4-oxo-pentanoic acid ethyl ester, 408.6 mg (1.99 mmol) of 4-trifluoromethyl-thiobenzamide and 403 mg (3.98 mmol) of triethylamine in 10 ml of toluene were stirred at 80° C. for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by chromatography (silica gel, n-heptane/ethyl acetate 8:1). Yield: 498.5 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH2:18][CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:33]([O:35][CH2:36][CH3:37])=[O:34])#N>C1COCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH:18]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2c1ccc1nn(Cc3ccccc3)cc21
Reactant: CCOC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2c(ccc3nn(Cc4ccccc4)cc23)C1=O
Temperature: -70 °C

Procedure:
A stirred suspension of 2-benzyl-7,8-dihydrocyclopenta[e]indazol-6(2H)-one (10.3 g, 39.3 mmol) in 180 mL of THF was cooled to −70° C. and a 1.0M solution of lithium bis(trimethylsilyl)amide in THF (86 mL, 86 mmol) was added dropwise during 20 minutes. The reaction mixture was allowed to warm to −33° C. during approximately 1 hour giving a reddish brown solution. The solution was re-cooled to −65° C. and ethyl cyanoformate (5.9 mL, 60 mmol) was added during 1 minute. The reaction mixture was allowed to warm to 15° C. during 2¾ hours and was then partitioned between ethyl acetate and 1N aqueous HCl. The organic phase was washed successively with water, saturated NaHCO3 and brine. After drying over Na2SO4 the solution was filtered through a short column of silica gel and evaporated under vacuum to give ethyl 2-benzyl-6-oxo-2,6,7,8-tetrahydrocyclopenta[e]indazole-7-carboxylate as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)[CH:6]=1
Reactant: Clc1cn[nH]c1
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cnn(CCCN2CC=C(c3ccccc3)CC2)c1
Temperature: 100 °C
Yield: 86 %

Procedure:
A solution of 2.05 g (20 mmol of 4-chloropyrazole in dimethylformamide is added dropwise to a suspension of 1.0 g of NaH in dimethylformamide. The white suspension is heated for 30 minutes at 100° C. Cooling is carried out and 4.7 g (20 mmol) of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine, dissolved in dimethylformamide, are added. Heating is carried out at reflux for 2 hours. Evaporation to dryness is then carried out and the residue is extracted with chloroform, washed with water and dried with sodium sulfate. The resulting crude product is purified by chromatography on silica gel. 5.2 g (17.2 mmol) of 4-chloro-1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1H-pyrazole are obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][O:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCc1ccccc1
Solvent: ClCCl
Product: c1ccc(CCCC2CO2)cc1

Procedure:
5-Phenylpent-1-ene (14.2 g, 0.0973 mol) and m-chloroperbenzoic acid (16.79 g, 0.0973 mol) in dichloromethane (300 ml) was stirred at room temperature for 4 hours. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give an oil which was distilled to give 2-(3-phenylpropyl)oxirane (b.p. 85° C., 0.4 mm.Hg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([O:21]CC)=[O:20].CO.[OH-].[K+].Cl>CC(O)(C)C>[NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Product: Nc1sc(-c2ccc(N3CCOCC3)nc2)nc1C(=O)O
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
Ethyl 5-amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxylate (Example 21, Step 4) (100 mg, 0.3 mmol) was taken up in t-BuOH (3 ml) and methanol (3 ml) and 1M aqueous potassium hydroxide (1.5 ml, 1.5 mmol) was added. The resulting mixture was stirred at 60° C. for 4.5 hrs. The reaction was then cooled to room temperature and neutralized with 1.5 mL 1M aqueous HCl. A yellow precipitate then formed. The resulting slurry was concentrated under reduced pressure, re-suspended in MeOH and concentrated again to give the title compound as a yellow solid which was used in the next step without further purification. LRMS (APCI) calc'd for (C13H15N4O3S) [M+H]+, 307.1; found 307.0.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>C(#N)C>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1cccnc1
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cccnc1
Temperature: 4 °C
Yield: 68.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with nicotinic acid (3.7 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-chloro-1,8-naphthyridine (3.6 g). The product precipitated in the mixture is separated by filtration, washed with tetrahydrofuran (3×20 cc) and water (3×50 cc), and is then dried at 50° C. under reduced pressure (0.067 kPa). The product produced (4.75 g; m.p. 200° C.) is dissolved in boiling acetonitrile (435 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3-pyridylcarboxamide (3.9 g) is produced, m.p. 200° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([N:41]2[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][CH:31]([NH:30][C:22]4[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=4)[CH2:32][CH2:33]3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40]2)=[O:11])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: O=C(O)c1cccc(-n2cnnn2)c1
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cccc(-n5cnnn5)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(I)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(I)c2)c1C

Procedure:
m-Iodoaniline (5 mmol, 1.1 g), 3-Oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized in ethanol (m.p. 111° C.-112.9° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)CBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-methylpropane (336 mg), and the mixture was stirred at room temperature for 19 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])C=O.[OH:12][CH:13](C1C=CC(OC(F)(F)F)=C(C=1)C#N)[CH3:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:7]([CH:13]([OH:12])[CH3:14])=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC(O)c1ccc(OC(F)(F)F)c(C#N)c1
Product: COc1cc(C(C)O)ccc1Br

Procedure:
This compound was prepared from 3-bromo-4-methoxybenzaldehyde in the same manner of Compound 21.
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14].O>CN(C=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[C:13]([NH:9][C:8]1[CH:7]=[CH:6][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:11][CH:10]=1)=[O:14]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
4-sec-butyl aniline (B) (1.49 g, 10.0 mmol) was added to a solution of isatoic anhydride (A) (1.63 g, 10.0 mmol) in anhydrous DMF (40 mL) and the reaction mixture was stirred at 115° C. for 16 hours under nitrogen. It was then cooled to room temperature and poured into water (200 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed with water (100 mL), 10% aqueous NaOH solution (100 mL), water (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-amino-N-(4-sec-butylphenyl)benzamide (C) as a brown solid. Yield: 1.27 g (47%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15][CH2:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38]I)=[CH:32][CH:31]=1)#[N:29]>CN(C)C=O>[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][N:17]2[C:18]3[C:13](=[CH:12][C:11]([NH:10][S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])=[CH:20][CH:19]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:32][CH:31]=1)#[N:29]
Reactant: O=S(=O)(Nc1ccc2c(c1)CCCN2)c1ccccc1
Reactant: N#Cc1ccc(CCCI)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCCN2CCCc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
1.73 g 6-phenylsulphonamido-1,2,3,4-tetrahydro-quinoline are dissolved with 0.7 g triethylamine in 10 ml of dimethylformamide and combined with 1.62 g of 3-(4-cyanophenyl)propyliodide in 15 ml of dimethylformamide and stirred for 5 hours at 40-50° C. Then the mixture is evaporated down, the residue is dissolved in ethyl acetate/water, the organic phase is dried and concentrated by evaporation in vacuo. The product is chromatographed with methylene chloride/ethyl acetate (19:1) over a silica gel column.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#[N:2].[C:11](=N)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:2][CH2:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(CN=C(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 164.8 %

Procedure:
33.73 g (0.2 mol) of 4-cyanobenzylamine and 36.25 g (0.2 mol) of benzophenone imine were dissolved in 540 ml of DCM at room temperature and stirred overnight. The reaction mixture was subsequently washed with 2×90 ml of water and dried with Na2SO4, and the solvent was removed in a rotary evaporator. 55.59 g (93.7%) of the crude product remained. Recrystallization from 550 ml of iPrOH resulted in 97.67 g (80.4%) of pure product. 1H-NMR (CDCl3, δ in ppm): 7.7-7.15 (m, 9H, Ar—H); 4.65 (s, 2H, CH2—N)