Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]([CH3:21])[C:15](=[O:22])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[CH3:24][C:25]1[O:29][N:28]=[CH:27][C:26]=1[C:30](O)=[O:31]>>[F:20][C:19]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:22])[N:16]2[CH3:21])=[CH:11][C:10]=1[C:6]1[C:5]([CH3:23])=[C:4]([CH2:3][NH:2][C:30]([C:26]2[CH:27]=[N:28][O:29][C:25]=2[CH3:24])=[O:31])[CH:9]=[N:8][CH:7]=1
Reactant: Cc1c(CN)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2
Reactant: Cc1oncc1C(=O)O
Agent: Cl
Product: Cc1oncc1C(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1C

Procedure:
In analogy to the procedure described for the preparation of example 219, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 226) has been coupled with 5-methyl-isoxazole-4-carboxylic acid to give the title compound as an off-white solid. MS: 409.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[N:19]=[N:20][C:21]([N:24]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[N:25]2)=[CH:22][CH:23]=1>CN(C=O)C>[CH3:30][C:26]1[CH:27]=[C:28]([CH3:29])[N:24]([C:21]2[N:20]=[N:19][C:18]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)[N:25]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(OCc3c(-c4ccccc4)noc3C)nn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (76 mg, 0.40 mmol) in DMF (0.8 mL) cooled to 0° C. was added sodium hydride (55% dispersion in mineral oil, 19.2 g, 0.44 mmol). The mixture was stirred at room temperature for 1 h. After addition of 3-chloro-6-(3,5-dimethylpyrazol-1-yl)-pyridazine (91.8 mg, 0.44 mmol) the mixture was stirred at room temperature overnight. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, heptane:ethanol=100:0 to 95:5) afforded the title compound (5.0 mg, 3%) as a white solid. MS: m/e=362.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[H][H]>[Pd].C(O)C>[NH2:14][C:3]1[C:2]([CH3:1])=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6]
Reactant: Cc1cccc(C(=O)NC(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)NC(C)C)c1N
Yield: 96.5 %

Procedure:
The 2-nitrobenzamide of Step D (1.70 g, 7.6 mmol) was hydrogenated over 5% palladium on carbon in 40 mL of ethanol at 345 kPa (50 psi). When the uptake of hydrogen ceased the reaction was filtered through Celite® filter agent and the Celite® was washed with ether. The filtrate was evaporated under reduced pressure to afford 1.41 g of the title compound as a solid melting at 149-151° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]=[S:26]1(=[O:33])[CH2:30][CH2:29][CH:28]([NH:31][NH2:32])[CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][NH:31][CH:28]3[CH2:29][CH2:30][S:26](=[O:33])(=[O:25])[CH2:27]3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC1CCS(=O)(=O)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC1CCS(=O)(=O)C1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.5 g) in EtOAc (20.0 mL) was treated with 2-(1,1-dioxotetrahydrothiophen-3-yl)hydrazine (0.3 g, 1.2 eq.). The mixture was cooled to −60° C. and treated simultaneously with T3P (50% in EtOAc; 2.0 mL, 2 eq.) and DIPEA (1 mL, 4 eq.). The reaction mixture was stirred for 30 min at −60° C. before being concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.60 g of a solid residue. Purification by column chromatography (SiO2; elution with MeOH:CH2Cl2; desired compound eluted at 5% MeOH in CH2Cl2) afforded 100 mg (yield=15%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(tetrahydrothiophen-1-1-dioxide-3-yl)acrylohydrazide. 1H NMR (400 MHz, CD3OD) δ=9.57 (s, 1H), 8.64 (s, 2H), 8.10 (s, 1H), 7.34-7.36 (d, J=10.4 Hz, 1H), 5.89-5.92 (d, J=10.8 Hz, 1H), 4.01 (m, 1H), 3.04-3.26 (m, 4H), 2.27-2.34 (m, 2H). LCMS for C17H15F6N5O3S [M+H]+ 484.40; found 483.39 (RT 2.63 min, purity: 66.39%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH2:22]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH2:23][CH2:24][CH3:25]>ClCCl>[CH2:22]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH:27]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCCCc1cc(CN)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1cc(CNc2c([N+](=O)[O-])cnc3ccccc23)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.9 %

Procedure:
4-Chloro-3-nitroquinoline (1.35 g, 6.48 mmol) and triethylamine (1.36 mL, 9.73 mmol) were sequentially added to a solution of (5-butylisoxazol-3-yl)methylamine (1.00 g, 6.48 mmol) in dichloromethane, and the solution was stirred for 48 hours at room temperature. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 3% methanol in dichloromethane) to provide 1.33 g of N-[(5-butylisoxazol-3-yl)methyl]-3-nitroquinolin-4-amine as a yellow, crystalline solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
A mixture of 59 mg (0.1 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 42 mg (0.3 mmol) of 2-chloro-5-nitropyridine and 65 mg (0.2 mmol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 12 h. The mixture was diluted with ethyl acetate and extracted with water. Evaporation of the solvent and chromatography on silica gel (1:1 ethyl acetate/hexane) gave the title compound (38 mg) as a white foam. 1H-NMR:0.83(6H,dd), 1.7(2H,m),1.8(2H,m), 2.8-3.2(7H,m), 3.7(3H.m), 3.8-4(4H,m), 5.0(2H,m), 5.62(1H,d), 6.03(2H,s), 6.85(1H,d), 6.97(1H,d), 7.02(2H,d), 7.18(1h,s), 7.35(2H,d), 7.4(1H,d), 8.42(1H,d), 8.90(1H,d). MS: 715
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)=[O:8].N1CCCCC1.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].C(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:30][C:31]([OH:33])=[O:32])=[CH:14][CH:13]=1)=[O:8]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=O)cc1
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=CC(=O)O)cc1

Procedure:
31.75 g. 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-benzaldehyde (m.p. 115°-116° C.) and 1 ml. piperidine are added to 11.5 g. malonic acid in 100 ml. anhydrous pyridine. The reaction mixture is heated on a waterbath until the evolution of carbon dioxide is finished. After cooling, the reaction mixture is poured on to ice/concentrated hydrochloric acid and the precipitate formed is filtered off with suction, whereafter it is recrystallized from ethanol. There are obained 23.4 g. (about 65% of theory) 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid; m.p. 197°-198° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([S:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NS(=O)(=O)c4ccccc4)nc23)CC1
Yield: 76.5 %

Procedure:
Beginning with 0.40 gm (1.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.267 mL (2.09 mMol) phenylsulfonyl chloride, 0.493 gm (76%) of the title compound were prepared as an orange solid essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:26][OH:27]>>[CH3:26][O:27][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Reactant: CO
Product: COC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 63 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazole-1-ylcarbonyl)-1,3-dihydro-indol-2-one (5.3 mg, 0.016 mmol) in 1.0 mL of methanol was stirred at room temperature for 64 h and filtered. The red solid was washed with methanol and dried in a vacuum oven overnight to afford 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid methyl ester (3.0 mg, 63%) as a red solid. 1H NMR (400 MHz, DMSO-d6) d 12.63 (s, 1H, NH-1′), 7.84–7.86 (m, 1H), 7.69 (s, 1H, H-vinyl), 7.56–7.68 (m, 1H), 7.19–7.22 (m, 2H), 6.06 (d, J=2.34 Hz, 1H, H-4′), 4.08 (s, 3H, OCH3), 2.40 (s, 3H, CH3), and 2.36 (s, 3H, CH3). MS m/z (relative intensity, %) 297 (100, [M+1]+.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH2:39][CH2:38]1.N1CCCC1.C(Cl)Cl>C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:47][C:43]([N:40]4[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]4)([CH3:44])[CH3:46])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCC(O)CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
A mixture of (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (150 mg, 0.31 mmol), 2-(4-hydroxy-1-piperidyl)-2-methyl-propanal (167 mg, 0.98 mmol), pyrrolidine (0.03 mL, 0.31 mmol) and DCM (10 mL) was stirred at room temp for 2 days and then diluted with aq. NaHCO3 (40 mL) and extracted with DCM. The organic was dried (MgSO4), filtered and concentrated to an oil. The crude material was purified at Isolera (25 g column: 30% iPrOH/DCM) to obtain the product which was isolated by lyophilization to provide 61 mg (32% yield) of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-hydroxypiperidin-1-yl)-4-methylpent-2-enenitrile as a powder. MS (pos. ion) m/z: 625 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17]CO)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:10]1([CH:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:7][O:6][C:4](=[O:5])[CH2:3][C:2](=[O:1])[CH2:8][CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
3.0 g (23.1 mg) of methyl 3-oxopentanoate and 4.9 g (23.1 mg) of 3,3-diphenylpropanol were stirred in 60 ml of toluene under heating at 100° C. overnight. Toluene was distilled out under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([O:24][C:25](=[O:35])[CH2:26][NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([CH3:23])([CH3:22])[CH3:21].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:20]([O:24][C:25](=[O:35])[CH2:26][N:27]([C:11](=[O:13])[CH:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)CNCC1CCCCC1
Reactant: N#Cc1ccc(CC(C(=O)O)C2CCCCC2)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC1CCCCC1)C(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
To 3-(4-cyano-phenyl)-2-(R,S)-cyclohexyl-propionic acid (5 g, 19.43 mmol) and (cyclohexylmethyl-amino)-acetic acid tert-butyl ester (4.42 g, 19.43 mmol) in dimethylformamide (50 ml) were added TOTU (7.01 g, 21.37 mmol) and diisopropylethyl amine (2.51 g, 19.43 mmol) at −15° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation, the residue was treated with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was evaporated to yield 10 g of crude material which was used in the next step without further purification, MS m/z: 467.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Br:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:15][C:12]1[CH:11]=[C:4]([CH:3]=[C:2](/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: Cc1c(Br)cc(C(=O)NC2CC2)cc1Br
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C(=O)NC2CC2)cc(Br)c1C
Temperature: 100 °C

Procedure:
To a solution of 3,5-dibromo-N-cyclopropyl-4-methylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow-orange oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([O:14][C:15](=[O:18])[CH2:16][NH2:17])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:17][CH2:16][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:18])=[N:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1ccc(C#N)cn1
Reaction time: 24 h

Procedure:
A solution of 6-chloronicotinonitrile (1.00 g, 7.2 mmol), glycine tert-butyl ester (1.04 g, 7.9 mmol) and DIEA (4.9 mL, 29 mmol) in anhydrous dioxane (20 mL) was heated at reflux. After 24 hours, an additional amount of glycine tert-butyl ester (0.5 g, 3.8 mmol) was added. After 24 additional hours at reflux, the reaction mixture was concentrated under reduced pressure. The residue was taken up with EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. After precipitation from EtOAc/Et2O/heptane, the title compound was obtained as an off-white powder (1.55 g, 92%). HPLC (Method A), Rt: 3.1 min (purity: 95.1%). UPLC/MS, M+(ESI): 178.0 ([M-tBu+2H]+), M−(ESI): 232.1. 1H NMR (DMSO-d6, 300 MHz) δ 8.39 (d, J=2.1 Hz, 1H), 7.91 (m, 1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 3.98 (d, J=6.1 Hz, 2H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[CH3:31].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:35]3[CH2:36][CH2:37][N:32]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH3:24])[CH:26]=4)[CH2:33][CH2:34]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)c(C)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
105 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(3,4-dimethylphenyl)piperazine (47 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[ClH:8].[Cl:9][C:10]([N:12]1[C:18]2[S:19][C:20]([CH2:22][CH3:23])=[CH:21][C:17]=2[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[N:15][CH2:14][CH2:13]1)=[O:11]>O1CCCC1>[ClH:9].[ClH:8].[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:16]1[C:17]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=2[N:12]([C:10](=[O:11])[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH2:13][CH2:14][N:15]=1
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1Cl
Reactant: CN(C)CCCN
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N(C(=O)NCCCN(C)C)CCN=C2c1ccccc1Cl
Temperature: 0 °C

Procedure:
To a solution of 9.2 g of 3-dimethylaminopropylamine in 50 ml of tetrahydrofuran is added 7.8 g of 1-chlorocarbonyl-5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring. After the mixture is reacted for two and half hours at room temperature, the reaction substance is poured into 200 ml of ice-cold water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-(3-dimethylaminopropylcarbamoyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloride as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 223°-224° C with decomposition.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[CH2:23][NH:24][C:25](=[O:27])[CH3:26])([O-])=O.O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[CH2:23][NH:24][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1N
Temperature: 25 °C
Yield: 104.5 %

Procedure:
To a solution of N-(2-nitro-4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide (0.5 g) and water-containing Raney-nickel (0.5 g) in ethanol (8 ml) was added dropwise hydrazine monohydrate (0.7 ml) and the mixture was refluxed under heating at room temperature for 1 hr. Raney-nickel was removed by passing the mixture through Celite and the solvent was evaporated to give a white solid (0.48 g). The obtained white solid was crystallized from hexane/ethyl acetate (1:1, 100 ml) to give the title compound (45.5 g) as white crystals, m.p.=148-149° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:12]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]3[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]4[N:34]=[N:35][NH:36][N:37]=4)=[O:31])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:38][CH:39]=2)[C:21]2[CH:20]=[CH:19][C:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(Nc1nn[nH]n1)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 μmol 3-cyanophenylisocyanate dissolved in 500 μL dichloroethane was added to the above resin bound 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (50 mg). Shaking the mixture for 5 hours at 25° C. followed by filtration and washing of the resin with 2×1 mL dichloromethane, 4×1 mL DMF, 2×1 mL H2O, 3×1 mL THF and 3×1 mL dichloromethane afforded the resin bound title compound.