Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1>O1CCCC1.C(O)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccnc(C2=CCOCC2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccnc(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred solution of 550 g (26.7 mmol) 2-(3,6-dihydro-2H-pyran-4-yl)-4-nitro-pyridine in 230 ml tetrahydrofuran and 5 ml glacial acetic acid was added 2.84 g of 10% palladium on charcoal and the mixture was then stirred for 16 h under an atmosphere of hydrogen at room temperature and 1.7 bar pressure. The mixture was then filtered, washing with methanol, and the filtrate concentrated in vacuo. Flash chromatography (methanol/dichloromethane/triethylamine 100/5/1) afforded 4.75 g (100%) 2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine as a light yellow oil. ES-MS m/e (%): 179 (M+H+, 100).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[S:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])[CH:13]=1>>[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[S:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:22][CH2:23][N:24]([C:3]([O:5][C:21]([CH3:26])([CH3:22])[CH3:19])=[O:4])[CH2:25][CH2:26]2)=[O:20])[CH:13]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)C3CCNCC3)c2)c(F)c1
Reactant: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1

Procedure:
t-Butyl 4-(4-{2-fluoro-4-[3-(4-fluorophenyl)acetylthioureido]phenoxy}pyridin-2-ylcarbamoyl)piperidine-1-carboxylate (38.8 mg, 0.062 mmol) and trifluoroacetic acid (0.50 ml) gave a crude product of piperidine-4-carboxylic acid (4-{2-fluoro-4-[3-(4-fluorophenyl)acetylthioureido]phenoxy}pyridin-2-yl}amide (ESI-MS (m/z):526). The crude product, formalin (37% aqueous solution; 0.0231 ml), acetic acid (0.0142 ml) and sodium triacetoxyborohydride (26.3 mg) gave the titled compound (1.1 mg, 3.29%) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:5]2=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[C:5]2=[CH:4][CH:3]=1
Reactant: O=c1n(Cc2nc3nc(Cl)ccc3n2CCCCO)c2cnccc2n1C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21

Procedure:
To the alcohol 14 (5 g, 12.11 mmoles) dissolved in DCM (80 mL) was added dess-martin periodinane (6.934 g, 1.35 eq, CAS 87413-09-0). The resulting mixture was stirred at Rt overnight. Diethylether was added (150 mL) and the mixture was stirred for 15 minutes. The mixture was filtrated and the filtrate washed quickly with an aqueous Na2S2O3 solution, dried on Na2SO4, filtrated and evaporated. The resulting solid was washed again with a solution of 5% methanol in dichloromethane and the filtrate was washed with a Na2S2O3 solution and dried over Na2SO4. The solution was concentrated and the aldehyde 67-1 was obtained as a light yellow solid (4.6 g, 93% yield) and was used as such in the next step. LCMS m/z=411 (M+H)+
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][OH:20])[CH2:13]1.[H-].[Na+].I[CH3:24].O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][O:20][CH3:24])[CH2:13]1
Reactant: OCCC1CCCN(CC2COc3ccccc3O2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCC1CCCN(CC2COc3ccccc3O2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]ethanol (0.1 g, 0.36 mmol) in THF (5 ml) was added NaH (79.0 mg, 1.79 mmol), which was previously washed with heptane. The reaction mixture was stirred at 70° C. for 1 h followed by a dropwise addition of a solution of iodomethane (0.034 ml, 0.54 mmol) in THF (1 ml). Stirring was continued for 1 h. Water was slowly added and the reaction mixture was extracted with DCM (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[CH2:28][C@@H:29]2[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:34][C:31]1([CH3:35])[O:30][C@H:29]([CH2:28][O:15][C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:33][O:32]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)O1
Temperature: 90 °C
Yield: 104.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.00 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (343 mg, 1.20 mmol) in DMF (5 mL) was added Cs2CO3 (650 mg, 2.00 mmol). The mixture was heated at 90° C. for 4 hours. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness to yield (R)-2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (350 mg) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:29]=[CH:28][C:19]([CH:20]=[C:21]4[S:25][C:24](=[O:26])[NH:23][C:22]4=[O:27])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:29]=[CH:28][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[NH:23][C:22]4=[O:27])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(-c2cccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1
Yield: 39.5 %

Procedure:
To a suspension of 58 (1.25 g, 3.0 mmol) in acetic acid (30 mL) was added ammonium formate (1.50 g, 24 mmol) and 10% Pd on carbon (1.30 g). After vigorous refluxing for 16 h, the mixture was filtered through Celite, which was subsequently washed with ethyl acetate (100 mL). The mixture was washed with water (2×75 mL), 1N NaHCO3 (50 mL), brine (75 mL) then dried (MgSO4), filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane, adsorbed onto silica gel and purified by flash chromatography using hexanes:ethyl acetate (3:7) to yield a white solid (0.48 g, 38%) after concentration then trituration and filtration from hexanes-ethyl acetate (4:1). 1H NMR (400 MHz, DMSO-d6): δ 12.04 (br s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.39 (dt, J=8.0, 1.6 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.22 (t, J=2.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 7.00 (d, J=9.2 Hz, 2H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.79 (s, 3H), 3.37 (dd, J=14.4 and 4.4 Hz, 1H), 3.13 (dd, J=14.4 and 8.8 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][C:3]([N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8](=[O:16])[C:7]4[CH:17]=[CH:18][CH:19]=[N:20][C:6]3=4)=[O:4])[CH2:33][CH2:32]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: C1CCN(CCCCC2CCNCC2)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ncccc21
Product: O=C1Nc2ccccc2N(C(=O)CN2CCC(CCCCN3CCCCC3)CC2)c2ncccc21
Yield: 37 %

Procedure:
Prepared analogously to Example 1 from 11-(chloroacetyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 4-[4-(1-piperidinyl)butyl]piperidine in a yield of 37% of theory.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:21]=2)[C:16]([CH3:30])([CH3:29])[CH2:15]1.N#N.C(N(CC)CC)C>CO.[Pd]>[CH3:29][C:16]1([CH3:30])[C:17]2[C:22](=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[N:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=3)[N:8]=[C:7]([CH3:12])[C:6]=2[CH3:13])[CH2:15]1
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(N4CCOCC4)cc32)c1C
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2c(N2CC(C)(C)c3ccc(N4CCOCC4)cc32)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(1-(6-chloro-2,3-dimethylquinolin-4-yl)-3,3-dimethylindolin-6-yl)morpholine (10 mg, 0.024 mmol) in MeOH (3 mL) was purged with N2. After the mixture was purged a catalytical amount of triethylamine and Pd/C (0.003 g, 0.002 mmol) were added. The resulting mixture was stirred at rt for 2 h under a hydrogen atmosphere. After this time the reaction mixture was filtered through a pad of Celite™ and the solvent was evaporated in vacuo to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-2,3-dimethylquinoline. 1H NMR (500 MHz, chloroform-d) δ ppm 8.06 (1H, br. s.), 7.73 (1H, d, J=8.3 Hz), 7.58 (1H, t, J=7.6 Hz), 7.33 (1H, t, J=7.6 Hz), 6.99 (1H, d, J=8.1 Hz), 6.23 (1H, d, J=7.1 Hz), 5.45 (1H, s), 3.63 (6H, m), 2.86 (4H, m), 1.43 (6H, m). Mass Spectrum (ESI) m/e=388 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([NH2:16])[CH:6]=[C:7]([CH2:11][P:12]([OH:15])([OH:14])=[O:13])[CH2:8][CH2:9][OH:10])C>O>[NH2:16][CH:5]([CH:6]=[C:7]([CH2:11][P:12]([OH:15])([OH:14])=[O:13])[CH2:8][CH2:9][OH:10])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(N)C=C(CCO)CP(=O)(O)O
Solvent: O
Product: NC(C=C(CCO)CP(=O)(O)O)C(=O)O

Procedure:
0.415 g (1.55 mmol) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated under reflux in 3 ml of water for 24 hours. The reaction mixture is concentrated by evaporation, purified by chromatography on 10 g of silica gel with ethanol/water (1:1) as eluant, and crystallised from ethanol. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid having a melting point >300° is obtained.
Reaction SMILES: [N:1]1([C:6]2[C:11]([F:12])=[CH:10][C:9]([N:13]3[CH2:17][C@H:16]([C:18]([O:20]C)=O)[O:15][C:14]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:5][CH:4]=[CH:3][CH2:2]1.[NH3:24]>CO>[N:1]1([C:6]2[C:11]([F:12])=[CH:10][C:9]([N:13]3[CH2:17][C@H:16]([C:18]([NH2:24])=[O:20])[O:15][C:14]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3CC=CC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3CC=CC3)c(F)c2)C(=O)O1
Yield: 58 %

Procedure:
A solution of methyl (5R)-3-[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidine-5-carboxylate (Step 4, 0.09 g, 0.28 mmol) in 2.0M ammonia in MeOH (2.8 mL) is heated to 55° C. for 4 h. The reaction mixture is cooled, concentrated and the residue purified by pTLC (5% MeOH/CH2Cl2) to give the title compound (50 mg, 58%); MS for C14H13F2N3O3MS m/z 310.5 (M+H)+; 1H NMR (300 MHz, d6-DMSO): δ 3.93–3.98 (m, 1H), 4.17–4.25 (m, 5H), 4.97–5.02 (m, 1H), 5.93 (s, 2H), 7.27 (d, 2H), 7.61 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][C:20]=2[CH3:33])=[O:18])=[C:13]([Cl:34])[CH:12]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:34][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[CH3:9])[CH:16]=[CH:15][C:14]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][C:20]=1[CH3:33])=[O:18]
Reactant: Cc1cc(F)ccc1Br
Reactant: Cc1cc(C(=O)N2CCOCC2)ccc1C(=O)c1ccc(N)cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2ccc(C(=O)N3CCOCC3)cc2C)c(Cl)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
2-Bromo-5-fluorotoluene (56 μL, 0.44 mmol) was dissolved in 3 mL dry 1,4-dioxane in a vial under an argon atmosphere. Compound 468 (132 mg, 0.37 mmol) was added and dissolved in the solvent. Rac-BINAP (8.6 mg, 0.014 mmol), Pd2(dba)3 (8.5 mg, 0.009 mmol) and Cs2CO3 (169 mg, 0.52 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 100° C. for 48 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/DCM 1:3 as the eluent to afford the title compound as yellow foam. 13C NMR (CDCl3) δ 195.5, 169.8, 160.7, 150.2, 141.1, 138.1, 137.2, 136.5, 135.7, 134.2, 133.6, 129.7, 129.2, 127.3, 127.3, 123.9, 117.9, 115.2, 113.9, 111.5, 66.9, 48.2, 42.5, 20.2, 18.1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:21][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])=[N:7][C:2]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1Cl
Reaction time: 3 h
Yield: 34 %

Procedure:
A solution of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)propanamide A30 (50 mg, 0.15 mmol), 4-amino-1-methylpyrazole (15 mg, 0.015 mmol) and p-toluenesulfonic acid (3.0 mg, 0.015 mmol) in 1,4-dioxane (2 mL) was heated at 80° C. under microwave irradiation for 3 hours, then at 120° C. for 3 hours and finally at 140° C. for 2 hours. The mixture was partitioned between water and EtOAc, the layers were separated and the aqueous phase was extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to give the crude product. Purification by silica gel column chromatography (Combiflash Rf, 0-10% MeOH in DCM) gave the title compound 36 as a pale solid (0.020 g, 34%). 1H NMR (300 MHz, CDCl3) δ 1.57 (d, J=7.26 Hz, 3H), 3.04-3.15 (m, 4H), 3.91 (s, 3H), 4.00 (q, J=6.97 Hz, 1H), 5.59 (brs, 2H), 7.19-7.31 (m, 3H), 7.34 (brs, 1H), 7.38-7.41 (m, 1H), 7.49 (s, 1H), 7.71 (s, 1H), 8.25 (s, 1H). LCMS-B: rt 6.09 min; m/z 385 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:11][CH3:12])[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[C:1]1([N:7]=[C:8]([S:11][CH3:12])[CH:9]=[CH:10][S:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: C#CC(=Nc1ccccc1)SC
Solvent: ClC(Cl)Cl
Product: CSC(C=CSc1ccc(C)cc1)=Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
Methyl N-phenylpropynthioimidate (0.30 g) was dissolved to chloroform (5 ml), 4-methylthiophenol (0.19 g) was added dropwise under ice-cooling and stirred for 15 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain methyl N-phenyl-3-(4-methylphenylthio)thioacrylimidate (0.20 g) as light yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH:34]([C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2/[CH:12]=[CH:34]/[C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1nccs1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (340 mg) obtained in Example 321b) in THF (5 ml) was added sodium hydride (50% oil dispersion, 55 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. A solution of 2-formylthiazole (86 mg) in THF (1 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 2 hr. The resultant precipitate was collected by filtration to give the title compound as a white solid (149 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Yield: 58.1 %

Procedure:
To a stirred and cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 mL) was added diisopropyl azodicarboxylate (DIAD) (11.4 mL, 0.06 mol), and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (30 mL) and TFA (30 mL). The resulting solution was stirred at room temp for 30 min., and the solution was evaporated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3:MeOH (9:1, v/v) as eluent to give 6.63 g (2 steps, 60%) benzyl (S)-4-(2-amino-1-propoxy)benzoate as a yellow oil. 1H-NMR (CDCl3) δ1.18 (d, J=6.3 Hz, 3 H), 3.35-3.39 (m, 1 H), 3.71-3.75 (m, 1 H), 3.90-3.93 (m, 1 H), 5.34 (s, 2 H), 6.90-6.93 (m, 2 H), 7.32-7.46 (m, 5 H), 8.01-8.04 (m, 2 H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[C:8]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[C:8]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)c2ccccc2N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1(N2C(=O)c3ccccc3C2=O)C(=O)N(c2ccccc2)c2ccccc21
Yield: 50 %

Procedure:
A mixed solution of 3.54 g of 1-phenyl-3-(1,3-dioxoisoindolin-2-yl)-2,3-dihydro-1H-indol-2-one, 8.4 g of ethyl bromoacetate, 2.76 g of potassium carbonate and 40 ml of acetone was stirred under argon atmosphere at room temperature overnight. After removing the solvent, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed and dried, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:ethanol=40:1 (v.v)) and recrystallized from ether to obtain 2.20 g of 1-phenyl-3-(ethoxycarbonylmethyl)-3-(1,3-dioxoisoindolin-2-yl)-2,3-dihydro-1H-indol-2-one as colorless prism crystals. Melting point: 148° to 149° C., IR (Nujol) (cm-1 ): 1780, 1740, 1720, 1610, MS (DI, m/z): 440 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 35.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 2-fluoro-5-trifluoromethyl aniline (0.070 g, 0.39 mmol) and trimethyl aluminium (2M solution in toluene (0.5 mL) to afford 0.049 g of desired product. 1H NMR (DMSO-d6): δ 4.05 (s, 3H), 7.50 (t, J=8.4 Hz, 1H), 7.57-7.70 (m, 3H), 7.72-7.77 (m, 2H), 7.85 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.67 (d, J=6.3 Hz, 1H), 10.38 (br s, 1H), 12.82 (br s, 1H); MS (m/z): 525.15 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[S:3].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=2)[CH2:18][CH2:17]1>O1CCCC1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][NH:13][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N+:10]([O-:12])=[O:11])=[S:3])[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 1.8 parts of 1-isothiocyanato-2-nitrobenzene, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 3.7 parts (67%) of N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]-N'-(2-nitrophenyl)thiourea as a residue.