Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CC=Cc1cccc(C)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)c1

Procedure:
A 20% sodium hydroxide solution (5 ml.) is added to a stirred solution of p-chlorobenzaldehyde(14 g., 0.1 mole) and 3-phenyl-6-(m-methylphenyl)-5-hexen-2-one (25.24 g., 0.096 mole) in ethanol (250 ml.). The yellowish solid that separates on continued stirring is collected, washed with cold ethanol, and air-dried, yield 34.9 g., m.p. 89°-93°C. Recrystallization from ethanaol produces material with m.p. 95°-98°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:20]=[C:12]3[CH:13]([C:17](O)=[O:18])[CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O.C(OCC)(=O)C>[C:28]1([NH:27][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:11]3[N:10]=[C:9]([C:7]4[CH:6]=[CH:5][C:4]([N:21]5[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]5)=[C:3]([O:2][CH3:1])[N:8]=4)[N:20]=[C:12]23)=[O:18])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1nc(-c2nc3n(n2)CCCC3C(=O)O)ccc1-n1cnc(C)c1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc(-c2nc3n(n2)CCCC3C(=O)Nc2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid obtained in Preparation Example 5-1 (25 mg) was dissolved in N,N-dimethylformamide (0.5 mL). Aniline (7.2 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (40.6 mg), 1-hydroxybenzotriazole (28.6 mg) and N,N-diisopropylethylamine (75.7 μL) were sequentially added and the mixture was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the organic layer and the aqueous layer were separated. The aqueous layer was further extracted with ethyl acetate. The resulting organic layers were combined, sprayed with nitrogen gas and concentrated. The residue was purified by NH silica gel column chromatography to obtain the title compound (14.1 mg). The compound was further separated by CHIRALPAK™ IA (2 cm×25 cm; mobile phase:hexane:ethanol=50:50) to obtain the title compound with a retention time of 7.6 minutes (4.5 mg). The property values of the compound are as follows.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].[Cl-].[NH4+]>CN(C=O)C>[CH:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([C:16]([N:15]([CH3:19])[CH3:14])=[O:17])[CH:2]=[CH:3]2)=[O:11]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CN(C)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)n1ccc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of 1H-indole-5-carbaldehyde (0.87 g, 6 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.36 g, 9 mmol) portionwise at 0° C. under argon. The reaction mixture was stirred at 0° C. for 10 min and rt for 20 min before dimethylcarbamic chloride was added dropwise at 0° C. After the reaction mixture was stirred at 0° C. for 10 min and rt for 2 hr, saturated ammonium chloride aqueous solution (10 mL) was added to quench the reaction. The reaction mixture was concentrated, diluted with water (10 mL) and extracted with dichloromethane (20 mL). The dichloromethane extract was dried (Na2SO4) and concentrated. Silica gel flash chromatography gave 5-formyl-N,N-dimethyl-1H-indole-1-carboxamide (1.3 g, 5.8 mmol, 97% yield) as a white solid, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC1C=CC2C(=CC=CC=2)C=1.BrC1C=CC(C=[O:38])=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCCCCC>[C:14]1([P:7](=[O:38])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
0.50 g (1.91 mmol) of triphenylphosphine, 0.42 g (1.90 mmol) of 2-bromomethylnaphthalene, 0.36 g (1.98 mmol) of p-bromobenzaldehyde, and 0.50 g (3.62 mmol) of K2CO3 were placed in a hardened-steel vial in a glove box under helium. The vial was sealed, and the sample was ball-milled for eight hours. The formed powder was first analyzed by solid state 31P{1H} CP MAS NMR spectroscopy, then loaded on a silica gel chromatography column, and the mixture of (E)- and (Z)-1-(p-bromophenyl)-2-(naphthyl)ethylenes (VII) (E:Z ratio ca. 3.5:1 by 1H NMR in CDCl3) was isolated in 93% yield, (0.54 g ) by eluation with hexane and toluene. Triphenylphosphine oxide was further obtained from the same column in 92% yield (0.53 g) using a hexane-acetone mixture as an eluant. The separation and purification of the E-isomer was performed according to the previously described procedure (Brooks et al., J. Am. Chem. Soc. 121, 5444 (1999)) by the column chromatography on silica gel.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:21]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)=[CH:17][NH:18]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:16]2[C:15]3[C:19](=[CH:20][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:13][CH:14]=3)[NH:18][CH:17]=2)[CH2:22]1)=[O:32]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3c(C4CCCNC4)c[nH]c3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[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)N1CCN(C(=O)c2ccc3c(C4CCCN(C(=O)c5cc(F)cc(F)c5)C4)c[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
A mixture of 0.02 g (0.56 mmol) (4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone, 0.01 g (0.06 mmol) 3,5-difluorobenzoic acid, 0.02 g (0.06 mmol) TBTU and 0.044 g (0.3 mmol) DIPEA in 0.8 mL DMF was stirred at room temperature for 16 h. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. Evaporation of the product fractions yielded 16 mg (57%) of the title compounds as off-white foam. MS (m/e): 495.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:15](=[O:34])[C@H:16]([CH2:28][C:29]2[N:33]=[CH:32][NH:31][CH:30]=2)[NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C1C=C2N=NN(O)C2=CC=1.O.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH2:62](OC(=O)CN)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.CCN(CC)CC>CN(C=O)C>[C:63]1([CH2:62][O:13][C:12](=[O:14])[CH2:11][N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:15](=[O:34])[C@H:16]([CH2:28][C:29]2[N:33]=[CH:32][NH:31][CH:30]=2)[NH:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COc1ccc(CN(CC(=O)O)C(=O)[C@H](Cc2c[nH]cn2)NC(=O)OCc2ccccc2)cc1
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN(CC(=O)OCc2ccccc2)C(=O)[C@H](Cc2c[nH]cn2)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of the acid from Step 3 (0.41 g, 0.88 mmol) in DMF (5 mL) was added HOBT hydrate (0.16 g, 1.05 mmol) and DCC (0.22 g, 1.05 mmol) followed by glycine benzyl ester hydrochloride (0.18 g, 0.88 mmol). Et3N (0.12 mL, 0.88 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was diluted with CHCl3, washed twice with saturated NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (2-5% MeOH/CHCl3) gave 0.29 g (54%) of the title compound as a white foam; ES-MS 614 (m+1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27]2[N:28]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]3[N:30]=[C:31]([NH2:35])[N:32]=[CH:33][C:34]=3[C:26]=2[CH:25]=[CH:24][N:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C(Cl)Cl.CO.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:21][C:22]1[C:27]2[N:28]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]3[N:30]=[C:31]([NH:35][C:2]4[N:7]=[CH:6][C:5]([N:8]5[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]5)=[CH:4][CH:3]=4)[N:32]=[CH:33][C:34]=3[C:26]=2[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reactant: Nc1ncc2c3ccnc(Cl)c3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5ccnc(Cl)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 80 °C
Yield: 72.6 %

Procedure:
Compound 196 (0.178 g, 0.521 mmol), compound 194 (0.125 g, 0.434 mmol), and LiHMDS 1M in THF (1.30 mL, 1.30 mmol) were combined in 5 mL of anhydrous toluene. N2 was bubbled through the solution briefly before adding Pd2(dba)3 (0.0298 g, 0.0326 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0377 g, 0.0652 mmol). The solution was then heated to 80° C. for 2 hours with microwave irradiation. The solution was diluted with DCM before it was poured into sat's NH4Cl. Partitioned the layers and washed the aqueous layer with 10% i-PrOH/DCM. The combined organics were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified on CombiFlash column (dry loaded), eluting with a gradient of 60% ethyl acetate/hexane to 100% ethyl acetate. The fractions containing the product were combined and concentrated under vacuum. The residue obtained was repurified on CombiFlash column (dry loaded), eluting with a gradient of 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 4% methanol/0.2% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum. The residue obtained was sonicated in methanol. Filtration provided an off-white solid as compound 197 (0.173 g, 72%). LCMS-ESI (POS), M/Z, M+1: Found 549.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:14])=[C:11]([F:13])[F:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]([F:13])([F:12])[CH:10]([F:14])[F:9])=[CH:4][CH:3]=1
Reactant: FC(F)=C(F)F
Reactant: Oc1ccc(Cl)cc1
Product: FC(F)C(F)(F)Oc1ccc(Cl)cc1

Procedure:
4-Chlorophenol reacts under basic catalysis with tetrafluoroethylene to give 1-chloro-4-(1,1,2,2-tetrafluoroethoxy)benzene as a colorless oil of b.p. 68° at 12 Torr. [For example, see J. Am Chem. Soc. 73, 5831 (1951) and Chem. Abstr. 73, 36584q.]
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[O:28][CH2:29][CH3:30])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[H-].[Na+].[CH2:43](I)[CH3:44].O>CN(C)C=O.C(OCC)(=O)C>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:43][CH3:44])[C:27](=[O:31])[O:28][CH2:29][CH3:30])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1
Reactant: CCOC(=O)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (980 mg) is dissolved in N,N-dimethylformamide (10 ml), and thereto is added sodium hydride (60%) (91 mg) under ice-cooling, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (182 μl) and the mixture is stirred at room temperature overnight. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (425 mg). MS (m/z): 673/675 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([N:9]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:8])=[CH:5][C:4]=1[N+:25]([O-])=O>ClCCl.CO.[Pd]>[NH2:25][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:3]=1[NH:2][CH3:1])[C:7]([N:9]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccn1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1

Procedure:
The process disclosed in WO 98/37075 also involves the reduction of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “nitro compound”) using Pd—C in a mixture of dichloromethane and methanol under hydrogen pressure to provide ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “diamine compound”).
Reaction SMILES: [C:1]1([S:7][C:8](=[C:16]([C:19]#[N:20])[C:17]#[N:18])SC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[NH2:20][C:19]1[N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=[C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]=1[C:17]#[N:18]
Reactant: NNc1ccccc1
Reactant: N#CC(C#N)=C(Sc1ccccc1)Sc1ccccc1
Solvent: CO
Product: N#Cc1c(Sc2ccccc2)nn(-c2ccccc2)c1N
Yield: 94 %

Procedure:
A mixture comprised of 14.7 g (50 mmol) of bis (phenylthio)methylenepropanedinitrile [see Chem. Ber., 99, 2900 (1966)], 6.5 g (60 mmol) of phenylhydrazine and 80 ml of methanol was heated under reflux for 7 hours. The solvent was removed by distillation, and 100 ml of ethanol was added to the residue to crystallize the residue. The crystals formed were taken out by filtration under suction to obtain 13.7 g (47mmols) of the intended product as colorless, needle-like crystals having a melting point of 172° to 173° C. The yield was 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12]([NH2:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH2:42][CH3:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:16]([O:15][C:14]1[C:13](=[O:23])[C:12]([NH:24][C:41](=[O:44])[CH2:42][CH3:43])=[CH:11][N:10]([CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[C:9]=1[C:7](=[O:8])[NH:6][CH2:5][C:4]1[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(=O)Cl
Reactant: COC(Cn1cc(N)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Reaction time: 0.33 h

Procedure:
To a solution of 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (55 mg) in chloroform (1 ml) were added, triethylamine (0.033 ml) and propanoyl chloride (0.012 ml) at 0° C. After stirring at the same temperature for 20 min, aqueous sodium hydrogen carbonate solution was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried, concentrated and purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give N-[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]propionamide (55 mg). By subjecting 51 mg of the obtained compound to a reaction operation similar to that in Example 187, Step 2, N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]propionamide (27 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)c1

Procedure:
The title compound was prepared from 2′-chloro-4-methyl-6-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.94) (0.349 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.267 g, 50%). MS (ISP) 532.1 [(M+H)+]; mp 209° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=2[C:4]([O:6][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:5])=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)cc1)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1

Procedure:
To a solution of 2-hydroxy-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 117; 2 g, 9.70 mmol) in acetone (50 ml) was added 1-(bromomethyl)-4-fluorobenzene (4.04 g, 21.35 mmol), potassium carbonate (4.02 g, 29.1 mmol) and the reaction was heated to reflux overnight. The mixture was filtered to remove the solid potassium carbonate. The solid was washed with acetone (50 ml). The organics were combined and evaporated under reduced pressure on a buchi to yield the title compound. The crude yellow oil was used directly without further purification. 4.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH:7](C(OCC)=O)[CH:6]1[CH3:17])=[O:4].C(O)(=O)C(O)=O>O>[CH3:17][CH:6]1[CH2:7][C:8](=[O:11])[CH2:9][CH2:10][N:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: CCOC(=O)C1C(=O)CCN(C(=O)OC)C1C
Agent: O=C(O)C(=O)O
Solvent: O
Product: COC(=O)N1CCC(=O)CC1C

Procedure:
76 parts of ethyl 1-(methoxycarbonyl)-2-methyl-4-oxo-3-piperidinecarboxylate are hydrolyzed with 600 parts of ethanedioic acid solution 14% in water and the whole is stirred and refluxed for 40 hours. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is distilled, yielding methyl 2-methyl-4-oxo-1-piperidinecarboxylate; bp. 96°-99° C. at 0.2-9.3 mm. pressure.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].CCOCC>Br.C(O)(=O)C>[C:1]([S:4][CH:5]([CH2:9][CH2:10][CH2:11][NH2:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)SC(CCCN)C(=O)O

Procedure:
A solution of 2-acetylthio-5-benzyloxycarbonylaminopentanoic acid (1.6 g.) in 2 N hydrobromic acid in acetic acid (10 ml.) is kept at room temperature for thirty minutes. Ether is added to maximum precipitation and the supernatant is decanted. The residue is dissolved in water and applied to a column of Dowex 50 in the hydrogen cycle. The column is washed with water, and 2-acetylthio-5-aminopentanoic acid is eluted with M pyridine-acetic acid buffer pH 6.5.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[N:19]=[C:18](Cl)[S:17][N:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH:26]([N:33]2[CH2:34][CH2:35][N:36]([C:18]3[S:17][N:16]=[C:15]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:8][CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:19]=3)[CH2:37][CH2:38]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Clc1nc(C(OC2CCCCO2)c2ccccc2)ns1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1ccc(C(c2ccccc2)N2CCN(c3nc(C(OC4CCCCO4)c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[1-phenyl-1-(tetrahydropyran-2-yloxy)methyl]-5-chloro-[1,2,4] thiadiazole (1.56 g, 5.02 mmol) in DMF (25 mL) was added 1-(4-chlorobenzhydryl) piperazine (2.88 g, 10.04 mmol) followed by triethylamine (2.03 g, 20.08 mmol). The resulting mixture was stirred at room temperature for 2 days. Volatile materials were removed in vacuo and the residue was partitionned between dichloromethane and water. The organic layer was collected, dried (sodium sulfate), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (8/2) thereby affording 1 -[(4-chlorophenyl)phenylmethyl]-4-{3-[phenyl-(tetrahydropyran-2-yloxy)methyl]-[1,2,4]thiadiazol-5-yl}-piperazine (1.90 g, 67%) as a white solid and as a mixture of diastereoisomers. 1H-NMR (CDCl3) δ7.55 (d, J=7.8 Hz, 1H), 7.22-7.39 (m, 13H, Ar--H), 5.89 and 5.85 (s, 0.4H and 0.6H each, αH), 4.90 and 4.64 (t, J=3.2 Hz, 0.4H and 0.6H each, OCHO), 4.29 (m, 1H, CH-Ar), 3.60-4.05 (m, 1H, OCH2), 3.50 (m, 5H, 2CH2 +1H, OCH2), 2.49 (m, 4H, 2CH2), 1.50-1.94 (m, 6H, 3CH2).