Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:8]([F:19])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](C(=O)C)[N:11]=[CH:10]2)(=O)C.O1CCCC1.Cl>CO>[F:19][C:8]1[C:7]([OH:6])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2
Reactant: CC(=O)Oc1ccc2c(cnn2C(C)=O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2[nH]ncc2c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.1 %

Procedure:
A 6N aqueous sodium hydroxide solution (5 ml, 30 mmol) was added dropwise to a solution of 1-acetyl-4-fluoro-1H-indazol-5-yl acetate (995 mg, 3.78 mmol) in methanol (5 ml)-tetrahydrofuran (5 ml) at room temperature, and the resulting mixture was stirred for 3.5 hours while being maintained at room temperature. The resulting reaction solution was adjusted to pH 5 to 6 by dropwise addition of a 1N aqueous hydrochloric acid solution (about 25 ml) and extracted with ethyl acetate, and the organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 4-fluoro-1H-indazol-5-ol (219 mg, 38%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1([CH3:18])[O:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[O:10][O:9]1)=O)C.[NH2:19][NH2:20].C(OCC)(=O)CCC(C)=O>OC(C)CC(OO)(C)C>[CH3:18][C:8]1([CH2:7][CH2:6][C:4]([NH:19][NH2:20])=[O:3])[O:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[O:10][O:9]1
Reactant: NN
Reactant: CCOC(=O)CCC1(C)OOC(C)(C)CC(C)O1
Agent: CC(O)CC(C)(C)OO
Agent: CCOC(=O)CCC(C)=O
Product: CC1CC(C)(C)OOC(C)(CCC(=O)NN)O1
Yield: 88 %

Procedure:
3-(1,4,4,6-Tetramethyl-2,3,7-trio-xacycloheptyl)propionhydrazide was prepared by reacting 3-(ethoxycarbonylethyl)-3,5,7,7-tetramethyl-1,2,4-trioxacycloheptane with 9 molar excess of 54% aqueous hydrazine. 3-(Ethoxycarbonylethyl)-3,5,7,7-tetramethyl-1,2,4-trioxacycloheptane was initially prepared in an assay of 89% and a corrected yield of 88% by reacting ethyl levulinate with 10% molar excess of 3-hydroxy-1,1-dimethylbutyl hydroperoxide using 70% aqueous sulfuric acid as a catalyst/dehydrating agent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C)C=O.O>C(Cl)(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of 3-chloro-4-fluoronitrobenzene (5 g, 27.1 mmol), 1-piperazinecarboxylic acid t-butyl ester (5 g, 26.8 mmol) and dimethylformamide (10 mL) was stirred for 3 hours and 30 minutes at an external temperature of 130° C. After adding water to the air-cooled reaction mixture, extraction was performed 3 times with chloroform. The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel colurn chromatography (ethyl acetate/heptane) to give 5.93 g of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2C=CC=C[C:29]=2N=N1.C1CCN2C(=NCCC2)CC1.[O-]CC.[Na+]>CCO>[CH2:29]([O:18][C:4]1[C:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1)[CH3:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Nc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc2sc(-c3ccc(F)cc3)cc12
Temperature: 60 °C
Yield: 54.6 %

Procedure:
To a solution of 2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (50 mg, 0.19 mmol) and BOP (110 mg, 0.25 mmol) in EtOH (1 ml) was added DBU (43 μl, 0.29 mmol). The resulting mixture was heated at 60° C. for 4 hours. After cooling down to room temperature, sodium ethoxide (26 mg, 0.38 mmol) was added. The mixture was again heated at 60° C. overnight. The solvents were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) yielding the title compound as a white solid (30 mg, 54%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[N:5]=1)([CH3:3])=[CH2:2].[Cl:12]N1C(=O)CCC1=O.C(OO)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[N:5]=1)=[CH2:3]
Reactant: C=C(C)c1cccc(OC)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C)OO
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1cccc(OC)n1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
A mixture of 13.6 g of 2-isopropenyl-6-methoxypyridine, 16.3 g of N-chlorosuccinimide, 0.2 g of t-butylhydroperoxide and 30 ml of carbon tetrachloride was stirred at 140° C. for 5 hours while being irradiated with light. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered out. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane 1:25) to obtain the following three fractions: 4.75 g of a first fraction (objective product/byproduct=0.2), 5.99 g of a second fraction (objective product/byproduct=0.714) and 0.41 g of a third fraction (objective product=1.0).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=[O:10].Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:37]([CH2:39][N:40]3[C:48](=[O:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:50])[N:38]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:37]([CH2:39][N:40]3[C:41](=[O:50])[C:42]4[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:48]3=[O:49])[N:38]=2)[CH2:30][CH2:29]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1sc(N2CCC(N)CC2)nc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared from 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) and ethyl 2-(4-aminopiperidin-1-yl)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazole-5-carboxylate hydrochloride (Intermediate 77) in a manner analogous to Example 29.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[OH:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1>>[Cl:12][C:13]1[N:14]=[N:15][C:16]([O:11][CH:4]2[CH:5]3[CH2:10][N:1]4[CH2:8][CH:7]([CH2:9][CH:3]2[CH2:2]4)[CH2:6]3)=[CH:17][CH:18]=1
Reactant: OC1C2CC3CC1CN(C3)C2
Reactant: Clc1ccc(Cl)nn1
Product: Clc1ccc(OC2C3CC4CC2CN(C4)C3)nn1

Procedure:
Prepared from 1-azaadamantan-4-ol (3:2 diastereomer mixture; 150 mg, 0.979 mmol; see WO 9215579) and 3,6-dichloropyridazine (182 mg, 1.22 mmol; Aldrich) according to Method B to afford the title compound as a mixture of stereoisomers: MS (DCI/NH3) m/z=266 (M+H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[CH3:14][O:15][C:16](=[O:25])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:25])[C@@H:17]([NH:18][C:2](=[O:4])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)c1ccccc1N)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a mixture of isatoic anhydride (250 mg, 1.53 mmol) and (S)-2-phenylglycine methyl ester hydrochloride (370 mg, 1.84 mmol) in DMF (5.0 mL) is added triethylamine (0.29 mL, 2.07 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated to afford (S)-(2-amino-benzoylamino)-phenyl-acetic acid methyl ester (330 mg, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CO>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH:19][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)aniline (10.6 g) and pyridine (8 ml) in dichloromethane (75 ml) was added dropwise ethanesulfonyl chloride (4.1 ml) in an ice bath and the mixture was stirred at room temperature for 5 hours. After addition of methanol (1 ml), the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (11.7 g, yield 84%) as a pale pink solid.
Reaction SMILES: C(O)C.C(O[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)=[O:8])C.CC[O-].[Na+].[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=O)N2
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Yield: 9.5 %

Procedure:
To 100 ml of ethanol was added 2.0 g of 6-ethoxycarbonyl-3,4-dihydrocarbostyril, 0.5 g of sodium ethylate and 1.6 g of benzylpiperazine, the mixture was reacted in an autoclave under 110 atmospheric pressure at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and the chloroform solution was washed with 1%-potassium carbonate aqueous solution, a diluted hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated by means of a silica gel column chromatography (Silica gel: Wako C-200, eluate: chloroform:methanol (volume/volume)=20:1) and the crude crystals were recrystallized from ethanol to obtain 300 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihyrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([CH2:15][C:16]([O:18]CC)=O)[N:13]=[C:12]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([CH2:15][C:16]([NH:32][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:18])[N:13]=[C:12]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)Cn1nc(-c2ccncc2)nc1-c1ccc(OC)c(Cl)c1
Reactant: NC1CCCC1
Product: COc1ccc(-c2nc(-c3ccncc3)nn2CC(=O)NC2CCCC2)cc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of ethyl {5-[3-chloro-4-(methyloxy)phenyl]-3-pyridin-4-yl-1H-1,2,4-triazol-1-yl}acetate (0.2 mmol) and cyclopentylamine (4 mL) were heated to reflux for 2 h. The mixture was cooled to room temperature and the excess cyclopentylamine was removed in vacuo. The crude solid was then triturated with methanol to afford the pure product (0.061 g, 75%). 1H NMR (400 MHz, d6-DMSO): δ 8.68 (dd, 2H), 7.92 (22, 2H), 7.82 (m, 1H), 7.75 (dd, 1H), 7.33 (d, 1H), 4.95 (s, 2H), 4.00 (m, 1H), 3.94 (s, 3H), 1.80 (m, 2H), 1.64 (m, 2H), 1.51 (m, 2H), 1.40 (m, 2H). MS (EI) for C21H23ClN5O2: 412 (MH+).
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47](I)=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:51]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[C:52]#[CH:53]>CN(C=O)C.[Cu](I)I>[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47]([C:53]#[C:52][CH2:51][NH:54][S:55]([CH3:58])(=[O:57])=[O:56])=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(I)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C#CCNS(C)(=O)=O
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CCNS(C)(=O)=O)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
Triethylamine (0.07 mL, 0.502 mmol) was added to a stirred solution of 4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-iodophenyl)-4-oxoazetidin-2-yl]phenyl methyl β-D-glucopyranosiduronate (i-7) (0.050 g, 0.071 mmol), N-prop-2-yn-1-ylmethanesulfonamide (i-5) (0.014 g, 0.105 mmol), tetrakistriphenylphosphine palladium(0) (0.012 g, 0.010 mmol) and copper iodide (0.005 g, 0.026 mmol) in DMF (0.5 mL) under a nitrogen atmosphere and the resulting solution aged at room temperature for 18 h. The volatiles were evaporated in vacuo and the crude residue purified by flash chromatography on silica gel (gradient elution; 0-25% methanol/methylene chloride as eluent) to afford the title compound; m/z (ES) 713 (MH+), 505.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[H-].[Na+].CN(C)C=O.Br[CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39]1>C(OCC)(=O)C>[CH:43]1([N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:29]=[C:5]23)[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: BrC1C=CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2C=CCCC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (5 g), sodium hydride (0.62 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 10 min, 3-bromocyclohexene (1.8 mL) was added, and the mixture was stirred at the same temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1 g, 17%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][Cl:31])=[CH:28][CH:27]=1>O1CCCC1.CCOCC>[ClH:31].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][S:8][C:6]2[NH:7][C:2]([CH3:1])=[C:3]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:5]=2)=[CH:28][CH:27]=1
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)NC(=S)N1
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CSC2=NC(c3cccc([N+](=O)[O-])c3)C(C(=O)OC(C)C)=C(C)N2)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(+)-1,2,3,4-Tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, 1-methylethyl ester (2.6 mmol, 884 mg) was dissolved in dry tetrahydrofuran and cooled to 0° C. 4-Methoxybenzyl chloride (1.1 eq, 32.9 mmol, 393 μl) was added dropwise. After the addition was complete, the bath was removed and the reaction stirred at room temperature for two hours. The mixture was then heated at 65° C. for 16 hours. TLC 35:65:acetone:hexane showed an incomplete reaction, so additional 4-methoxybenzyl chloride (0.5 eq, 1.3 mmol, 176 μl) was added to the mixture. After seven hours at 65° C., the mixture was allowed to come to room temperature and diluted with ether. As the mixture cooled to 0° C., a white solid formed. The solid was collected by suction filtration, washed with ether, and dried to afford (+)-1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester hydrochloride, 493 mg (38%).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:5].O.Cl>O1CCCC1.C(OCC)(=O)C>[OH:5][CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH3:1]
Reactant: NC(=O)c1cccc(C=O)n1
Reactant: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(C(N)=O)n1

Procedure:
An ethereal solution of methyl magnesium bromide (3 mol/l) (546 ml) was added dropwise to a solution of 6-formyl-2-pyridinecarboxamide (61.5 g) in tetrahydrofuran (900 ml) at 0°-13° C. with stirring. After the mixture was stirred at the same temperature for 2 hours and cold water was dropped to the reaction mixture under ice-cooling. To the mixture was added ethyl acetate and adjusted to pH 7 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 6-(1-hydroxyethyl)-2-pyridinecarboxamide (63.2 g) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.CI.[C:15](=O)([O-])O.[K+]>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]([O:12][CH3:15])=[O:11])[CH2:7][CH2:8][CH2:9]1
Reactant: O=C([O-])O
Reactant: O=C(O)C1(c2cccs2)CCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(c2cccs2)CCC1

Procedure:
1-(2-Thienyl)cyclobutanecarboxylic acid, methyl iodide, and potassium hydrogen carbonate were reacted in DMF at room temperature to obtain methyl 1-(2-thienyl)cyclobutanecarboxylate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1COc1cccc(C(C)=O)c1
Yield: 80.9 %

Procedure:
3.0 g (0.022 mol) of 3-hydroxyacetophenone and 6.0 g (0.021 mol) of methyl 2-bromomethylphenylglyoxylate O-methyloxime are dissolved in 30 ml of dimethylformamide, and 5.5 g (0.040 yol) of potassium carbonate are added. The mixture is stirred at room temperature for 24 hours, hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.8 g (85%) of methyl 2-(3-acetylphenoxymethyl)phenylglyoxylate O-methyloxime are obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([F:13])=[C:9]([Cl:12])[C:10]=1[OH:11])C(O)=O.CN(C)C=O.C(=O)=O.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([F:14])=[CH:4][C:8]([F:13])=[C:9]([Cl:12])[C:10]=1[OH:11]
Reactant: O=C(O)c1c(F)c(Cl)c(O)c(Cl)c1F
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Oc1c(Cl)c(F)cc(F)c1Cl

Procedure:
50 g of 3,5-dichloro-2,6-difluoro-4-hydroxybenzoic acid and 10 ml of dimethylformamide are mixed, and the mixture is heated. Carbon dioxide is evolved at 105°-130° C., and the mixture is allowed to react at this temperature until the reaction is complete. After this, 200 ml of toluene and then 80 ml of water are stirred in, the phases are separated, and the organic phase is dried and then distilled. This gives 34 g of the product having a boiling point of 87°-88° C. and a refractive index of [n]D20 : 1.5310.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:31])[C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Reaction time: 0.25 h

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisoxazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (10.5 g, 0.0255 mol) and potassium carbonate (7.04 g, 0.051 mol) in N,N-dimethylformamide is stirred for 15 minutes, treated with methyl iodide (7.24 g, 0.051 mol), stirred overnight, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacua to obtain a brown glass. Dry column chromatography of the glass using silica gel and a hexanes/ethyl acetate solution (3:1) gives the title product as an off-white solid which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[C:8](=[O:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][CH:4]2[CH2:3]1.[C:17]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([OH:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][CH:4]2[CH2:3]1
Reactant: [Li]c1ccccc1
Reactant: CN1CCC2C(=O)c3ccccc3SC2C1
Solvent: CCOCC
Solvent: O
Product: CN1CCC2C(C1)Sc1ccccc1C2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
40 g of 1,2,3,4,4a,10a-hexahydro-2-methyl-5H-[1]-benzothiopyrano[2,3-c]pyridin-5-one were dissolved in 2 liters of dry ether and the solution obtaining was cooled to 5° C. in an ice bath while 220 ml (2 moles) of phenyl lithium were added dropwise thereto over 30 minutes with the temperature held below 0° C. When the addition was complete, the ice bath was removed and the solution thus obtained was stirred at room temperature for 30 minutes. 3 liters of water were added dropwise thereto and the resultant suspension was stirred vigorously for 2 hours and then was filtered. The product was washed with water and ether and was dried to obtain 20.5 g of 2-methyl-5-phenyl-1,3,4,4a,5,10a-hexahydro-2H[1]benzothiopyrano[2,3-c]pyridin-5-ol (37% yield) melting at 176°-181° C.