Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:14][CH2:13][NH:12][C@H:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C@H:3]2[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.[C:20]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[C:35](O)=[O:36])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(#N)C>[CH3:1][C@@:2]12[CH2:14][CH2:13][N:12]([C:35]([C@H:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]3[NH:28][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:36])[C@@H:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C@@H:3]2[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1
Reactant: C[C@]12CCN[C@H]1c1ccccc1N[C@H]2c1ccsc1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@]12CCN(C(=O)[C@H]3CCCC[C@H]3NC(=O)c3ccccc3)[C@@H]1c1ccccc1N[C@@H]2c1ccsc1
Reaction time: 0.17 h
Yield: 7.9 %

Procedure:
To a mixture of (3aS*,4R*,9bR*)-3a-methyl-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (750 mg, 2.77 mmol), (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (685 mg, 2.77 mmol), triethylamine (606 mg, 6.10 mmol), acetonitrile (14 ml) and tetrahydrofuran (14 ml) was added DEPC (500 mg, 3.05 mmol) under ice-cooling, and the mixture was stirred for 10 min. The mixture was allowed to return to room temperature and stirred for 12 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g), and eluted with hexane-ethyl acetate (4:1-1:1, v/v) to give the title compound (3aR,4R,9bR) (110 mg, 8%) as an amorphous form from the first eluted fraction.
Reaction SMILES: [ClH:1].[CH3:2]OC1C=CC2OC=C(CCCN3CCN(C4C(OC)=CN=CN=4)CC3)C=2C=1.S(O[CH2:41][CH2:42][CH2:43][C:44]1[C:45]2[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:46]=2[O:47][CH:48]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:55][O:56][C:57]1[C:58]([N:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)=[N:59][CH:60]=[CH:61][CH:62]=1>>[ClH:1].[CH3:54][O:53][C:51]1[CH:50]=[CH:49][C:46]2[O:47][CH:48]=[C:44]([CH2:43][CH2:42][CH2:41][N:66]3[CH2:67][CH2:68][N:63]([C:58]4[C:57]([O:56][CH2:55][CH3:2])=[CH:62][CH:61]=[CH:60][N:59]=4)[CH2:64][CH2:65]3)[C:45]=2[CH:52]=1
Reactant: COc1cccnc1N1CCNCC1
Reactant: COc1ccc2occ(CCCOS(=O)(=O)c3ccc(C)cc3)c2c1
Reactant: COc1ccc2occ(CCCN3CCN(c4ncncc4OC)CC3)c2c1
Agent: Cl
Product: CCOc1cccnc1N1CCN(CCCc2coc3ccc(OC)cc23)CC1

Procedure:
The title compound was prepared (0.69 g, 75%, mp 174°-176° C.) in a manner analogous to the preparation of 1-[3-(5-methoxybenzo[b]furan-3-yl)propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine hydrochloride (Example 39) by the reaction of 5-methoxy-3-benzo[b]furanpropanol tosylate with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][C:20]=2[C:19](C=O)=[CH:18][CH:17]=1.[Cl-].[CH2:28]([O:30][CH:31]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:29].[C:56](=O)([O-])[O-].[K+].[K+]>ClCCl.CC(O)C>[CH2:35]([O:34][C:32](=[O:33])/[C:31](/[O:30][CH2:28][CH3:29])=[CH:56]/[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[C:24]2[C:20]=1[CH2:21][CH2:22][CH2:23]2)[CH3:36]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2c1CCC2
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)OCC
Temperature: -10 °C
Reaction time: 8 h

Procedure:
1.39 g of 7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-carbaldehyde (4.00 mmol) and 1.89 g of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride [Tetrahedron 50(25), 7543-56(1994)] (4.40 mmol) were dissolved in 9 ml of dichloromethane/2-propanol (1/1, v/v) under argon. This solution was cooled down to −10° C. and 855 mg of potassium carbonate (6.00 mmol) was added. The resulting suspension was stirred overnight and allowed to reach room temperature. Additional 1.89 g of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride (4.40 mmol) were added, the solution was cooled down to −10° C. and 855 mg of potassium carbonate (6.00 mmol) were added. The resulting suspension was stirred for 60 hours and allowed to reach room temperature. Again, 1.89 g of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride (4.40 mmol) were added, the solution was cooled down to −10° C. and 855 mg of potassium carbonate (6.00 mmol) were added. The resulting suspension was stirred overnight and allowed to reach room temperature. The mixture was filtered, washed with dichloromethane and the filtrate evaporated. The residue was dissolved in dichloromethane and washed with brine. Drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, cyclohexane, then cyclohexane/ethylacetate=95/5, then cyclohexane/ethylacetate=4/1) left finally 1.215 g (65.8%) of 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-acrylic acid ethyl ester as beige crystals.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N+:17]([O-])=[CH:16][C:15]=2[CH3:21])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(Cl)(=O)=O)=CC=1.C(C[NH2:36])O>N1C=CC=CC=1.C(#N)C>[NH2:36][C:18]1[CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:15]([CH3:21])=[CH:16][N:17]=1
Reactant: Cc1c[n+]([O-])ccc1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: NCCO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cnc(N)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 36.3 %

Procedure:
4-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (0.467 g, 1.64 mmol) was dissolved in a mixture of pyridine (0.53 mL) and acetonitrile (15 mL) under an atmosphere of argon. 4-Methylbenzene-1-sulfonyl chloride (0.406 g, 2.13 mmol) was added and the reaction mixture was stirred at 75° C. for 72 hours. Ethanolamine (7 mL) was then added and the reaction mixture was allowed to stir for 5 minutes at room temperature. The crude product was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate and then purified on 40 g of silca gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield the pure product (0.169 g, 0.594 mmol, 36.3%). ESI-MS m/z calc. 284.2. found 285.1 (M+1)+. Retention time of 1.28 minutes. 1H NMR (400.0 MHz, DMSO-d6) δ 7.94-7.91 (m, 1H), 7.84 (s, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.62-7.56 (m, 2H), 6.33 (s, 1H), 5.78 (s, 2H), 1.99 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)(=O)C.[Pd]>[CH2:17]([O:16][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1
Yield: 88 %

Procedure:
4-Chloro-3-ethoxycarbonyl-7-methoxyquinoline (43 g, 162 mmol) was dissolved in acetic acid (250 ml), with 10% palladium on charcoal (1.5 g) and hydrogenated at atmospheric pressure during 8 hours. The catalyst was removed by filtration over a pad of celite and the solvent evaporated. The residue was diluted with water and the pH adjusted to 7-8 with a saturated solution of sodium hydrogen carbonate. The solid was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide to give 3-ethoxycarbonyl-7-methoxyquinoline (33g, 88%) as a beige powder.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:9]1[N:14]=[C:13]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1nccc(OC2COC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a suspension of oxetan-3-ol (100 mg, 1.35 mmol) in tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL) was added 60% sodium hydride in mineral oil (81 mg, 2.03 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction was then cooled to 0° C. and a solution of 2,4-dichloropyrimidine (300 mg, 2.03 mmol) in tetrahydrofuran (1 mL) and N,N′-dimethylformamide (1 mL) was added. The mixture was warmed to room temperature and stirred for 24 h. The reaction was then diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Chromatography on silica gel (10-60% ethyl acetate in hexanes) to afford 2-chloro-4-(oxetan-3-yloxy)pyrimidine (91 mg, 0.49 mmol, 36% yield) as a white solid. MS ESI: [M+H]+ m/z 186.8.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:19]=[C:20]([NH2:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)[CH:17]=1.C(N(CC)C(C)C)(C)C>O=S(Cl)Cl.CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:28][C:20]1[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:18]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)[CH:19]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Iodo-4-methylbenzoic acid (2.62 g, 10 mmol) was refluxed in SOCl2 (10 mL) for 1 h. The volatile components were removed on a rotavap and the residue was dissolved in benzene (10 mL), concentrated to dryness on a rotavap and further dried under vacuum. The resulting acyl chloride was added to a solution 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzenamine (2.46 g, 10.2 mmol), N,N-diisopropylethylamine (1.56 g, 12 mmol), and a catalytic amount of DMAP in THF (20 mL). After stirring at rt for 2 h, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and used without purification in next step.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].[NH2:22][C:23]1[CH:24]=[C:25]([N:29]([CH3:39])[S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=1>C1COCC1.CCOC(C)=O>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:39])[S:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:24]=2)[N:20]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CN(c1cccc(N)c1)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccc(Nc2nc(Cl)ccc2C(N)=O)c1)S(=O)(=O)c1ccccc1
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A 1 M THF solution of LiHMDS (2.302 mL, 2.302 mmol) was added dropwise to a suspension of 2,6-dichloronicotinamide (163 mg, 0.855 mmol) and N-(3-aminophenyl)-N-methylbenzenesulfonamide (172.5 mg, 0.658 mmol) in THF (3 mL) at room temperature. After 18 h at room temperature, the mixture was diluted with EtOAc and washed with saturated NH4Cl (5 mL). The EtOAc phase was concentrated and purified by silica gel chromatography, eluting with 20-100% EtOAc in hexanes, to give a yellow solid (218.8 mg, 51% yield). LCMS: (M+H)+=417.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH:15]=C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[O+][O-].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH2:15][OH:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=[O+][O-]
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(CO)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1-methylallyl)piperidine-1-carboxylic acid 1-tert-butyl ester (25.5 g) in chloroform/methanol (250 ml/250 ml) cooled to −78° C. was flowed ozone air for 30 minutes. To the reaction mixture was added sodium borohydride (7.5 g) in small batches, and the mixture was warmed to room temperature. To the mixture was added 5% aqueous sodium bicarbonate solution (250 ml), and the mixture was extracted with chloroform (125 ml). The separated aqueous layer was extracted with chloroform (125 ml) again. The combined organic layer was sequentially washed with a mixed aqueous solution of sodium bicarbonate/sodium thiosulfate (12.5 g/25.0 g, 275 ml), water (125 ml) and 10% aqueous sodium chloride solution (125 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 2/3) to give the titled compound (21.9 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[N:3]1.[CH:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(O)C.C1(=O)CCCCC1>C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[N:3]1.[CH:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: Cn1nc(C2CCCCN2)cc1N
Agent: O=COCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Solvent: CCO
Product: Cn1nc(C2CCCCN2)c(C2=CCCCC2)c1N
Temperature: 25 °C
Yield: 109.1 %

Procedure:
Under nitrogen atmosphere, to a 250 mL three-neck reaction flask were added the compound of Example 11B (11.7 g, 37 mmol), ethanol (150 mL) and cyclohexanone (15.5 mL, 149 mmol). The mixture reacted overnight at 50° C. to 60° C. After cooled to room temperature, acetic acid was removed by rotary-evaporation to obtain a crude product. The crude product was subject to column chromatography (eluant: petroleum ether:ethyl acetate=2:1) to give 8.0 g of the title compound. Yield: 54.4%. MS (ESI): m/z 395 (M+H)+
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1)=[O:7])(=O)[CH3:2].S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[CH2:24]([O:23][C:21]1[CH:20]=[C:15]([CH:14]=[C:13]([O:12][C:11]2[CH:31]=[CH:32][C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:9][CH:10]=2)[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)NNC(C)=O)cc2)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Yield: 97.8 %

Procedure:
To a stirring solution of Methyl 3-[4-(2-acetylhydrazinecarbonyl)phenoxy]-5-(benzyloxy)benzoate (32 g) (Intermediate 9) in dry toluene was added thionyl chloride (10.5 g) drop wise at room temperature under nitrogen atmosphere. The reaction was refluxed and monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with EtOAc. All organic layers were combined and washed with saturated sodium bicarbonate solution, water, and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude pale yellow solid (30 g). The crude compound was purified by solvent trituration.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[CH3:30][C:16]1([CH3:31])[CH2:17][N:18]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1N1CC(C)(C)NCC1=O
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
10 ml of trifluoroacetic acid (134 mmol) was added to a solution of 4.5 g of 2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (70c) (13.4 mmol) in methylene chloride (20 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 2.71 g of the title compound (yield: 86%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(Cl)Cl.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>>[NH:12]1[CH2:11][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C2=CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of tert-butyl 4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (332 mg, 1168 μmol) in CH2Cl2 (4.00 mL, 62167 μmol) was added TFA (0.0900 mL, 1168 μmol). The yellow solution was stirred at RT for 3 h. The reaction mixture was dried under reduced pressure providing an off-white crystalline material 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile-TFA (305 mg, 87.6%). MS (ESI, pos. ion) m/z: 185.4 (M+1).
Reaction SMILES: C(#N)C.Br[CH2:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH3:21][SH:22].[Na].O>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:9]2[CH:19]=[CH:20][C:6]([CH2:5][S:22][CH3:21])=[CH:7][CH:8]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: CS
Agent: [Na]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: CSCc1ccc(C(=O)c2ccc(F)cc2)cc1

Procedure:
To an acetonitrile solution (200 ml) of 4-bromomethyl-4'-fluorobenzophenone (20 g), an aqueous 15% sodium methylmercaptan solution (60 ml) was added and the mixture was heated for 6 hours with refluxing. After the reaction mixture was restored to room temperature, water (500 ml) and toluene (300 ml) were added. The organic layer was separated, which was then successively washed with an aqueous 2N sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent n-hexane:ethyl acetate=9:1) to obtain 4-fluoro-4'-methylmercaptomethylbenzophenone (17 g).
Reaction SMILES: [CH3:1][O:2][S:3]([O:6]C)(=[O:5])=[O:4].[CH3:8][N:9]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10]1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:1][N+:10]1[N:9]([CH3:8])[C:13]([Cl:14])=[CH:12][C:11]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cn1nc(-c2ccccc2)cc1Cl
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1C
Product: COS(=O)(=O)[O-]
Product: Cn1c(Cl)cc(-c2ccccc2)[n+]1C

Procedure:
Dimethylsulfate (30 g, 0.22 mole) is added to a stirred solution of 1-methyl-5-chloro-3-phenylpyrazole (39.5 g, 0.2 mole) in dry xylene (350 ml) and the reaction mixture is warmed to 105°C to 115°C for 18 hours. A brown syrup separates out, the reaction is cooled and the xylene is decanted off. Dry acetone (300 ml) is added and after stirring a white precipitate separates out and is filtered off, m.p. 100°C to 102°C 33.8 g (55%). Recrystallization from dry acetone-toluene gives white needles m.p. 102°C to 104°C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[O:17])[CH:14](Br)[CH3:15])[CH:10]=[CH:11][CH:12]=1>>[CH3:15][CH:14]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)=[O:17]
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(C)N
Product: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
t-Butylamine was added to m-chloro-α-bromopropiophenone obtained above and the reaction mixture was refluxed for 3 hours. Excessive t-butylamine was removed by evaporation below 80° C. The concentrated solution was cooled down to room temperature and then extracted with 800 ml of ethyl acetate and 280 ml of water. The organic phase was dried with anhydrous magnesium sulfate (15 g) to obtain a solution of bupropion free base. A solution of HCl in ethyl acetate was added at room temperature to the organic phase. Crude product of bupropion hydrochloride was obtained after filtration. The crude product of bupropion hydrochloride was dissolved in 1200 ml of methanol and 120 ml of water at 80° C., decolorized with activated carbon (5 g) for 20 minutes and filtered. The filtrate was cooled and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (−0.04˜−0.09 MPa, 80° C.) for 3 hours to obtain pure product. Total yield was 70% based on m-chloropropiophenone, and the HPLC's purify was higher than or equal to 99.9%.
Reaction SMILES: C(O[C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1.[CH3:40][C:41]([CH3:44])([O-])[CH3:42].[K+].O>CN(C)C=O>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:18]([CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([C:41]([CH3:44])([CH3:42])[CH3:40])=[O:27])[S:12][CH:13]=2)[C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)C(C)(C)C)n2)Cc2ccc(C(=O)OC)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 265-1 and 4-(bromomethyl)benzoic acid methyl ester (2.0 g) were dissolved in N,N-dimethylformamide (37 mL), potassium tert-butoxide (0.91 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (2.2 g) as a colorless oil.