Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCC1C=C[C:6]([C:7]([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][N:14]3[C:22]4[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH3:26])[C:17]=4[N:16]=[CH:15]3)=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.O>[CH3:24][N:20]1[C:21](=[O:23])[C:22]2[N:14]([CH2:13][C:12]3[CH:27]=[CH:28][C:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:40]([C:39]5[CH:38]=[CH:7][CH:6]=[CH:5][CH:4]=5)=[CH:41][C:42]=4[CH2:37][N:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)=[CH:10][CH:11]=3)[CH:15]=[N:16][C:17]=2[N:18]([CH3:26])[C:19]1=[O:25]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(CBr)cc3)cc2)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(-c4ccccc4)cc3CN3CCNCC3)cc2)n(C)c1=O
Yield: 14.7 %

Procedure:
A solution of 7-[4-(4-bromomethylbenzoyl)benzyl]-1,3-dimethylxanthine (232 mg), potassium carbonate (109 mg) and 1-phenylpiperazine (92 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane: triethylamine =3:1:0.1) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (20 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>O>[F:19][C:20]([F:24])([F:23])[CH2:21][O:22][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:16][CH2:13][C:20]([F:24])([F:23])[F:19])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: O=C([O-])[O-]
Reactant: OCC(F)(F)F
Agent: [K+]
Solvent: O
Product: Cc1cc(OCC(F)(F)F)c([N+](=O)[O-])c(OCC(F)(F)F)n1
Yield: 94 %

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (30 g, 144.9 mmol) was dissolved in 2,2,2-trifluoroethanol (250 mL), and potassium carbonate (50 g, 361.8 mmol) was added thereto, followed by reflux for 21 hours. The reaction mixture was diluted with water, and then subjected to extraction with chloroform. The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure, to thereby yield 2,4-bis(2,2,2-trifluoroethoxy)-6-methyl-3-nitropyridine (45.40 g, yield 94%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[C:15]3[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=3)=[C:7]([O:48][CH3:49])[CH:6]=[CH:5]2.[ClH:50]>CO.C(OCC)C>[ClH:50].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[C:15]3[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=3)=[C:7]([O:48][CH3:49])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(Br)ccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
A solution of tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55 mg, 75 μmol) in methanol (500 μl) at room temperature was treated with a 2 M hydrochloric acid in diethyl ether solution (1.3 ml) and stirred for 3.5 h. The reaction was then concentrated in vacuo, dissolved in water and placed on a lyophilizer over night to afford (S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (43 mg, 86%) as an off white powder: LC-MS m/z 637 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:2].CO[CH:17]=[CH:18][C:19](=O)[CH3:20].COCCO.CCCCCCCC>C(Cl)Cl>[CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][N:5]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:7]([C:8]#[N:9])[C:6]1=[O:10])[CH3:2]
Reactant: CCCCC(CC)CNC(=O)CC#N
Reactant: COC=CC(C)=O
Solvent: CCCCCCCC
Solvent: COCCO
Solvent: ClCCl
Product: CCCCC(CC)Cn1c(C)ccc(C#N)c1=O
Reaction time: 2 h
Yield: 90 %

Procedure:
N-(2-ethylhexyl) cyanoacetamide (60.4 g., 0.30 mole), 4-methoxy-3-butene-2-one (60.0 g., 0.60 mole), methylcello-solve (250 ml.) and 1,4-diazobicyclo [2.2.2.] octane (6.0 g.) are heated at reflux for 4 hours. Additional 4-methoxy-3-butene-2-one (30 g.) is added and reflux is continued for another 2 hours. The solvent is removed in vacuo to give an oil. The oil is dissolved in methylene chloride and extracted first with 2N--HCl (150 ml.) and then with water (2 × 250 ml.). The organic layer is dried over sodium sulfate, filtered and evaporated to dryness to give a 90% yield of crude product which is characterized by nmr and ir analysis.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1>[Rh].C1CCCCC1>[CH2:4]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)[CH2:3][CH:2]([CH3:12])[CH3:1].[CH2:4]([C@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)[CH2:3][CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)=CCc1ccc(O)cc1
Agent: [Rh]
Solvent: C1CCCCC1
Product: CC(C)CC[C@H]1CC[C@@H](O)CC1
Product: CC(C)CC[C@H]1CC[C@H](O)CC1
Reaction time: 5 h

Procedure:
85 g 4-(3-methyl-but-2-enyl)-phenol, 3 wt. % rhodium-on-active charcoal (Rh content, based on the weight of the dry catalyst: 5%; wafer content about 50%) are initially introduced into 300 ml cyclohexane in a stirred autoclave with a gassing stirrer. Hydrogenation is carried out for 5 hours at 100° C. under a hydrogen pressure of 20 bar. After filtration, 85 g 4-isoamylcyclohexanol are obtained as a crude product. After distillation, 80 g 4-isoamylcyclohexanol, which has the following composition: 50.4% cis-4-isoamylcyclohexanol and 49.1% trans-4-isoamylcyclohexanol, are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.CCN(C(C)C)C(C)C.[NH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH2:33]>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:33][NH:32][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:11])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)NNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 6-(methyloxy)-2-pyridinecarboxylic acid (1.00 g, 6.53 mmol) in dichloromethane (DCM) (13.52 ml) was stirred and cooled to 0° C. Oxalyl chloride (0.686 ml, 7.84 mmol) was added dropwise followed by DMF (5.06 μl, 0.065 mmol). The solution immediately turned yellow and the reaction was followed by LCMS. LCMS after circa 1 hour showed the methyl ester of the acid chloride to be present. The solvent was removed under reduced pressure and the residue was azeotroped with toluene. The residue was dissolved in dichloromethane (DCM) (27.0 ml) and cooled to 0° C. DIPEA (1.711 ml, 9.80 mmol) was added dropwise followed by 1,1-dimethylethyl hydrazinecarboxylate (0.949 g, 7.18 mmol) and the solution was left to stir at 20° C., under an argon atmosphere for 18 hours. A dark brown solution formed and LCMS showed the desired compound to be present. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate, saturated ammonium chloride, water and brine. The organic extracts were dried over magnesium sulfate and the solvent was removed under vacuum to yield the desired product in 1.685 g.
Reaction SMILES: [CH3:1][C:2]1([C:10]([O-])=O)[CH2:6][CH2:5][C:4](C)([CH3:7])[C:3]1=[O:9].[K+].Cl>CO.O>[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][CH:4]([CH3:7])[C:3]1=[O:9]
Reactant: CC1(C)CCC(C)(C(=O)[O-])C1=O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1CCC(C)(C)C1=O

Procedure:
A solution of the product of Example 8c in methanol and water (7.4 g, ˜35.7 mmol) was acidified with concentrated hydrochloric acid to pH=1 and then heated to reflux for 1 hour. The reaction mixture was cooled and then diluted with water (70 mL) and the organics were extracted with diethyl ether (80 mL×4). The combined organic phase was washed with brine (160 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a light yellow liquid contaminated with some solvent (4.93 g, Purity: ˜85%). 1H NMR (400 MHz, CDCl3) δ 2.26-2.09 (m, 2H), 1.85-1.79 (m, 1H), 1.72-1.64 (m, 1H), 1.54-1.45 (m, 1H), 1.12 (d, J=6.8 Hz, 3H), 1.08 (s, 3H), 0.98 (s, 3H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(C1C=CC(NC(=O)C2C=CC(N3CCNCC3)=NC=2)=CC=1)(C)(C)C>>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:20](=[O:32])[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)[CH:27]=[CH:26][CH:25]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Agent: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-4-piperazin-1-yl-benzamide was prepared from 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(4-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide above. HRMS m/z calcd for C21H27N3O [M+H]+: 338.2225. Found: 338.2227.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: NCC(F)(F)F
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-azidobenzoic acid (0.65 g) in acetonitrile-DMF (2:1, 15 ml) were successively added 2,2,2-trifluoroethanamine (0.38 ml), triethylamine (0.67 ml), HOBt (0.79 g) and WSC (0.92 g), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white powder (0.98 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH3:12])[CH2:5][NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.[C:25](=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:2][C:3](=[O:13])[CH:4]([CH3:12])[CH2:5][N:6]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:25]
Reactant: O=C([O-])O
Reactant: COC(=O)C(C)CNCCC(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)CN(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a mixture of 0.94 g (0.005 mole) of (rac)-2-methyl-3-(3-methyl-butylamino)-propanoic acid methyl ester, 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine, 25 mL of ethyl acetate and 12.5 mL of water was added 1.5 g (0.015 mole) of potassium bicarbonate. The mixture was stirred for 3 hours, then diluted with 50 mL of ethyl acetate and 50 mL of water. The layers were separated, and the aqueous layer was extracted with twice with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97:3) to give 1.06 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(3-methyl-butyl)-amino]-2-methyl-propanoic acid ethyl ester (IV-27) as a pale yellow oil.
Reaction SMILES: [C:1](=[O:11])(SC)[S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=[CH:13]1>C(O)CO>[C:3]1([S:2][CH:1]([OH:11])[CH3:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: CSC(=O)Sc1ccccc1
Solvent: OCCO
Product: CC(O)Sc1ccccc1
Temperature: 160 °C
Yield: 90 %

Procedure:
S-phenyl S-methyl dithiocarbonate prepared as described in Example 3 (5 g), ethylene glycol (5 ml), and imidazole (0.1 g) were placed in a stirred flask and heated to 160° C. for 10 hours. At this time, the major component (excepting ethylene glycol) was identified by g.c. comparison with an authentic sample as phenylmercaptoethanol (g.c. suggested over 90 percent yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Temperature: 85 °C
Yield: 40 %

Procedure:
A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (2.22 g, 10 mmol), 1,3-dibromo-5-fluorobenzene (3.05 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0) (0.6 g, 0.52 mmol), and sodium carbonate (2.2 g, 21 mmol) in a mixture of DME and water (70 mL/15 mL) was degassed to remove the oxygen and then heated at 85° C. under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/1:1) to give 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one as a white solid (1.4 g, 40%): mp 182-183° C.; 1H-NMR (DMSO-d6) δ 10.36 (s, 1H, D2O exchangeable), 7.78 (s, 1H), 7.58-7.65 (m, 3H), 7.49 (dd, 1H, J=8.3, 1.8 Hz), 6.96 (d, 1H, J=8.5 Hz), 1.69 (s, 6H); 19F-NMR (DMSO-d6) δ-112.46 (m, 1F); MS (CI) m/z 352 ([M+H]+, 78%), 350 ([M+H]+, 75%). Anal. Calcd. For C16H13BrFNO2: C, 54.88; H, 3.74; N, 4.00. Found: C, 54.83; H, 3.82; N, 3.95.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>C(O)CO>[C:9]1([C:6]2([NH2:5])[CH2:8][CH2:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)NC1(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: NC1(c2ccccc2)CC1
Temperature: 110 °C
Yield: 8.4 %

Procedure:
To a suspension of 0.84 g (4.1 mmol) of the above carbamate in a 1:2 mixture of H2O:ethylene glycol (4.5 mL) was added 1.0 g (25 mmol) of sodium hydroxide as a solid in one portion. The slurry was heated to 110° C. for 15 h during which time a solid precipitated out of solution. The mixture was cooled to room temperature and poured into a solution of 2N HCl (30 mL). The mixture was washed with Et2O and the aqueous layer made basic to pH 12 by addition of 6N NaOH. The aqueous phase was washed with CH2Cl2 and the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 0.046 g (8%) of 1-phenyl -cyclopropylamine as a clear oil. m/z cacld. C9H12N [M+H]+: 134.20. Found: 133.90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[S:10])[NH2:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=2)[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: NC(=S)c1cc(Cl)nc(Cl)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(-c2cc(Cl)nc(Cl)c2)n1
Temperature: 25 °C

Procedure:
2,6-Dichloropyridine-4-thiocarboxamide (1.0 g, 4.83 mmol) was dissolved in dry 1,4-dioxane followed by adding ethyl bromopyruvate (0.9 mL, 7.24 mmol) and pyridine (0.4 mL, 4.83 mmol). The resulting mixture was heated to reflux under N2 for 5 h. After cooling to RT, solvent was removed. The residue was extracted with CHCl3. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated to give a brownish solid. This crude was purified by chromatography on silica gel. Elution with hexane:acetone (90:10) gave a title compound as yellow solid. MS m/z: 303 (M+H). Calc'd. for C11H8Cl2N2O2S-303.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([OH:23])[CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH3:22])[C:17]([O-:19])=O)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].Cl.C(O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[O:23][C:17](=[O:19])[CH:16]([CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CCCC(CCC(O)c1cc(F)c(C(F)(F)F)c(Cl)c1)C(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC1CCC(c2cc(F)c(C(F)(F)F)c(Cl)c2)OC1=O
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A solution of 12.0 g (31.2 mmol) of ethyl=5-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-5-hydroxy-2-propylpentanoate [prepared by reacting 3-propyl-5-formylpentanoic acid with 3-chloro-5-fluoro-4-trifluromethylphenylmagnesium bromide], 25 ml of a concentrated hydrochloric acid, and 100 ml of ethanol was heated at 50° C. while being stirred for 3 hours. To the reaction solution was added 50 ml of toluene, and the organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel chromatography (eluent: heptane/toluene=1/1) to obtain 7.7 g of a crude 6-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-3-propyltetrahydro-2-pyrone. (Yield: 73.3%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:27][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(N)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(-n2nc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
A mixture of 1-(4-aminophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (1 g), methyl iodide (0.42 g) and potassium carbonate (0.6 g) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue (1.2 g) was purified by column chromatography on silica gel (20 g) eluting with chloroform to give crystals of 1-[4-(methylamino)phenyl]-5-[4-(methylsulfonyl)phenyl]pyrazole-3 -carbonitrile (0.31 g).
Reaction SMILES: [OH-].[NH4+:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)/[C:11](=[N:15]\[OH:16])/[CH2:12][CH2:13][CH3:14])=[CH:6][CH:5]=1.[C:18]([N:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[CH:27]=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(OCC)(=O)C>CO>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:2]=[C:27]([C@@H:26]3[CH2:29][CH2:30][CH2:31][N:25]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:15]([OH:16])[C:11]=2[CH2:12][CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: [NH4+]
Reactant: CCC/C(=N/O)C(=O)c1ccc(Br)cc1
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(-c2ccc(Br)cc2)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1O
Temperature: 24 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
The 28% ammonium hydroxide (15 mL) was added to a solution of (Z)-1-(4-bromophenyl)-2-(hydroxyimino)pentan-1-one (1.5 g, 5.55 mmol) and (S)—N—BOC-prolinal (1.1 g, 5.55 mmol) in methanol (60 mL) and stirred for 18 hours at 24° C. The reaction mixture was partitioned between CH2Cl2 and water and the organic phase concentrated and applied (CH2Cl2) to a 40 (M) Biotage silica gel column. Gradient elution, 5-100%, over 1L (A=Hexanes; B=ethyl acetate) gave (S)-tert-butyl 2-(4-(4-bromophenyl)hydroxy-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (863 mg, 34.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (m, 4H), 5.0-4.88 (m, 1H), 3.53-3.41 (m, 1H), 3.41-3.36 (m, 1H), 2.72 (t, J=7.0 Hz, 2H), 2.24-2.03 (m, 2H), 1.96-1.91 (m, 1H), 1.89-1.81 (m, 1H), 1.60 (h, J=7.6 Hz, 2H), 1.39/1.17 (s, 9H). 0.92 (t, J=7.0 Hz, 3H). RT=1.9 min, (Condition 1) LCMS: Anal. Calcd. for C21H28BrN3O3 450.13; found: 450.33 (M+H)+.