Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11](=[O:13])[CH3:12])[CH:3]=1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[N:20]([CH2:24][C:25](O)=O)[CH:21]=[CH:22][N:23]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:9]([N:8]1[C:7]2[CH:6]=[N:5][C:4]([C:11](=[O:13])[CH3:12])=[CH:3][C:2]=2[N:1]=[C:25]1[CH2:24][N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:15]1[S:14][CH:18]=[CH:17][N:16]=1)[CH3:10]
Reactant: CCNc1cnc(C(C)=O)cc1N
Reactant: O=C(O)Cn1ccnc1-c1nccs1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(C)=O)ncc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(4-amino-5-ethylamino-pyridin-2-yl)-ethanone (54 mg, 0.3 mmol), (2-thiazol-2-yl-imidazol-1-yl)-acetic acid (61 mg, 0.3 mmol), EDCI (60 mg, 0.3 mmol), and pyridine (2 mL) is stirred at room temperature for 72 hr and then poured into water. The aqueous layer is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is evaporated in vacuo and the residue is taken up in acetic acid (5 mL). The mixture is heated to reflux for 16 hr and saturated NaHCO3 solution is added to neutralize the reaction. The aqueous solution is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is removed in vacuo and purification by preparative TLC provides the product as white solid. 1H NMR (CDCl3) δ 8.79 (d, 2H), 8.47 (d, 1H), 7.83 (d, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 6.39 (s, 2H), 4.02 (q, 2H), 2.77 (s, 3H), 1.86 (t, 3H). LRMS 353.2 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].BrC([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.[CH3:24]N(C)C=O>O>[C:18]1([C:17](=[CH2:16])[CH2:24][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C=O
Reactant: CC(Br)C=Cc1ccccc1
Agent: [K]
Solvent: O
Product: C=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
A mixture of 60 g of potassium pthalimide and 66.4 g of α-bromoethyl styrene (prepared by the method of S. F. Reed, Jr., J. Org. Chem., 30, 3258 (1965)) in 150 ml of dimethylformamide is refluxed for 2 hours, cooled, and diluted with 400 ml of water. The resulting solid is filtered and dried in vacuo to give 83.4 g of N-(2-phenyl-2-propenyl)-pthalimide. A small sample that is recrystallized from acetone-hexane has a melting point of 118°-121°C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:10]1([S:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:17][S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CSc1ccccc1)c1ccccc1O
Reactant: c1c[nH]cn1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Oc1ccccc1C(=CSc1ccccc1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resultant mixture was stirred for 30 minutes, followed by an addition of 2.10 g of 2-phenylthio-2'-hydroxyacetophenone. The thus-obtained mixture was stirred at room temperature for 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The methylene chloride extract was then subjected to a post treatment in the same manner as in Example 10. The reaction product was separated by column chromatography, thereby obtaining 0.2 g of Isomer A (Compound 61) and 1.0 g of Isomer B (Compound 62) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-phenylthioethylene as colorless crystals respectively.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])CC2C(F)=CC=CC=2Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:34]=1[CH2:35][Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:35][C:34]2[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:33]=2[O:32][CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OC)c(C[Mg]Cl)c1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: COc1ccc(OC)c(CC(O)(c2ccccc2)C2CN(Cc3ccccc3)CCO2)c1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-dimethoxybenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=434 @ Rt 3.10 min. major peak.
Reaction SMILES: O[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[Cl:22][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: COCc1ncnc(O)c1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COCc1ncnc(Cl)c1OC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
85.0 g (0.5 mol) of 4-hydroxy-5-methoxy-6-methoxymethylpyrimidine were suspended in 600 ml of dichloroethane, 50.5 g of triethylamine were added, and 260 g (1.7 mol) of phosphorus oxychloride were then added without cooling. The mixture was stirred for 3 hours at 80° C., poured into ice-water and neutralized by adding solid sodium carbonate, the organic phase was separated, and the water phase was extracted several times by stirring with methylene chloride. The combined organic phases were dried and concentrated. The residue was distilled under a water pump vacuum. 66.1 g (70% of theory) of a yellow oil were obtained. B.p. 93°-96° C./0.1mm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9](=O)([O:15]C(C)(C)C)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([O:10][C:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCCCCN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCCCN
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A solution of 1,6-diaminohexane (14 g, 0.12 mol) in ethanol (500 mL) was mixed with a solution of di-t-butyl carbonate (23 g, 0.1 mol) in ethanol (500 mL) and stirred overnight. The mixture was filtered, concentrated and the residue was shaken with a mixture of ether (200 mL) and water (50 mL). The aqueous phase was extracted twice with ether (50 mL) and the organic phase was extracted sequentially with brine, cold 0.4N hydrochloric acid (150 mL) and water (2×100 mL). The pH of the acidic extract was brought to 12-13 with 1N sodium hydroxide and it was extracted twice with ether (50 mL). The organic phase was washed with brine, dried (sodium sulfate) and concentrated to yield the title compound (13.16 g, 49%). TLC Rf 0.53 (Kieselgel 60 F254, 15:3:2 2-butanol:formic acid:water); MS(ES) m/e 217.0; 1NMR (400 MHz, CDCl3): δ4.57 (br s, 1H), 3.10-3.12 (m 2H), 2.68-2.71 (m 2H), 1.84 (br s 2H), 1.44-1.48 (br s 9H), 1.32-1.34 (br s 8H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:38]([CH3:46])[C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[O:37])[CH2:31][CH2:30]1.N1CCCCC1.O>CN(C)C=O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:38]([C:39]2[CH:44]=[CH:43][C:42]([NH:45]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:41][CH:40]=2)[CH3:46])=[O:37])[CH2:31][CH2:30]1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
10.5 g (30.0 mmol) of 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone (for preparation see WO 01/27081 mentioned above) and 8.60 g (33.0 mmol) N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (for preparation see WO 01/27081 mentioned above) are dissolved in 80 mL of dimethylformamide and stirred for 1 hour at 80° C. After cooling 6.50 mL of piperidine are added and the mixture is stirred for another two hours at ambient temperature. Water is added, the precipitate formed is suction filtered and washed with a little water. The residue is suspended in 200 mL of methanol, suction filtered and washed with cold water and diethyl ether. The substance is dried in vacuo at 110° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:27][CH2:26][N:25](C(OCC3C=CC=CC=3)=O)[CH2:24][CH:23]=2)=[CH:18][CH:17]=1.O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[Pd]>[NH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccc(O)cc2)CC1
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
DIAD (5.20 mL, 26.39 mmol) was added dropwise to benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (6.80 g, 21.99 mmol), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (5.91 g, 24.19 mmol) and triphenylphosphine (6.92 g, 26.39 mmol) in THF (100 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated to dryness then the residues were dissolved in ether (50 mL) and stirred for 10 minutes at ambient temperature. The resulting precipitate was removed by filtration. The filtrate was washed with water (50 mL) and saturated brine (50 mL), then dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (50 mL) and the solution was washed with 2M NaOH (50 mL), followed by saturated brine (50 mL), then dried over MgSO4, filtered, evaporated and purified by flash silica chromatography, elution gradient 30 to 70% ethyl acetate in isohexane. Fractions were evaporated to a gum, which was dissolved in MeOH (150 mL) and stirred with 5% palladium on carbon (50% wet, 1.907 g, 0.45 mmol) under an atmosphere of hydrogen at 5 bar and 25° C. for 16 hours. The catalyst was removed by filtration, washed with MeOH and the solvents were evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 2M ammonia in methanol in DCM. Fractions containing the desired product were evaporated to dryness to give tert-butyl 4-[3-[4-(piperidin-4-yl)phenoxy]propyl]piperazine-1-carboxylate (4.95 g, 56%) as a solid.
Reaction SMILES: C1CC1.[CH2:4]([O:6][C:7]([CH:9]1[CH2:11][C:10]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:5].[N:24]([O-])=[O:25].[Na+].O>C(C(O)=O)(F)(F)F>[CH2:4]([O:6][C:7]([C:9]1[CH2:11][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:25][N:24]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Reactant: O=N[O-]
Agent: C1CC1
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=NOC(c2ccccc2)(c2ccccc2)C1
Temperature: 18 °C
Yield: 87.7 %

Procedure:
The cyclopropane derivative, 2,2-diphenylcyclopropanyl carboxylate ethyl ester (0.97 g, 3.7 mmol) was dissolved in 3.7 mL CF3CO2H. Into the solution was added NaNO2 (0.28 g, 4.0 mmol, 1.1 eq.) in several ports so that the reaction temperature did not excess 40° C. After addition, the reactants were stirred at room temperature (about 18° C.) for half an hour. And the reactants were poured into an iced water and extracted with diethyl ether (2×20 mL); the ethereal solutions were combined and subsequently washed with sat. NaHCO3 (2*20 mL), then water (20 mL) and brine (20 mL). The washed ethereal solution was then dried over anhydrous Na2SO4. After removing the desiccant, the ethereal solution was concentrated to obtain a light brown oil. The crude product 1H NMR of the crude product showed that the reaction was clean and a virtual 100% yield. The crude product was further purified over silica chromatography (Rf: 0.45, eluent: 20% ethyl acetate in petrol) to obtain 5,5-diphenylisoxazoline carboxylate ethyl ester 0.958 g (89% yield) as a white solid. 1H NMR (400 MHz, CDCl3): 7.41-7.26 (10H, m), 4.34 (2H, q, J=7.1 Hz), 3.86 (2H, s), 1.36 (3H, t, J=7.1 Hz). 13C NMR (400 MHz, CDCl3): 160.54, 151.09, 142.99, 128.54, 128.02, 125.95, 94.79, 62.15, 46.78, 14.12.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][O:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-:20].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[C:11]([O:20][CH2:17][CH2:16][O:15][CH3:14])[CH:2]=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COCCCl
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(OC)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate (Danishefsky et al., J. Med. Chem. 1979, 101, 7001-7008, 0.73 g, 4 mmol), 2-chloroethyl methy ether (1 mL, 12 mmol, Aldrich Chemical Company), potassium carbonate (0.55 g, 4.8 mmol) and dimethylformamide (20 mL) at 50° C. overnight. Cool to room temperature, add 2-chloroethyl methy ether (1 mL) and potassium carbonate (1.36 g), and heat with stirring at 70° C. for six hours. Cool and dilute with ethyl acetate, wash with saturated brine, dry (Na2SO4) the organic phase, filter and concentrate the filtrate in vacuo. Vacuum dry the residue overnight at room temperature to afford 0.94 g of 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid methyl ester.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:23])[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[CH2:20]([O:19][C:17]1[C:16]([Br:23])=[CH:15][C:9]2[CH:10]([CH:12]([CH3:13])[CH3:14])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:18]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CNCC2
Reaction time: 3 h
Yield: 118.6 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.011 g, 0.026 mmol) in methanol (0.5 mL) was treated with of 15% aqueous NaOH (0.5 mL), and stirred for 3 hours at 50 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.010 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.09 (s, 1H), 6.62 (s, 1H), 5.94 (m, 1H), 5.32 (dd, 1H), 5.12 (dd, 1H), 4.46 (d, 2H), 3.19 (m, 1H), 3.05 (m, 2H), 2.66 (m, 1H), 2.5 (bm, 2H), 2.3-2.1 (m, 2H), 0.95 (d, 3H), 0.63 (d, 3H). MS calculated for C16H22BrNO+H: 324, observed: 324.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:24](=[S:25])[N:23]([CH3:27])[CH3:22])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(OC(=S)N(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 3.0 g (14.4 mmol) of 3-tert-butyl-4-hydroxy-benzoic acid methyl ester (Aust. J. Chem., 1978;31:907-916), cesium carbonate (7.04 g, 21.6 mmol), and acetonitrile (50 mL) was heated to reflux and then treated with N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) all at once. The mixture was refluxed for 2 hours, cooled to room temperature, and quenched with 1N HCl. The solution was extracted with EtOAc; the organic layer was washed with 1N NaOH and brine, dried (MgSO4), and concentrated. The residue was chromatographed over silica gel, eluting with 3:2 hexane:EtOAc, to give 3-tert-butyl-4-dimethylthiocarbamoyloxy-benzoic acid methyl ester.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13]O)=[CH:5][C:4]=1[C:18]1[NH:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:19]=1.CCN(S(F)(F)[F:41])CC>C(Cl)Cl>[F:41][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]([NH:10][CH2:9][C:6]1[CH:7]=[N:8][C:3]([CH:2]([F:1])[F:34])=[C:4]([C:18]2[NH:22][C:21](=[O:23])[N:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:19]=2)[CH:5]=1)=[O:17]
Reactant: CC(C)(CO)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(CF)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 8.5 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Example-134 by using N-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-3-hydroxy-2,2-dimethylpropanamide (0.060 g, 0.12 mmol), DAST (0.060 g, 0.37 mmol), DCM (10 mL) to afford 0.005 g the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.80 (br s, 6H), 4.22 (br s, 1H), 4.38-4.42 (m, 3H), 7.41-7.66 (m, 3H), 7.95 (br s, 1H), 8.08-8.11 (m, 211), 8.61 (s, 1H); MS (m/z): 488.23 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.O>C(OCC)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]([C:2]5[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=5)[OH:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Reactant: Cn1ccnc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cn1ccnc1C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: -75 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
2-Bromo-1-methyl-1H-imidazole (47 μL, 0.48 mmol) was dissolved in diethyl ether (2 mL) and cooled to −75° C. under argon. Butyl lithium (2.5 M in hexanes; 192 μL, 0.48 mmol) was added dropwise and the mixture stirred at −75° C. for 1 hour. A solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (252 mg, 0.5 mmol) in diethyl ether (2 mL) was added dropwise. The reaction mixture was stirred for 16 hours whilst warming slowly to room temperature. The reaction mixture was cooled and treated with water (10 mL) and the phases separated. The organic phase was extracted with further diethyl ether (×2) followed by dichloromethane (×2). The combined organic phases were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 17.5 to 25% acetone in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)-(R/S)-methanol as a white powder (82 mg) LCMS (Method A, ESI): RT 2.74 min, m+H=588.1
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[NH:5][C:4](=[O:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N:5]([CH3:26])[C:4](=[O:25])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1,2-dihydroquinolin-2-one (370 mg, 0.86 mmol, 1.00 equip), potassium carbonate (355 mg, 2.57 mmol, 3.00 equip), and N,N-dimethylformamide (10 mL). To the resulting mixture was then added CH3I (182 mg, 1.28 mmol, 1.50 equip) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 447 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[O-]CC.[Na+]>C(O)C>[C:13]1(=[O:15])[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[N:4]2[CH2:3][CH2:2][NH:1]1
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NCCn2c1cc1c2CCCC1
Temperature: 55 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 104i (1.80 g, 7.63 mmol), sodium ethoxide (1.55 g, 22.8 mmol) and ethanol (50 mL). The mixture was stirred at 55° C. for 5 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromato-graphy to afford a 42% yield (605 mg) of 104j as a white solid: mp 207-209° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.41 (s, 1H), 6.36 (s, 1H), 3.84 (t, 2H, J=6.0 Hz), 3.42 (m, 2H), 2.51 (t, 2H, J=6.0 Hz), 2.42 (t, 2H, J=6.0 Hz), 1.76 (m, 2H), 1.65 (m, 2H); (APCI+) m/z 191.3 (M+H)
Reaction SMILES: BrC1C=CC(N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=CC=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][N:9]=[C:10]2[C:11]([NH2:12])=[N:30][N:29]=[C:13]2[NH2:14])=[CH:18][CH:17]=1
Reactant: N#CC(C#N)=NNc1ccc(Br)cc1
Reactant: Nc1ccc(Br)cc1
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(Br)cc1

Procedure:
4-[(4-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 125 mg (0.5 mmol) of 2-[(4-bromophenyl)hydrazono]malononitrile, which was derived from 4-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 109 mg (78%) of the compound as a yellow solid; 1HNMR (ppm, DMSO-d6): 6.15 (brs, 4H), 7.52 (d, 2H), 7.61 (d, 2H), 10.71 (s, 1H).