Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([CH3:23])([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C:6](=[O:13])[NH:7]2>CO>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]2([CH3:23])[C:4](=[O:24])[C:3]3[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=3[Cl:1])[NH:7][C:6]2=[O:13])=[CH:19][CH:18]=1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Solvent: CO
Product: CC1(c2ccc(N)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 66.4 %

Procedure:
To a solution of 5,7-dichloro-3-methyl-3-(4-nitro-phenyl)-1H-quinoline-2,4-dione (1.0 g, 2.74 mmol) in methanol (30 mL) was added SnCl2-2H2O (1.85 g, 8.22 mmol). The resulting solution was stirred at reflux temperature overnight. After the reaction was completed, a yellow residue was obtained after evaporating solvent under reduced pressure. The residue was then diluted with 1N HCl solution (200 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (200 ml×2) and water (200 mL×2) and dried over magnesium sulfate anhydride. After evaporation of the solvent, the objective compound (0.61 g, 66%) was obtained as pale yellow solid by purifying the residue with flash column chromatography (n-hexane:ethyl acetate=4:1): 1H NMR (200 MHz, CDCl3) δ 1.68 (s, 3H, CH3), 3.68 (br s, 2H, NH2), 6.58 (d, J=8.8 Hz, 2H, ArH), 6.73 (d, J=1.8 Hz, 1H, ArH), 6.96 (d, J=8.8 Hz, 2H, ArH), 7.08 (d, J=1.8 Hz, 1H, ArH), 8.21 (br s, 1H, NH); MS(EI) m/e 335 [M++1].
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)C.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)(=O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COCCN
Solvent: CC(=O)O
Solvent: CCO
Product: COCCN=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 72.7 %

Procedure:
A suspension of 6-nitroveratraldehyde (84 g, 0.4 mole), 600 ml of ethanol, and 1 of acetic acid was refluxed with 2-methoxyethylamine (30 g, 0.44 mole) for 1.5 hrs. After cooling overnight filtration gave 78 g of the product; m.p. 65°-66°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:17])=[O:16].[Cl-].[NH4+].O>[Fe].C(O)(C)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:16])=[O:17]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2OCCOC)c(O)cc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2OCCOC)c(O)cc1C
Reaction time: 1 h

Procedure:
32 g of 2-[2'(2-methoxyethoxy)-5'-nitrobenzenesulfonamido]-4-hexadecyloxy-5-methylphenol prepared as described in Step (b) above, 24 g of iron powder, 12 g of Fe2O4, 0.6 g of ammonium chloride and 25 ml of water were added to 300 ml of isopropyl alcohol and the mixture was refluxed on a stream bath with stirring for 1 hour. After completion of the reaction, the mixture was filtered while hot and the filtrate was cooled with ice. The crystals thus precipitated were recovered by filtration, washed with 50 ml of isopropyl alcohol and air-dried. Yield: 23 g; Melting Point: 142°to 144° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[O:10]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:11][C:12]2([OH:10])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 71.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3.1 g, 21.0 mmol), tert-butyl 1-oxa-6-azaspiro[2,5]octane-6-carboxylate (4.4 g, 21.0 mmol) and sodium hydrogen-carbonate (1.94 g, 23.1 mmol) in ethanol (20 ml) were stirred under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water. The resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(2-chloro-4-nitroimidazol-1-ylmethyl)-4-hydroxypiperidine-1-carboxylate (5.4 g, yield 72%) as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([NH:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([NH:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(-c2c(-c3nc(/C=C/C(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2c(-c3nc(CCC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Yield: 54 %

Procedure:
A solution of (2E)-3-{2-[1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}-N-(tetrahydro-2H-pyran-4-ylmethyl)prop-2-enamide (46.7 mg, 0.10 mmol) and 10% palladium carbon (10 mg, 0.09 mmol) in methanol (15 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) and crystallized from ethyl acetate and hexane to give the title compound (26.2 mg, 0.054 mmol, 55.9%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:44])[NH:32][CH2:33][CH:34]([C:40]([F:43])([F:42])[F:41])[CH2:35][CH2:36][C:37](O)=[O:38])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([NH:32][CH2:33][CH:34]([C:40]([F:42])([F:43])[F:41])[CH2:35][CH2:36][CH2:37][OH:38])=[O:44])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(O)CCC(CNC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCC(CCCO)C(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.8 %

Procedure:
To a solution of 4-((3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)methyl)-5,5,5-trifluoropentanoic acid (40 mg, 0.061 mmol), prepared by method described in Procedure 3, 5, 6, 7 and 2, in anhydrous THF (1.5 mL) added was dropwise LAH (1.0 M in THF, 0.2 mL). The reaction mixture was stirred at rt for 40 min, then quenched by the addition of 4 N NaOH (1 mL). The aqueous portion was extracted with EtOAc (3×20 mL). The combined organic portions were washed with water and sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The resulting oil was purified by preparative HPLC (YMC ODS S5 30×100 mm column 20-100% MeOH (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm), then further purified by ISCO chromatography (4 g) with 0-50% EtOAc in hexane over 18 min (RT=14-15.5 min) to yield 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(5-hydroxy-2-(trifluoromethyl)pentyl)urea as white solid (30 mg, 77% yield). LCMS: RT=2.003 min [M+H] 639 (LCMS Method 2). HPLC: RT=4.10 min, 100% purity (HPLC Method 1). NMR: 400 MHz 1H (CDCl3) 8.17 ppm, 1H, s; 7.59 ppm, 1H, dd, J=8.57, 2.42 Hz; 7.05 ppm, 7H, m; 6.82 ppm, 1H, d, J=8.79 Hz; 6.51 ppm, 2H, t, J=6.81 Hz; 5.82 ppm, 1H, m; 4.60 ppm, 1H, ddd, J=12.08, 6.37, 6.15 Hz; 4.29 ppm, 1H, d, J=12.74 Hz; 3.56 ppm, 2H, dt, J=10.55, 5.27 Hz; 3.43 ppm, 2H, m; 3.34 ppm, 1H, m; 1.64 ppm, 4H, m; 1.54 ppm, 2H, s.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]=O.[C:12]1([C:18]2[CH:19]=[C:20]([NH:23][C:24](=[O:30])[C@@H:25]([NH2:29])[CH2:26][CH2:27][CH3:28])[NH:21][N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:12]1([C:18]2[CH:19]=[C:20]([NH:23][C:24](=[O:30])[C@@H:25]([NH:29][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:26][CH2:27][CH3:28])[NH:21][N:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC[C@H](N)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Reactant: O=CCc1cccc(F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC[C@H](NCCc1cccc(F)c1F)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-amino-5-phenyl pyrazole (31.2 mmol) was combined with (S)-2-tert-butoxycarbonylamino-pentanoic acid (37.5 mmol) and dissolved in 50 mL of anhydrous dichloromethane. Triethylamine (93.6 mmol) was added, followed by TBTU (37.5 mmol) and the reaction mixture was stirred at rt for 2 h. The solution was then diluted with 50 mL of fresh dichloromethane and extracted with 50 mL portions of aqueous saturated bicarbonate solution, water and then brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified through flash chromatography on silica gel. The purified product was then heated neat at 150° C. for 3 h. The reaction mixture (14.4 mmol) was then cooled to rt and dissolved in 40 mL of anhydrous 4.0 N HCl dioxane solution and stirred at rt for 3 h. The reactions were concentrated under reduced pressure and triturated with 20 mL of anhydrous Et2O. The solids were filtered and dried to give the desired amine, (S)-2-Amino-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide. 2-(2,3-Difluoro-phenyl)-acetaldehyde (0.2 mmol) was combined with (S)-2-Amino-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide (0.2 mmol) in 2 mL of anhydrous dichloromethane under N2. Sodium triacetoxyborohydride (0.3 mmol) and two drops of acetic acid were then added and the reaction was stirred at rt for 16 h. The crude solution was then concentrated under reduced pressure and purified through flash chromatography on silica gel to give 2-(S)-[2-(2,3-Difluoro-phenyl)ethylamino]-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide, LC-MS 2.7 min, 398 [M+1].
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:11][N:12]([CH3:14])[NH2:13]>>[CH3:11][N:12]([CH3:14])[N:13]=[C:6]1[CH2:7][CH2:8][N:3]([N:2]([CH3:10])[CH3:1])[CH2:4][CH2:5]1
Reactant: CN(C)N
Reactant: CN(C)N1CCC(=O)CC1
Product: CN(C)N=C1CCN(N(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
3.0 g 1-Dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961) is cooled to 0° C., and 3.8 g N,N-dimethylhydrazine is added at such a rate, that the internal temperature does not exceed 15° C. The mixture is stirred at ambient temperature for 3 hours. Then the excess of N,N-dimethylhydrazine is evaporated. Thus, 3.65 g [4-(Dimethyl-hydrazono)-piperidin-1-yl]-dimethyl-amine is obtained. 1H-NMR (CDCl3): 2.80 ppm (m, 2H), 2.70 ppm (m, 4H), 2.45 ppm (s, 6H), 2.42 ppm (m, 2H), 2.40 ppm (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:18][CH3:19].O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(N)cc2)ccc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-methyl-2-(methyloxy)-4-[(4-nitrophenyl)oxy]benzene (Intermediate 19, 1.43 g) in tetrahydrofuran (65 mL)/water (32.5 mL) iron (1.540 g, 27.6 mmol) and then ammonium chloride (1.475 g, 27.6 mmol) were added and the reaction mixture was stirred for 5 hours at room temperature. The catalyst was filtered off and the solution was diluted with a saturated solution of Na2CO3 (10 mL) and extracted with ethyl acetate (2 times 60 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated to the title compound (1.25 g) as a brown/red solid.
Reaction SMILES: OO.C(OCC)(=O)C.[Br:9][C:10]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25](=[O:32])[NH:26][CH:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])=[O:16])[N:12]([C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[N:11]=1>O>[Br:9][C:10]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25](=[O:32])[NH:26][CH:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])=[O:16])[N:12]([C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[N:11]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 60.6 %

Procedure:
1.13 g of a 30% hydrogen peroxide solution was added to an ethyl acetate 12 ml solution comprising 0.53 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide, followed by reflux with heating. 30 hours later, the reaction liquid was stood to cool and poured to water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to obtain 0.32 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][C@@H:14]([C:16]([OH:18])=[O:17])[NH:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:52](O)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:12][NH:13][C@H:14]([C:16]([O:18][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:17])[CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:25])([F:24])[F:26])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C

Procedure:
To a flask equipped with a Dean Stark trap were added (2S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2-carboxylic acid (1 g, 1.78 mmol), toluene (25 mL), and p-toluene sulfonic acid monohydrate (336 mg, 1.77 mmol), and n-octanol (690 mg, 5.30 mmol). The reaction mixture was heated to reflux for 48 h, cooled to RT, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (CH2Cl2/MeOH/NH4OH) provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[N:18]=[CH:17][C:16]([O:19][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1
Reactant: N#Cc1ccc(F)nc1
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (500 mg, 1.671 mmol) and 6-fluoronicotinonitrile (224 mg, 1.838 mmol) in dry DMSO (5.570 mL) was added Cs2CO3 (653 mg, 2.005 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 25° C. for 16 h. The reaction was quenched with water and extracted with Et2O (3×). The combined organic layers were dried by passing through a phase separator and volatiles were removed under a gentle stream of N2. The resulting residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 5-30% EtOAc/Hexanes over 8 min, 30% for 4 min) to yield the title compound as a colorless oil (667 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.2 Hz, 1H), 8.44 (dd, J=2.3, 0.7 Hz, 1H), 8.00 (dd, J=8.6, 2.3 Hz, 1H), 7.61 (dd, J=8.6, 2.5 Hz, 1H), 7.57 (dd, J=8.6, 0.7 Hz, 1H), 7.41 (dd, J=14.7, 8.2 Hz, 1H), 7.15 (dd, J=8.6, 0.7 Hz, 1H), 6.89-6.82 (m, 1H), 6.76 (ddd, J=9.8, 8.9, 2.5 Hz, 1H), 3.47 (d, J=4.9 Hz, 1H), 3.02-2.98 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −106.85 (dd, J=258.0, 8.5 Hz, 1F), −107.45-−108.24 (m, 2F), −109.31 (q, J=8.5 Hz, 1F); ESIMS m/z 402 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O1CCCC1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2Br)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (134 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (116 mg, 91%) as a pale-brown solid.
Reaction SMILES: C[O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>ClCCl>[CH3:12][C:11]1[C:3]([OH:2])=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: COc1cc2scnc2cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2ncsc2cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-methoxy-5-methylbenzo[d]thiazole (5B) (160 mg, 0.89 mmol) in dichloromethane (5 mL) was added boron tribromide (1 M in dichlormethane, 1.8 ml) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched by adding a saturated NaHCO3 solution, extracted with dichlormethane and trace MeOH. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-100% Ethyl acetate/hexanes). LCMS-ESI+: calc'd for C8H7NOS: 166.0 (M+H+). Found: 166.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O>CC(O)=O.[Pd]>[CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COC(=O)C1(C)Cc2ccccc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1(C)Cc2ccccc2C1
Reaction time: 4 h

Procedure:
A mixture of the methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.04 g, 9.99 mmol) and 10% Pd/C (0.200 g; wet) in HOAc/conc H2SO4 (22/2 mL respectively) was hydrogenated under 50 psi H2 for 4 h using a Parr hydrogenation apparatus. The mixture was filtered through Celite (2×MeOH wash) and the filtrate was partially concentrated in vacuo. The residue was neutralized with satd Na2CO3 and the whole was extracted with EtOAc (2×25 mL). Combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo affording the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.35 (s, 3H), 2.81 (d, J=15.6 Hz, 2 H), 3.47 (d, J=15.6 Hz, 2 H), 3.71 (s, 3H), 7.12-7.23 (m, 4H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]1[S:15][CH2:11][CH2:12][CH2:13][S:14]1
Reactant: SCCCS
Reactant: COc1ccccc1C=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccccc1C1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
A solution of 20.4 g (150 mmol) of o-anisaldehyde and 24 mL (239 mmol) of propane-1,3-dithiol in 300 mL of methylene chloride was cooled to 0° C. Boron trifluoride etherate (4.0 mL, 33 mmol) was added dropwise to the cooled solution and the reaction mixture was stirred at 0° C. for 0.5 h, then at ambient temperature for 18 h. The methylene chloride solution was washed with 2×100 mL of 10% aqueous sodium hydroxide solution, 100 mL of water and 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 35.4 g (95% yield) of 2-(2'-methoxyphenyl)-1,3-dithiane, m.p. 127°-128° C.; 1H NMR (CDCl3) δ 1.8-2.0 (m, 1H), 2.1-2.25 (m, 1H), 2.87 (t, 1H), 2.92 (t, 1H), 3.05-3.2 (m, 2H), 3.85 (s, 3H), 5.69 (s, 1H), 6.87 (d, 1H), 6.97 (t, 1H), 7.25 (dt, 1 H), 7.59 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([S:6][C:7]2[CH:24]=[CH:23][C:10]([CH2:11][NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=3[Cl:22])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:27]([N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[S:32]Cl)[CH2:28][CH2:29][CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:27]([N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[S:32][N:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([S:6][C:5]2[CH:25]=[CH:26][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:24][CH:23]=1)[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=1[Cl:22])=[O:14])[CH2:28][CH2:29][CH3:30]
Reactant: Cc1ccc(Sc2ccc(CNC(=O)c3c(Cl)c(C)nn3C)cc2)cc1
Reactant: CCCCN(CCCC)SCl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCN(CCCC)SN(Cc1ccc(Sc2ccc(C)cc2)cc1)C(=O)c1c(Cl)c(C)nn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
To a stirred mixture of N-[4-(4-methylthiophenoxy)benzyl]-4-chloro-1,3-dimethylpyrazole-5-carboxamide (300 mg, 0.746 mM), 4-(N,N-dimethylamino)pyridine (119 mg, 0.970 mM) and dry pyridine (5 ml) was added dropwise N,N-di-n-butylaminosulfenyl chloride (190 mg, 0.970 mM) at 0°-10° C., and the mixture was stirred for 4 h at the room temperature. The mixture was poured into ice water, and the mixture was extracted with dichloromethane. The extract was washed with saturated ammonium chloride solution(x2) and brine, dried with sodium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-(N,N-di-n-butylaminosulfenyl)-N-[4-(4-methylthiophenoxy)benzyl]4-chloro-1,3-dimethylpyrazole-5-carboxamide (217 mg, 52%) as a colorless oil, nD23.3 1.5748.