Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH3:9][C:10]1[NH:7][C:1]2[C:6]([C:11]=1[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: CCCCC(C)=O
Reactant: NNc1ccccc1
Product: CCCc1c(C)[nH]c2ccccc12
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Phenylhydrazine (162.2 g) was placed in a reaction flask fitted with a mechanical stirrer, reflux condenser with attached drying tube, internal thermometer, and addition funnel. Acetic acid (900 ml) was added, resulting in an orange solution. To this mixture was then added 2-hexanone (170 g) over 5 min, and the resulting mixture was heated to reflux with stirring for three hours. After cooling, the acetic acid solvent was removed by rotary evaporation, and the residue was poured into water (4.5 liters). This mixture was extracted three times with ethyl ether (1 liter each) and the combined organic extracts were washed twice with 1N HCl (1 liter each), once with water (1.5 liters), once with saturated sodium bicabonate solution (1 liter) and then once with brine (1 liter). The organic layer was then dried (MgSO4) and evaporated to afford an oil which was purified by two successive vacuum distillations. The title compound (72.1 g) was obtained as an oil distilling between 91.5° and 95° at a pressure of 0.0067 Pascals (0.05 mTorr). An additional portion of the title compound was obtained by chromatography of the stillpot residue over flash silica gel (500 g), eluting with dichloromethane. Evaporation of the appropriate fractions afforded more material which was combined with the distillate above to provide a total of 159.1 grams (61% yield) of the title compound, which was used immediately in step (c).
Reaction SMILES: [CH:1]1([N:7]([CH2:39][CH2:40][N:41]([CH2:49][CH2:50][C:51]2[C:56]3[O:57][CH2:58][C:59](=[O:61])[NH:60][C:55]=3[C:54]([OH:62])=[CH:53][CH:52]=2)[C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:8](=[O:38])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:37][CH2:36][C:24]4([O:29][CH2:28][CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25]4)[CH2:23][CH2:22]3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO>[O:29]1[C:24]2([CH2:36][CH2:37][N:21]([CH2:20][C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:8]([N:7]([CH2:39][CH2:40][N:41]([CH2:49][CH2:50][C:51]3[C:56]4[O:57][CH2:58][C:59](=[O:61])[NH:60][C:55]=4[C:54]([OH:62])=[CH:53][CH:52]=3)[C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:45])[CH3:46])[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:38])[CH2:22][CH2:23]2)[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1)C1CCCCC1
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 4.25 h

Procedure:
A solution of tert-butyl 2-(N-cyclohexyl-3-(3-((4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step g] (1.1 g) in methanol (10 mL) was treated with 35% aqueous ammonia (2.5 mL) and stirred at room temperature for 4.25 hours, then concentrated in-vacuo to afford the subtitled compound as a pale yellow foam. Yield 0.97 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([Br:8])[CH:7]=1>C(O)(=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
3,5-dibromo-nitro-benzene (262) (500 mg, 1.78 mmol) was dissolved in 4 mL of glacial acetic acid first. TiCl3 with 30 wt % in 2 N HCl was added gradually until the purple color disappeared even after long stirring at room temperature. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated down under vacuum to remove the acetic acid. H2O and 1 M NaOH was then added to neutralize the product followed by adding EtOAc solvent. The resulting wax like solid was filtered off under vacuum. Liquid-liquid extraction was then performed twice using EtOAc and H2O as solvents and the organic layer was dried over anhydrous Na2SO4 for 0.5 h. The drying reagent was then filtered off under vacuum and the filtrate was first dried under vacuum on rotary evaporator and then dried over oil pump overnight. 387.3 mg of the desired product (273) was obtained as a neutral base in 86.7% yield with HPLC purity of >95% (ELSD). LC-MS: m/e 250 [M+1]+, 252.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH:22]([CH3:29])[CH:23]2O>C1(C)C=CC=CC=1>[C:13]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][C:22]([CH3:29])=[CH:23]2
Reactant: CC1Cc2c(-c3ccccc3-c3ccccc3)cccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(-c3ccccc3-c3ccccc3)c2C1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (1.57 g, 8.26 mmol, 0.2 equiv), compound 18 (13.0 g crude, 41.17 mmol, 1.0 equiv) and toluene (300 mL) was refluxed for 1 hour. After cooling to room temperature, the mixture was washed sequentially with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an AnaLogix (65-200 g) column, eluting with a gradient of 0 to 10% ethyl acetate in heptanes to give compound 19 (10.25 g, 88% overall yield for 2 steps) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:11]([O-])([O-:13])=[O:12].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C=O)cc1
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-Methoxy-benzaldehyde (1 g, 7.34 mmol) was added to a mixture of ammonium nitrate (0.58 g, 7.34 mmol) and trifluoroacetic anhydride (3.56 mL, 25.69 mmol), which was cooled to 0° C. The reaction mixture was stirred at 0° C. for 15 min and then allowed to stir at room temperature for about 7 h. Ice was added and stirred for 30 min. The solid obtained was filtered, washed with cold water (3×5 mL) and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:42])([C:18]3[N:19]=[CH:20][N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=3)[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:43][C:44](=[O:46])[CH3:45].Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:42])([C:18]3[N:19]=[CH:20][NH:21][CH:22]=3)[CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:43][C:44](=[O:46])[CH3:45]
Reactant: CC(=O)Nc1cc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)ccc1F
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)ccc1F
Yield: 51.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-{4-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide (1.29 g) and pyridine hydrochloride (297 mg), the title compound (399 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[OH:23])=[O:14])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]([CH:35]=O)=[CH:33][N:34]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20]([CH2:35][C:32]3[S:31][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[N:34][CH:33]=3)[CH2:19][C@H:18]2[OH:23])=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NC[C@@H]2CCNC[C@H]2O)cc(N)c1C#N
Reactant: O=Cc1cnc(-c2ccccn2)s1
Product: CCOc1nc(C(=O)NC[C@@H]2CCN(Cc3cnc(-c4ccccn4)s3)C[C@H]2O)cc(N)c1C#N

Procedure:
According to the same procedure described in Example 101, starting with the compound prepared in Example 268 and the compound prepared in Example 139, the title compound having the following physical data was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:7][CH:8]=2)[N:3]=1.ClCCl.CN(C)CCN(C)C.[BH4-].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.ClCCl>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[N:3]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of ethyl 2-(2-chloro-7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (5 g, 12.8 mmol) in THF (50 mL) was degassed with nitrogen for 5 minutes and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.36 g, 1.67 mmol) was added, followed by N1,N1,N2,N2-tetramethylethane-1,2-diamine (3.84 mL, 25.6 mmol) and sodium tetrahydroborate (969 mg, 25.6 mmol). The resulting solution was stirred at ambient temperature. After 4 h an additional portion of 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (50 mg, 0.06 mmol) and sodium tetrahydroborate (969 mg, 25.6 mmol) were added and stirred overnight. The reaction was quenched into sat. aqueous NH4Cl and extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford a brown oil. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a colorless oil (2.5 g, 55%) that crystallized upon standing. 1H NMR (400 MHz, CDCl3) 8.76 (d, J=2.3 Hz, 1H), 8.02 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.52-7.43 (m, 2H), 7.32 (dd, J=6.5, 12.7 Hz, 4H), 5.19 (s, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.77 (s, 2H), 1.26 (t, J=7.0 Hz, 3H). [M+H]=356.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][Si](C)(C)C)[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:18])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)nnn1C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)nnn1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
To a stirred solution of 5-(4-bromo-phenyl)-3-trimethylsilanylmethyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (1.9 g, 4.974 mmol) in THF (40 mL), was added water (0.18 mL, 9.948 mmol) and cooled to 0° C. Then TBAF (1M) solution in THF (5.9 mL, 5.9 mmol) was added and the mixture was stirred at 0° C. for 10 min. Volatiles were distilled off and crude mass was purified by normal silica gel column chromatography using EtOAc-hexane as eluting solvent to get 5-(4-bromo-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (0.7 g, 45.42% yield) as an off white solid. LC-MS: 310 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.0 Hz, 3H), 4.27 (s, 3H), 4.31 (q, J=7.0 Hz, 2H), 7.68 (s, 4H). The regio-chemistry was confirmed by NOE study.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:46])[O:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][N:18](CC3C=CC=CC=3)[S:19]([NH:22][C:23](=[O:38])[C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)(=[O:21])=[O:20])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]1([NH:7][C:8](=[O:46])[O:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][S:19]([NH:22][C:23](=[O:38])[C:24]3[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:25]=3)(=[O:20])=[O:21])[CH2:15][CH2:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)OCC1CCC(CNS(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
7 (31.5 mg, 47 mmole, 1.0 eq) was dissolved in 4/1 methanol/ethyl acetate (1.25 mL) and 15 mg of 20% palladium hydroxide on carbon (wet) was added. The vessel was evacuated and charged with hydrogen and stirred overnight. The catalyst was fitered over celite and the filtrate evaporated to give the title compound in nearly quantitative yield. 1H NMR (500 MHz, DMSO-d6): δ 12.23 (br s, 1H), 9.54 (s, 1H), 8.50 (s, 2H), 8.28 (s, 1H), 7.42 (d, 2H), 7.24 (t, 2H), 6.95 (t, 1H), 3.84 (d, 2H), 2.70 (br s, 2H), 1.54-1.38 (m, 2H), 0.88 (m, 4H).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH2:32]([S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:31])=[O:30])[CH3:33]
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CCS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 77 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(ethane-2-sulfonyl)-benzoic acid and morpholine and obtained in 77% yield. MS (m/e): 298.2 (MH−, 100%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1>CN(C)C=O>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:3])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Temperature: 0 °C
Yield: 92.3 %

Procedure:
Phosphorous oxychloride (16.76 g, 10.19 mL, 109.3 mmol) was added slowly dropwise to a suspension of 7-bromo-3-nitro[1,5]naphthyridin-4-ol (21.09 g, 78.1 mmol) in N,N-dimethylformamide (250 mL) (DMF) at ambient temperature and maintained overnight. The reaction mixture was then added to ice water (400 mL) with stirring. A solid precipitate formed, which was isolated by vacuum filtration and washed with water. The material was dried under high vacuum at ambient temperature overnight to yield 20.79 g of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine as a tan solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([F:12])[C:6]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)(=O)C.[OH-].[K+].O.[OH-].[K+].O>O1CCOCC1>[Br:11][C:9]1[CH:8]=[C:7]([F:12])[C:6]2[O:13][CH2:14][CH:15]([CH2:17][OH:16])[O:4][C:5]=2[CH:10]=1
Reactant: CC(=O)Oc1cc(Br)cc(F)c1OCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OCC1COc2c(F)cc(Br)cc2O1
Yield: 35 %

Procedure:
5-bromo-3-fluoro-2-(oxiran-2-ylmethoxy)phenyl acetate (2.6 g, 8.7 mmol) was stirred in dioxane at RT. Aqueous KOH (10%) was added until basic pH was reached (1:1 water/KOH (10%)). Water was added and the solution was extracted with EtOAc: The combined organic phases were washed with brine, dried and evaporated to dryness to give the title compound (0.8 g). MS m/z (rel. intensity, 70 eV) 263 (M+, 97), 262 (M+, bp), 218 (39), 207 (50), 206 (51).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12]/[N:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:11].[C:37](=O)([O-])[O-].[K+].[K+].ICI>CC(=O)CC.C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[CH2:37][S:11]/[C:10]/1=[N:12]/[N:13]=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: Fc1cccc(F)c1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ICI
Solvent: ClCCl
Solvent: CCC(C)=O
Product: Fc1cccc(F)c1N1CS/C1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 55 °C
Reaction time: 48 h
Yield: 16.7 %

Procedure:
To a mixture of (E)-N-(2,6-difluorophenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (0.50 g, 0.96 mmol) and potassium carbonate (0.53 g, 3.9 mmol) in butanone (10 mL) in a 25 mL vial equipped with a magnetic stir bar was added diiodomethane (0.093 ml, 1.2 mmol). The reaction was heated to 55° C. and stirred for two days. The reaction mixture was diluted with DCM, washed with water, and the phases separated. The aqueous phase was extracted with DCM and the combined organic phases were dried by passing through a phase separator cartridge and then concentrated. Purification by flash column chromatography provided a yellow oil which crystallized upon standing. The solid was slurried in diethyl ether and hexanes and collected by vacuum filtration. The solid was washed with hexanes and dried to provide the title compound (0.086 g, 0.16 mmol, 17%) as a light yellow solid: mp 144-146° C.; 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.34 (s, 1H), 8.20 (d, J=8.3 Hz, 2H), 7.81 (d, J=8.8 Hz, 4H), 7.40 (d, J=8.3 Hz, 2H), 7.31-7.23 (m, 1H), 7.03-6.97 (m, 2H), 5.05 (s, 2H); ESIMS m/z 532 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([Cl:24])[C:9]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>CO>[Cl:7][C:8]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([Cl:24])[C:9]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13](=[N:2][OH:3])[NH2:14]
Reactant: NO
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C#N)c1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C(N)=NO)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
To a room temperature solution of hydroxylamine hydrochloride (1.362 g, 19.62 mmols) in 40 mL of methanol is added sodium methoxide (1.030 g, 19.06 mmols). The mixture is stirred at room temperature for 15 minutes, then filtered. The filtrate is added to a suspension of 2-(2,6-dichloro-3-methylanilino)benzonitrile (3.109 g, 11.20 mmols) [prepared according to Juby, J. Med. Chem., 11, 111 (1968)] in 70 mL of methanol and the mixture is heated at reflux overnight. The clear yellow solution is cooled and concentrated in vacuo. Flash chromatography eluting with 6:1 hexane: ethyl acetate provides 2.079 g (60%) of 2-(2,6-dichloro-3-methylanilino)benzamide oxime as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]2)[CH:7]=1.C([O-])(=O)C.[Na+]>CO.[Pd]>[F:21][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C@:8]1([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:15])([F:16])[F:17])[C:10]([NH2:19])=[N:9]1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@]1(c2ccccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1

Procedure:
A solution of (2R,5R)-5-(5-bromo-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (1.66 g, 4.5 mmol) and sodium acetate (0.369 g, 4.5 mmol) in MeOH (50 ml) was hydrogenated over 10% Pd—C for 6 h at 50° C. The catalyst was filtered off over Celite and the filtrate was concentrated. The residue was dissolved in saturated NaHCO3 solution and extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound as a colorless oil: TLC (hexane-EtOAc 1:1): Rf=0.19; HPLC RtH5=0.777 min; ESIMS: 291 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 7.41 (dt, 1H), 7.26 (m, 1H), 7.11 (t, 1H), 7.05 (dd, 1H), 4.11 (dd, 1H), 3.94 (dd, 1H), 1.54 (s, 3H), 1.49 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([NH2:10])[CH2:5][C:4]=2[CH:3]=[N:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@@H:19]1[CH2:23][CH:22](O)[O:21][C:20]1=[O:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@H:19]([CH2:23][CH2:22][NH:10][C@H:6]1[CH2:7][CH2:8][C:9]2[NH:1][N:2]=[CH:3][C:4]=2[CH2:5]1)[C:20]([OH:25])=[O:21]
Reactant: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Reactant: N[C@H]1CCc2[nH]ncc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)[C@@H](CCN[C@H]1CCc2[nH]ncc2C1)Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
To a solution of 0.30 g (2.2 mmoles) of (S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amine in 15 mL of ACN at 43° C., add 0.732 g (2.05 mmoles) of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxy-dihydro-furan-2-one. Heat the mixture at 50° C. for 0.5 h and allow to cool to room temperature. Add 0.70 g (3.3 mmoles) of sodium triacetoxyborohydride. After 2.5 h, add an additional charge of sodium triacetoxyborohydride (100 mg). After 1 h, heat to 50° C. and add 15 mL of water slowly. Allow to cool to room temperature and stir the slurry overnight. Collect the solids by filtration and rinse with water (2×5 mL). Stir the wet cake with 15 mL of acetonitrile and filter. Rinse the cake with acetonitrile (2×5 mL) and dry in a vacuum oven to afford 0.65 g (62%) of the title compound as a solid. MS (m/z): 476 (M+1, 35Cl), 478 (M+1, 37Cl).