Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:47])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:47])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: Cc1c(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
Trifluoroacetic acid (1.0 ml) was added to a stirred solution of 4-(6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)butanoic acid (Preparation 34; 50 mg, 0.09 mmol) in dry dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvents were evaporated and the residue co-evaporated with toluene. Trituration of the residue with diethyl ether gave a gummy solid, which was purified by MDAP to give the title compound (26 mg) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>C1COCC1>[NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:4])=[O:10]
Reactant: CC(C)C(C)(N)C#N
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)C(C)(N)C(N)=O

Procedure:
In a similar way, hydrolysis of the (+)-2-amino-2,3-dimethylbutyronitrile with sulfuric acid yields the (-)-2-amino-2,3-dimethylbutyramide, mp 81°-82° C., [α]D25 =-57.14° (c=0.0654 g/ml THF).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].Cl[C:7]1[CH:8]=[CH:9][C:10]2[C:11]([C:20]=1OC)=[CH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N+:18]=1[CH:19]=2>Br>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:8]([C:19]1[N+:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]2[CH:20]=[CH:7][CH:8]=[CH:9][C:10]=12)[CH2:7][CH2:20][CH3:11]
Reactant: COc1c(Cl)ccc2c[n+]3ccccc3cc12
Agent: Br
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CCCCc1c2ccccc2cc2cccc[n+]12
Reaction time: 18 h
Yield: 152.6 %

Procedure:
A reaction mixture containing 9-chloro-10-methoxybenzo[b]quinolizinium perchlorate (5 g; 14.83 mmol) and 48% HBr (50 ml) was refluxed with stirring for 18 hours. The mixture was concentrated in vacuo, the residue was redissolved in water, filtered, and the filtrate was treated with a sodium perchlorate solution with stirring for 40 minutes. The solid was filtered and recrystallized from acetone/ether (1:1) to afford 3.8 g (79%) of 9-chloro-10-hydroxy-benzo[b]quinolizinium perchlorate (Formula II: R1 =R2 =H; R7 =9-Cl; 10-OH; X- =ClO4-), m.p. 203°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].C(N(CC)C(C)C)(C)C.[CH3:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH:17]1[C:8]2[CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=4[CH3:35])=[CH:24][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A mixture of 0.31 g of 5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine and 0.15 g of N,N-diisopropylethylamine in 10 ml of methylene chloride is cooled in an ice bath while 0.18 g of 2-methylbenzoyl chloride is added. The bath is removed and the reactants stirred at room temperature for 18 hours. The mixture is washed with water, 1N HCl, water, 1M NaHCO3, brine and dried (Na2SO4). The methylene chloride is removed in vacuo to give 0.34 g of the desired product as crystalline solid, m.p. 138°-150° C. M+ =467.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27])(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:27]([CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)(=O)c1ccccc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 20.1 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.8 g), 1-[2-(methylsulfonyl)phenyl]methanamine hydrochloride (1.5 g) and potassium carbonate (1.8 g) were stirred in ethanol (30 ml) at 80° C. for 16 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.29 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]CC)=[O:14])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[OH-].[Na+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Br)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Br)ccc21
Yield: 70.2 %

Procedure:
The ester of example 2 (0.33 g, 1 mmol) was reacted with 4% NaOH (9 ml) for 3 h at room temperature. The mixture was cooled in an ice bath and the pH was adjusted to 1 with 4M hydrochloric acid. The precipitate was filtered off, washed with water and recrystallized from acetic acid to afford 0.21 g (70%) of the title compound. M.p. >320° C. 1H-NMR (DMSO-d6): 4.86 (s, 1H), 7.29 (m, 3H), 12.24 (s, 1H), 13.28 (br.s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:22])[C:10]3[N:11]2[C:14]([CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[N:15][CH:16]=3)=[CH:6][C:5]=1[C:23]([O:25]C)=[O:24].[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:22])[C:10]3[N:11]2[C:14]([CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[N:15][CH:16]=3)=[CH:6][C:5]=1[C:23]([OH:25])=[O:24]
Reactant: COCc1cc2c(cc1C(=O)OC)[nH]c(=O)c1cnc(C3CCOC3)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1cc2c(cc1C(=O)O)[nH]c(=O)c1cnc(C3CCOC3)n12
Temperature: 70 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a mixture of 4.54 g of methyl 8-(methoxymethyl)-4-oxo-1-(tetrahydrofuran-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate and 45.0 mL of methanol was added 17.0 mL of a 3 M aqueous sodium hydroxide solution, followed by stirring at 70° C. for 5 hours. Concentrated hydrochloric acid and 1 M hydrochloric acid were added thereto to adjust the pH to about 3, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 4.31 g of 8-(methoxymethyl)-4-oxo-1-(tetrahydrofuran-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[N:11](S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(=[O:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)ncc1N(S(=O)(=O)c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cc(Cl)ncc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 84 %

Procedure:
To a solution of N-(4-acetyl-6-chloropyridin-3-yl)-4-nitro-N-(4-nitrophenylsulfonyl)benzenesulfonamide (1.0 equiv.) in 2:1 THF/MeOH (0.05 M) was added 1 M LiOH (aq.) (3.1 equiv). The resulting purple solution was stirred at rt for 15 hours, at which time 1 M HCl (3.1 equiv) was added. The volatiles were removed in vacuo and ethyl acetate (700 mL) and H2O (200 mL) were added. Upon separating the organic was washed with NaHCO3(sat.) (200 mL), with NaCl(sat.) (200 mL), dried over MgSO4, filtered and concentrated. Purification by column chromatography (50% ethyl acetate/hexanes with 0.1% AcOH, Rf=0.6) yielded N-(4-acetyl-6-chloropyridin-3-yl)-4-nitrobenzenesulfonamide (84%). LCMS (m/z): 356.0 (MH+); LC Rt=3.81 min. 1H NMR (CDCl3): δ 8.89 (s, 1H), 8.32 (m, 2H), 8.06 (m, 2H), 7.62 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[C:10]([CH3:29])=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:6]=2[N:5]=[C:4]1SC)[CH3:2].C(O)(=O)C>COCCOC.C(O)C.[Ni]>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[C:10]([CH3:29])=[CH:11][N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20](=[O:28])[C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[CH:18][CH:19]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1c(SC)nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: CCO
Product: CCn1cnc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 40 °C
Yield: 74.8 %

Procedure:
In a mixture of DME (50 ml) and ethanol (2 ml) was dissolved 3-ethyl-7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (344 mg) followed by addition of acetic acid (224 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (230 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:26][OH:27]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[N:26][OH:27])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(=NO)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of the 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 43, 144.6 mg, 0.38 mmol) and hydroxylamine hydrochloride (39.7 mg, 0.57 mmol) in methanol (1.1 mL) and pyridine (1.1 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with ethyl acetate (75 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 70% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-hydroxyimino-cyclopentyl)-N-thiazol-2-yl-propionamide (138.9 mg, 92%) as a white foam: mp 98–101° C. (foam to gel); (ES)+-HRMS m/e calcd for C17H17Cl2N3O2S (M+H)+ 398.0492 found 398.0496.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].C(Cl)(=O)C(Cl)=O.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C=O)C.Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-bromo-3-fluorobenzoic acid (19 g, 87 mmol) in DCM (200 mL) was added oxalyl chloride (9.10 mL, 104 mmol), followed by 1 drop of DMF. The mixture was allowed to stir at rt for 2 h. Upon clarification of the suspension, the solution was concentrated to dryness. The residue was redissolved in DCM (200 mL) and cooled to 0° C. Next the solution was treated with TEA (30.2 mL, 217 mmol) followed by tert-butyl amine (12.0 mL, 113 mmol). The solution was allowed to stir for 12 h. The reaction was diluted with 1N HCl (200 mL). The organic layer was then removed and washed with 1N NaOH. The organic layer was dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]([C:16]2([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[Pd].C(O)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: COC(=O)CC1(c2ccc(F)c(N(Cc3ccccc3)Cc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CC1(c2ccc(F)c(N)c2)CC1
Reaction time: 12 h

Procedure:
At room temperature, 200 mg of palladium on carbon (10%) were added to a solution of 2.1 g (5.2 mmol) of methyl {1-[3-(dibenzylamino)-4-fluorophenyl]cyclopropyl}acetate in 100 ml of ethanol, and the mixture was hydrogenated at atmospheric pressure for 12 h. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 647 mg (2.9 mmol, 56% of theory) of the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[C:11](=[O:13])[CH2:12][C:9]=2[CH:8]=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[C:10]2[CH:11]([OH:13])[CH2:12][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2c1C(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1C(O)C2
Temperature: 0 °C
Yield: 67 %

Procedure:
13.21 g (0.35 mol) of sodium borohydride are added in small fractions to a solution, maintained at 0° C., of 42.8 g (0.29 mol) of 6-methoxybenzocyclobutan-1-one in 1.5 liters of methanol. The temperature is maintained at 0° C. for 2 hours. After returning to room temperature, the reaction mixture is evaporated to dryness and then taken up in water. The aqueous phase is extracted several times with ethyl acetate. The organic phases are combined, washed with brine, dried over MgSO4, filtered and evaporated to yield, after chromatography on silica, 29.2 g of the expected product in the form of a solid, the melting point of which is 71-73° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:26][N:23]1[CH2:24][CH2:25][C@@H:21]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:22]1=[O:27]
Reactant: CN1CCC(Br)C1=O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H]2CCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-hydroxy-5-phenylmethoxy-benzoate (CAS no. 54915-31-0) (10.3 g, 40 mmol) and 3-bromo-1-methyl-pyrrolidin-2-one (Intermediate 4) (8.54 g, 48 mmol) were dissolved in DMF and treated with potassium carbonate (12.1 g, 88 mmol) and stirred at room temperature for 16 hours and then at 50° C. for 3 hours. The DMF was evaporated under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate in hexane to give the racemic product (8.7 g). The desired product was separated from its enantiomer by chiral HPLC using Merck 50 mm 20 μm Chiralpak AS—No ASV00SC JG001 and ASV000SC BD004 columns in series, eluting with 30% ethylacetate in isohexane at a flow rate of 60 mL/min, using 9 separate injections of 70 mL of a 14 mg/ml solution of the racemate in Ethanol (32 mL) and isohexane (38 mL) to afford the product (3.6 g, 41%) which eluted after its enantiomer. 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.51-2.63 (m, 1H), 2.94 (s, 3H), 3.31-3.54 (m, 2H), 3.89 (s, 3H), 4.87 (t, 1H), 5.08 (s, 2H), 6.90 (t, 1H), 7.27-7.46 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1[CH:5]=[CH:6][S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([OH:17])[CH:16]=1)(=[O:9])=[O:8].C(Br)(Br)(Br)Br.C(N(CC)CC)C.[P:40]([O-:57])([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[P:40]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([O:17][C:15]1[CH:16]=[C:11]([CH2:10][S:7](/[CH:6]=[CH:5]/[C:4]2[C:20]([O:26][CH3:27])=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:3]=2[O:2][CH3:1])(=[O:9])=[O:8])[CH:12]=[CH:13][C:14]=1[O:18][CH3:19])=[O:57]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Cc2ccc(OC)c(O)c2)c(OC)c1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: BrC(Br)(Br)Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(OP(=O)(OCc3ccccc3)OCc3ccccc3)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxy-phenol (1.9 g, 4.8 mmol) in acetonitrile (24 mL) at room temperature, was added carbon tetrabromide (1.94 g, 1.22 eq) and triethylamine (0.728 g, 1.5 eq). The resulting mixture was stirred for 10 minutes and than cooled to 0° C. in an ice-water bath. Dibenzyl phosphite (1.51 g, 1.2 eq) dissolved in acetonitrile (16 mL) was added dropwise to the cooled reaction mixture. The reaction mixture was stirred for 2 h and monitored by TLC. The reaction was terminated by dropwise addition of aqueous potassium dihydrogen phosphate (10 mL, 0.5 M). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extract was dried (Na2SO4) and concentrated in vacuo to yield the desired product.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([O-:19])=[O:18].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[C:11]=1[OH:16])([O-:19])=[O:18]
Reactant: O=C(Nc1ccccc1)c1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 42.1 %

Procedure:
2-Phenylaminocarbonylphenol (5.00 g, 23 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (2.20 g, 25.5 mmol). The addition of sulfuric acid (30 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(2.50 g, 42%). 1H NMR (CD3COCD3): δ 8.15 (d,1H), 8.09 (d,1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[C:31]#[C:32][CH:33]([OH:36])[CH2:34][CH3:35])[CH2:11][CH2:10]1)(=[O:8])=[O:7].[H-].[Na+].[CH3:39]I>C1COCC1>[F:28][C:26]([F:27])([F:29])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[CH2:10][CH2:11]2)=[C:16]([C:31]#[C:32][CH:33]([O:36][CH3:39])[CH2:34][CH3:35])[CH:17]=1)([OH:30])[C:22]([F:25])([F:23])[F:24]
Reactant: CI
Reactant: CCC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
To a solution of 1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol (186 mg, 0.33 mmol, Example 154) in dry THF (5 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil, 134 mg, 3.34 mmol). The reaction mixture was stirred at room temperature for 10 min then methyl iodide (0.21 mL, 3.34 mmol) was added. After stirring for an additional 2 h, the solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (12 g of silica gel, 10 to 30% ethyl acetate in hexanes), to provide 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxy-1-pentyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (156 mg) as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Br:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:37][O:38][CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[Br:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:40][CH2:39][O:38][CH3:37])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Br)c(Cl)cn2)CC1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Br)c(Cl)cn2)CC1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-3-bromo-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (30 mg, 0.061 mmol) and sodium carbonate (19 mg, 0.18 mmol) in DMSO (0.6 ml) was added p-toluenesulfonic acid 2-methoxyethyl ester (21 mg, 0.091 mmol). The mixture was stirred at 85° C. for 20 hr in a sealed microwave vial. The cooled reaction mixture was filtered. The filtrate was concentrated and the resulting residue was purified by reverse phase HPLC and lyophilized to give 3.8 mg of 3-bromo-5′-chloro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 554.1 (MH+), retention time=0.61 min.