Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=O)[NH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.C(OCC)(=O)C.CO>O1CCCC1>[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[NH:16][C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCNC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
Part B. To a solution of lithium aluminum hydride (0.96 g, 0.025 mol) in dry tetrahydrofuran (30 mL) was added, dropwise, a solution of 8-(4,5-diphenyl-1H-imidazole-2-ylthio) -N-heptyloctanamide (2.82 g, 0.0057 mol) in tetrahydrofuran (15 mL) and the reaction mixture was stirred at reflux for 18 hours. The reaction mixture was cooled to 0°, quenched by the slow and careful sequential addition of water (0.96 mL), 15% sodium hydroxide (2.88 mL), and water (2.88 mL), and then stirred at 0° for 30 minutes. The solution was then dried over magnesium sulfate and concentrated, and the residue was chromatographed with 1:1 hexane:ethyl acetate and then with a gradient of 1:0 to 3:1 to 1:1 ethyl acetate-methanol to give 8-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptyl-1-octanamine (1.07 g, 0.0022 mol) as a white solid, mp 87°-89°. 1H NMR (CDCl3) δ 7.6-7.2(m,11H), 3.1(t,2H,J=7 Hz), 2.7-2.5(m,2H), 1.8-1.1(m,25H), 0.9(t,3H,J=8 Hz).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:30][CH2:29]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1>C(Cl)Cl>[C:35]([N:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:29][CH2:30]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C(C)=O)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To a solution of Compound (6) (8 mg, 0.02 mmol) in DCM (2.0 mL) was added acetic anhydride (0.1 mL) and pyridine (0.1 mL) and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between EtOAc (25 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo (32 mg). The crude material was purified by reverse phase preparative LCMS: Acetonitrile/water (0.1% formic acid) to give Compound (8) (2.14 mg, 20%). ESI-MS m/z calculated for [M+H]+: 544.2. found: 544.1. 1H NMR (400 MHz, CD3CN) δ 7.85 (s, 1H), 7.63-7.54 (m, 4H), 7.40 (s, 1H), 7.05 (br s, 1H), 4.21-4.14 (m, 1H), 3.93 (td, J=8.9, 3.2 Hz, 1H), 3.76-3.67 (m, 3H), 3.49-3.43 (m, 1H), 3.11 (d, J=1.0 Hz, 3H), 2.93 (d, J=4.8 Hz, 3H), 2.77-2.64 (m, 1H), 2.46-2.36 (m, 1H), 1.95-1.81 (m, 2H), 1.73 (d, J=2.4 Hz, 3H), 1.14-1.02 (m, 3H), 0.69-0.58 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([NH2:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>C(#N)C.CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([NH:17][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCN(c2ncc(Cl)cc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CO
Product: COC(=O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 0.45 g (1.7 mmol) of 3′-amino-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methyl ester in acetonitrile (20 mL) is added 0.23 mL (1.0 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature overnight then concentrated under reduced pressure and the residue is taken up in water and extracted with ethyl acetate. The combined organic phase is washed with a 10% aqueous solution of sodium hydroxide followed by brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide, after concentration of the eluent, a yellow oil. The oil is dissolved in methanol and upon standing a solid precipitates from solution. The material is collected by filtration and dried on the filter pad to provide 0.38 g (56%) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)phenyl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride. 1H NMR (CDCl3): δ 7.06 (d, J=8.0 Hz, 2H), 7.36 (m, 3H), 7.40-7.44 (m, 2H), 7.49 & 7.52 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 9.81 (s, 1H). MS: m/z 456.0 (M++1).
Reaction SMILES: Cl.[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[C@H:8]([NH2:27])[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3].Br[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1.CC(C)([O-])C.[Na+].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:24]([CH3:26])[CH3:25])=[CH:12][CH:13]=2)[C@H:8]([NH:27][C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3]
Reactant: Brc1ncccn1
Reactant: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](Nc2ncccn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-2-methyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (for a preparation see Intermediate 108) (295 mg, 0.7 mmol), 2-bromopyrimidine (334 mg, 2.100 mmol), sodium tert-butoxide (336 mg, 3.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (641 mg, 0.700 mmol) and 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (DavePhos) (551 mg, 1.400 mmol) then filled with toluene (10 mL) and the resulting mixture was stirred at 100° C. under nitrogen for 1.5 h then cooled to room temperature and partitioned between water and AcOEt, The two layers were filtered through celite then separated. The aqueous phase was extracted with AcOEt and the combined organic were washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient:13 to 63% AcOEt in Hexanes) gave (2S,4R)-1-acetyl-2-methyl-N-2-pyrimidinyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine (220 mg, 0.475 mmol, 67.9% yield) as a brown foam.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=1
Reactant: NCCC1CCOCC1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)nn1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example 721, Part C) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0993 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 10% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.154 g, 54%): TOF MS ES+ 387.2 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2024, time 0.52 min; Anal. Calcd for C20H26N4O4: C, 62.16; H, 6.78; N, 14.50. Found: C, 61.58; H, 6.66; N, 14.13.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([NH:8][C:9](=[O:23])[C:10]4[N:11]3[C:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:15][N:16]=4)=[CH:6][C:5]=2[C:24]([OH:26])=O)[CH2:3][CH2:2]1.BrC1C=C2C(NC(=O)C3N2C(C2CCOCC2)=NN=3)=CC=1C(O)=O.[CH2:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][NH:52]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([NH:8][C:9](=[O:23])[C:10]4[N:11]3[C:14]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[N:15][N:16]=4)=[CH:6][C:5]=2[C:24]([N:52]2[CH2:53][C:54]3[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:51]2)=[O:26])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc2[nH]c(=O)c3nnc(C4CCOCC4)n3c2cc1C1CC1
Reactant: c1ccc2c(c1)CNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc2[nH]c(=O)c3nnc(C4CCOCC4)n3c2cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2[nH]c(=O)c3nnc(C4CCOCC4)n3c2cc1C1CC1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 95.0 mg of a mixture of 8-cyclopropyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid and 8-bromo-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid, 39.0 mg of isoindoline, 190 μL of diisopropylethylamine, and 1.50 mL of N,N-dimethylformamide was added 156 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, followed by stirring at room temperature overnight. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative LC-MS (methanol/0.1% aqueous formic acid solution) to obtain 24.8 mg of 8-cyclopropyl-7-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-1-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a pale brown solid.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([CH:28]3[CH2:30][CH2:29]3)[C:24](=[O:27])[NH:25][N:26]=2)=[CH:18][CH:17]=1>C(#N)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]([CH:28]3[CH2:29][CH2:30]3)[C:24](=[O:27])[N:25]([CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:26]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 85 °C

Procedure:
384 mg (2.12 mmol) of ethyl 2-bromopropionate and 1.38 g (4.24 mmol) of caesium carbonate are added to 500 mg (2.12 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 36A in 5 ml acetonitrile and the reaction mixture is heated at 85° C. overnight. It is then concentrated in vacuo, the residue is partitioned between water and dichloromethane, and the separated organic phase is dried over sodium sulphate and again evaporated. After purification of the residue by flash chromatography over silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1), 729 mg (97% of theory) of the target compound are obtained.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[CH3:14]C1C=CC(S(O)(=O)=O)=CC=1.COC(OC)(C)C>CO>[C:1]([O:13][CH3:14])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COC(C)(C)OC
Product: COC(=O)/C=C/c1ccc(O)c(O)c1
Yield: 98 %

Procedure:
Put a 10 g caffeic acid (1) in a reaction bottle, and add 1 g TsOH and 3 ml 2,2-dimethoxypropane and 10 ml methanol thereinto, followed by refluxing for 6 hours. After the refluxation, remove the solvent and pour the resultant solution into 100 ml water, followed by being extracted by the ethyl acetate for three times, neutralizing with 3% NaHCO3, and finally performing a column chromatography. Therefore, the product, methyl caffeate (the compound 2) is obtained with 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH3:29])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]O.[OH-].[Na+]>CCOC(C)=O.Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH3:29])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:36])=[O:18])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)sc2ccccc12
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)c(C(F)(F)F)c2)c2sc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-Fluoro-3-(trifluoromethyl)-benzyl]-N-(3-methylbenzo[b]thiophen-2-yl)-4-carboxy-benzenesulfonamide (not shown). A 3-L 4-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, condenser and thermocouple was charged with MeOH (1.9 L) and compound 141 (190 g, 0.35 mol) followed by 3M NaOH (412 mL, 1.2 mol) and the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 L) and 1N HCl (2 L), the layers separated and the aqueous phase extracted with EtOAc (2 L). The organic extracts were combined, washed with brine (1.5 L), dried over Na2SO4, filtered and evaporated under reduced pressure. The yellow solid was placed in vacuum oven for 18 h at 50° C. to afford 158 g of the titled compound (not shown) as a yellow solid. 1H-NMR (DMSO-d6): δ 13.63 (s, 1H), 8.19 (d, 2H), 8.01 (d, 2H), 7.86-7.83 (m, 1H), 7.71-7.63 (m, 3H), 7.49-7.37 (M, 3H), 4.89 (br s, 1H), 1.95 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:6][CH:5]=1)([O-:3])=[O:2].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)[CH2:16][CH2:17]1)=[O:25]
Reactant: O=C(O)c1ccccc1F
Reactant: O=[N+]([O-])c1cnc(OC2CCNCC2)c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Yield: 92 %

Procedure:
Stir a reaction mixture of 4-(4-nitro-isoquinoline-1-yloxy)-piperidine (4.0 g, 14.6 mmol), 2-fluorobenzoic acid (2.45 g, 17.5 mmol), DCC (3.6 g, 17.5 mmol), and HOBt (2.37 g, 17.5 mmol) in THF (100 mL) at 22° C. overnight. Filter then concentrate. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to provide (2-fluoro-phenyl)-[4-(4-nitro-isoquinoline-1-yloxy)-piperidin-1-yl]-methanone as a yellow solid (6.82 g, 92% yield, ES+ (m/z) 396.3 [M+H]).
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:5][CH:6]([CH2:11][OH:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[H-].[Na+]>O1CCCC1>[CH3:9][CH:8]([CH3:10])[CH2:7][CH:6]1[NH:5][C:3](=[O:4])[CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][CH2:11]1
Reactant: CC(C)CC(CO)NC(=O)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC1COC(c2ccccc2)C(=O)N1
Reaction time: 8 h

Procedure:
α-Bromo-N-[(1-hydroxymethyl)-3-methylbutyl]benzeneacetamide (α-center is RS, other center with NH-substituent is S), 9.1 g (0.029 mole), was dissolved in 200 ml of tetrahydrofuran, the solution is cooled to 0°-5° and 1.65 g (0.0413 mole) of 60% sodium hydride in mineral oil dispersion slowly added. The mixture was allowed to reach room temperature and stirred overnight, the solvent was evaporated in vacuo and the residue dissolved in 200 ml of dichloromethane and extracted twice with water. The dichloromethane layer was separated, dried over sodium sulfate, evaporated in vacuo and the residue chromatographed using 200 g of silica gel and eluting with 1 l of dichloromethane-methanol (99.5:0.5) to give 5-(2-methylpropyl)-2-phenyl-3-morpholinone (center phenyl is R, S, other center is S), 5.48 g; [α]D25 =-22.9° (C, 0.62, methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=3[CH3:23])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:25])=[C:19]([CH:20]=[CH:21][C:22]=3[CH3:23])[O:24][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(CNc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 3-[[3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (168 mg, 0.50 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (245 mg, 0.75 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (109 mg, 0.6 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 40:1 to 30:1) to give the title compound as a colorless oil (151 mg, 69%).
Reaction SMILES: Cl(O)(=O)(=O)=O.CC1(C)[O:11][C@@H:10]2[O:12][C@H:13]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[N:38][CH:39]=[N:40][CH:41]=4)=[CH:32][CH:31]=3)[C@H:14]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[N:19]=[N:18]3)[C@@H:9]2[O:8]1>C(#N)C.C(OCC)(=O)C.O>[OH:8][C@@H:9]1[C@H:10]([OH:11])[O:12][C@H:13]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[N:38][CH:39]=[N:40][CH:41]=3)=[CH:34][CH:35]=2)[C@@H:14]1[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1
Reactant: CC1(C)O[C@@H]2O[C@H](CCc3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2nnn1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccc(-c2cncnc2)cc1
Temperature: 55 °C

Procedure:
Perchloric acid (0.2 mL) was added to a solution of the compound obtained from step l above (0.3 g) in acetonitrile (4 mL) and water (0.2 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using sodium bicarbonate solution. The solvents were evaporated under reduced pressure. The residue thus obtained was taken up in ethyl acetate and water. The organic layer was separated and washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.25 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.ClCCCl.C(O)(=O)C>[OH:9][C:3]1[C:2]([NH:1][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cnc(O)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cnc(O)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 76.2 %

Procedure:
At room temperature, to a mixed solvent solution of 3-amino-5-methylpyridin-2-ol (4.03 g) in tetrahydrofuran (50 ml) and 1,2-dichloroethane (50 ml) were added tert-butyl 4-oxopiperidine-1-carboxylate (13.04 g), sodium triacetoxyborohydride (13.87 g) and acetic acid (3.75 ml), followed by heating at reflux for 16 hours. After the temperature was brought back to room temperature, 1 N aqueous sodium hydroxide solution was added, and extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 4-[(2-hydroxy-5-methylpyridin-3-yl)amino]piperidine-1-carboxylate (7.6 g).