Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[O:13][CH3:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[N:4]=[C:2]([NH2:3])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[O:13][CH3:14])=[CH:25][CH:26]=1)[CH3:32]
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)N)cc2)c(F)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)N=C(N)c1ccc(CNC(=O)C(OC)c2ccc(OC)cc2F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
(RS)-N-(4-Carbamimidoyl-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide hydrochloride (example 15.3, 200 mg) was dissolved in DMF (2.2 ml). The flask was placed in an ice bath. Ethyl chloroformate (58 mg) and triethylamine (160 mg) were added dropwise. The reaction mixture was stirred for 1.5 h at 0° C. Ethyl acetate (30 ml) and ice water (40 ml) were added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated. The product was purified by chromatography (silicagel, ethylacetate) to give (RS)-[amino-(4-{[2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetylamino]-methyl}-phenyl)-methylene]-carbamic acid ethyl ester (218 mg) as a colorless amorphous solid. MS 418.3 ([M+H]+)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[CH3:27].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:18][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:20]([CH3:27])[CH:21]=1)=[O:24]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)Cc1ccccc1Oc1ccc(C=O)cc1C
Yield: 95.6 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.50 g (3.68 mmol) of 4-hydroxy-3-methylbenzaldehyde was alkylated with 0.926 g (4.05 mmol) of methyl 2-bromophenylacetate to afford 1.00 g (96%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]([C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([NH2:22])=[CH:14][C:13]=1[NH2:23])[C:7](=O)[O:8]CC.[H-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:22][C:15]1[CH:16]=[C:17]([C:18]([F:21])([F:20])[F:19])[C:12]2[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:8])[NH:23][C:13]=2[CH:14]=1
Reactant: CCOC(=O)N(Cc1cccc(Cl)c1)c1c(N)cc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1cccc(Cl)c1
Yield: 32 %

Procedure:
Ethyl 3-chlorobenzyl[2,4-diamino-6-(trifluoromethyl)phenyl]carbamate (110.3 mg) was dissolved in ethanol (10 ml), and to the solution was added sodium hydride (56.9 mg). The reaction mixture was heated at reflux for 5 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted 4 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3-methanol=5:1) to give the title compound (31.1 mg).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][O:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:14]=1.C(N(CC)CC)C>CO>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:28][C:25]1[CH:24]=[CH:23][C:22]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:13]([O:12][CH3:11])=[N:14]2)=[CH:27][CH:26]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1nn(-c2ccc(O)cc2)c2ncccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1nn(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc12
Temperature: 160 °C
Reaction time: 7 h
Yield: 13.2 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (0.23 g), 4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (0.24 g) and triethylamine (1.0 ml) was stirred under a nitrogen atmosphere at 160° C. for 7 hr. The reaction mixture was cooled to room temperature, and methanol was added to the reaction mixture. The precipitated solid was filtered off, silica gel was added to the filtrate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). Then, it was purified by HPLC(C18) (mobile phase: water/acetonitrile (0.1% TFA-containing eluents)) to give the title compound (0.047 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C@H:26]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]2[O:28][C:29](=[O:31])[CH3:30])[C@@H:18]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[O:17][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C@H:26]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]2[O:28][C:29](=[O:31])[CH3:30])[C@@H:18]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[O:17][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc([N+](=O)[O-])cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 12 h
Yield: 79.3 %

Procedure:
To 91.3 g of 4-nitrophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside suspended in 100 ml of acetic acid was added 10 g of 10% palladium-on-charcoal catalyst in a Parr hydrogenation bottle, and this was hydrogenated on a Parr hydrogenator for 12 hours. The catalyst was filtered from the solution through diatomaceous earth and washed thoroughly with methanol. The solvents were evaporated in vacuo. The residue was dissolved into one liter of toluene and again evaporated. The residue was dissolved in methylene chloride and passed through a pad of magnesium silicate and the volume of the solution was adjusted to about 300 ml. To this was added 1.5 liters of ether and 5 g of activated charcoal, the solution was boiled for 3 minutes, the charcoal was filtered off and the solvents were again evaporated. The yellow foam was crystallized from 1.5 liters of ether to yield 69.6 g of the desired compound as light yellow crystals, isolated in three crops, m.p. 145°-148° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1.[OH:17][C:18]1[C:23]([CH:24]=[O:25])=[CH:22][C:21]([O:26][CH3:27])=[N:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[CH:14]([N:13]1[C:9]([C:4]2[CH2:5][O:6][CH2:7][CH2:8][C:3]=2[CH2:2][O:17][C:18]2[C:23]([CH:24]=[O:25])=[CH:22][C:21]([O:26][CH3:27])=[N:20][CH:19]=2)=[CH:10][CH:11]=[N:12]1)([CH3:16])[CH3:15]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: CC(C)n1nccc1C1=C(CBr)CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(OCC2=C(c3ccnn3C(C)C)COCC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (50 mg, 0.19 mmol) (see the synthesis of Compound L) and 5-hydroxy-2-methoxyisonicotinaldehyde (30 mg, 0.23 mmol) in DMF (1 mL) was added K2CO3 (50 mg, 0.38 mmol). After stirred at room temperature for 3 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=1:1) to give 5-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (26 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 10.40 (s, 1H), 7.81 (s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.05 (s, 1H), 6.08 (d, J=1.6 Hz, 1H), 4.42 (s, 2H), 4.40 (m, 1H), 4.19 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 2.47 (s, 2H), 1.41 (d, J=6.8 Hz, 6H); MS (ESI) m/z 358.4 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].Br[CH2:28][CH2:29][S:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:28][CH2:29][S:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: BrCCSc1nccs1
Product: COC(=O)[C@H]1CN(CCSc2nccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12

Procedure:
Methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-ylthio)ethyl]piperidine-3-carboxylate was prepared, by analogy with Example 4, from methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate and 2-bromo-1-(1,3-thiazol-2-ylthio)ethane.
Reaction SMILES: O=S(Cl)Cl.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][CH2:13]O>>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][Cl:5])[CH3:13]
Reactant: CCO
Reactant: O=C(O)CCCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCCl
Temperature: 25 °C

Procedure:
SOCl2 (60.0 mL, 820 mmol) was added to a solution of 4-chloro-butyric acid (50.0 g, 410 mmol) in EtOH (1.2 L) at 0° C. The mixture was heated to reflux for 2 hr then cooled to room temperature and concentrated under reduced pressure to afford the crude 4-chloro-butyric acid ethyl ester.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4cc(C)ccc4C)c3O2)cc1
Product: CNCC1Cc2cc(F)cc(-c3cc(C)ccc3C)c2O1

Procedure:
The title compound was prepared (0.76 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) and methylamine (0.152 g, 4.9 mmol). mp 186-188° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])[CH:18]=[CH:17]3.[CH3:32][Cu]C.[Li].[Cl-].[NH4+].C1C=CC=CC=1>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19]([CH2:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])=[CH:18][C@H:17]3[CH3:32]
Reactant: C[Cu]C
Reactant: C[C@H]1CC(=O)C=C2C=C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C[C@@H]1C=C2CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17β, 19-dihydroxy-1α-methyl-4,6-androstadien-3-one diacetate in anhydrous tetrahydrofuran is slowly added to an ice cold ethereal solution of lithium dimethylcopper prepared as in the preceding Example. Stirring is continued for an additional 30 minutes and the mixture is poured onto a saturated aqueous ammonium chloride solution. Benzene is added and the mixture filtered through a bed of diatomaceous earth. The organic layer is separated, washed with aqueous ammonium chloride, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on a silica gel column and eluted with benzene. The eluant is evaporated and the residue recrystallized from a hexane solution to yield 17β,19-dihydroxy-1α,7α-dimethyl-5-androsten-3-one diacetate.
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][C:26]1[C:34]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:33]2[C:29]([CH:30]=[C:31]([C:44](O)=[O:45])[NH:32]2)=[CH:28][CH:27]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:25][C:26]1[C:34]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:33]2[C:29]([CH:30]=[C:31]([C:44]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:45])[NH:32]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc2cc(C(=O)O)[nH]c2c1NS(=O)(=O)c1cccs1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c2c1NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.7 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.44 g), triethylamine (0.17 mL) and N,N-dimethylformamide (15 mL) were added 6-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.34 g), 1H-1,2,3-benzotriazol-1-ol (0.21 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.26 g) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (585 mg, yield 91%) as colorless prism crystals. melting point 245-246° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][N:22]=[N+]=[N-])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=NCCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-{[1-(phenylsulfonyl)-1H-indole-4-yl]oxy}ethylazide (3.3 g, 9.6 mmol) and triphenylphosphine (3.67 g, 14 mmol) in tetrahydrofuran and water is stirred under nitrogen for 24 hr at room temperature and filtered. The filtrate is concentrated in vacuo and the resultant residue is purified by flash chromatography (silica gel, EtOAc/MeOH/NH4OH: 8.5/1.5/0.05) to afford the title compound as an off-white solid, 2.54 g (80%), mp 71-73° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15](OC)=[O:16])([O-:3])=[O:2].[BH4-].[Na+].CO.Cl>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][CH2:15][OH:16])([O-:3])=[O:2]
Reactant: COC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCO)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 101.6 %

Procedure:
A portion (3.4 g, 0.013 mol) of the methyl 2-nitro-4,5-dimethoxyphenylacetate produced in (2) above and sodium borohydride (2.52 g, 0.067 mol) were dissolved in tetrahydrofuran (100 ml), followed by heating at the reflux temperature for 30 min. Methanol (10 ml) was added dropwise to the reaction mixture over 30 min, followed by heating for 1 h. The mixture was cooled to room temperature and the residual reagents were decomposed with an aqueous solution of 1N HCl, followed by neutralization with an aqueous solution of sodium bicarbonate and three extractions with ethyl acetate. The organic extracts were dried with sodium sulfate and the solvent was evaporated, with the residue being purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing n-hexane (33%). The fractions containing the end product were collected and the solvent was evaporated to yield the end compound 2-nitro-4,5-dimethoxyphenethyl alcohol (3.0 g) as a pale yellow solid mass.
Reaction SMILES: Cl.[F:2][C:3]1([F:30])[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23](=[O:24])[C:22]4[C:21]([C:25](O)=[O:26])=[CH:20][C:19]([F:28])=[CH:18][C:17]=4[CH:16]3[CH3:29])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C[N:32](C)C=O.C(N(CC)C(C)C)(C)C>>[F:2][C:3]1([F:30])[CH2:4][CH2:5][CH:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:23](=[O:24])[C:22]4[C:21]([C:25]([NH2:32])=[O:26])=[CH:20][C:19]([F:28])=[CH:18][C:17]=4[CH:16]3[CH3:29])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: CC1c2cc(F)cc(C(=O)O)c2C(=O)N1C1CCN(C2CCC(F)(F)CC2)CC1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2cc(F)cc(C(N)=O)c2C(=O)N1C1CCN(C2CCC(F)(F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid hydrochloride (80 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) hydroxybenzotriazole ammonium salt (61 mg, 0.4 mmol), 1-ethyl-3-(3′-dimethylamino) carbodiimide hydrochloric acid salt (77 mg, 0.4 mmol) and N,N-diisopropylethylamine (0.14 mL, 1 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduce pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with sodium carbonate saturated aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol 96:4) to afford the title compound (60 mg, 73%) as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][S:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:39][CH:38]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, off-white solid (95 mg, 75%), MS (ISP) m/z=509.3 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-methanesulfonyl-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[O:8]1[CH2:11][CH2:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: BrCCBr
Reactant: Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)NCCO2
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A mixture of 2-aminophenol (5 g, 45.87 mmol), 1,2-dibromoethane (4.3 g, 22.93 mmol), and K2CO3 (15.8 g, 114.67 mmol) in THF (30 mL) was heated at 100° C. for 16 h. After completion of reaction, water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (using 100-200 mesh size silica, the desired product was eluted at 15% EtOAc in hexane) to obtained 1 g of desired product.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:26]=[CH:25][C:18]2[NH:19][C:20]([CH:22](Cl)[CH3:23])=[N:21][C:17]=2[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CN(C=O)C.ClCCCl.C(O)(C(F)(F)F)=O>[F:27][C:28]([F:36])([F:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:22]([C:20]2[NH:19][C:18]3[CH:25]=[CH:26][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6]([NH2:5])(=[O:7])=[O:8])=[CH:16][C:17]=3[N:21]=2)[CH3:23])=[CH:31][CH:30]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(Cl)c1nc2cc(-c3ccccc3S(=O)(=O)NC(C)(C)C)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C(F)(F)F)cc1)c1nc2cc(-c3ccccc3S(N)(=O)=O)ccc2[nH]1
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of N-tert-butyl-2-[2-(1-chloro-ethyl)-1H-benzoimidazol-5-yl]-benzenesulfonamide (0.042 g, 0.107 mmol), 4-trifluoromethyl-phenol (0.069 g, 0.428 mmol), Na2CO3 (0.045 g, 0.428 mmol), and NaI (0.064 g, 0.428 mmol) in DMF at rt (2 mL) was stirred for 24 hours. The reaction mixture was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the protected product. This material dissolved in 1,2-dichloroethane (1 mL) and TFA (1 mL), was heated to 60° C. for 2 hours, and then cooled. The solvent was evaporated and the resulting crude material was purified by chromatography (silica, EtOAc: hexanes, 2:1) afforded the title compound as a pale yellow oil (0.033, 67%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.14 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.70 (dd, 1H, J=1.6 Hz, J=0.8 Hz), 7.67-7.58 (m, 4H), 7.55 (td, 1H, J=8.6 Hz, J=1.6 Hz), 7.39 (td, 2H, J=9.0 Hz, J=1.6 Hz), 7.20 (d, 2H, J=8.8 Hz), 5.91 (q, 1H), 1.87 (d, 3H, J=6.8 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H22F3N4O3S: 503.5 (M+MeCN+H), Found 503.2.