Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]acetamide was oxidized using a procedure similar to that described in Example 1. Chromatography, with ethyl acetate:dichloromethane (gradient, 15:85, 30:70) as the eluent, gave 2-[5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl]acetamide as a white solid; 300 MHz NMR (DMSO/D2O): 8.41 (s,1), 7.79 (d,1), 7.35 (m,6), 7.10 (m,1), 5.17 (s,2), 4.90 (d,1), 4.76 (d,1), 4.08 (d,1), 2.25 (m,1), 0.90 (d,3), 0.75 (d,3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH2:25]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH:25][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(-c2cn[nH]c2)ccc1C(=O)O
Reactant: NCc1ccccc1Cl
Product: COc1cc(-c2cn[nH]c2)ccc1C(=O)NCc1ccccc1Cl

Procedure:
Example 53 was synthesized by following a similar procedure as described in Example 1 by replacing Intermediate 1 with Intermediate 2 and replacing (3-methoxyphenyl)methanamine with (2-chlorophenyl)methanamine. LCMS (ESI) m/z: 342.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (1H, s), 8.13 (2H, s), 7.73 (1H, d, J=8.03 Hz), 7.39 (1H, dd, J=7.65, 1.63 Hz), 7.16-7.34 (5H, m), 4.50 (2H, d, J=6.02 Hz), 3.93 (3H, s). Analytical HPLC RT=7.97 min (Method A), 7.21 min (Method B).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[NH:13][C:12](=[C:14]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[NH:20][C:19]=3[C:18](=[O:29])[NH:17][CH2:16][CH2:15]2)[C:11](=[O:30])[N:10]=1.O.O.O.C([O-])(=O)C.[Na+]>CO.[Pd]>[NH2:8][C:9]1[NH:13][C:12](=[C:14]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[C:18](=[O:29])[NH:17][CH2:16][CH2:15]2)[C:11](=[O:30])[N:10]=1
Reactant: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4ccc(Br)cc4c32)N1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4ccccc4c32)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-bromo-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one TFA salt (13 mg, 0.027 mmol), in MeOH (5 mL) is added sodium acetate trihydrate (24 mg, 0.18 mmol) and 10% Pd/C (4.5 mg). It is stirred at room temperature under a hydrogen atmosphere overnight and then the catalyst is removed by filtration. The solution is concentrated and the residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give 5-(2-amino-5-oxo-3.5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one; 1H NMR (DMSO-d6) δ 3.30-3.36 (m, 4H), 7.20 (t, 1H, J=7.6 Hz), 7.33 (t, 1H, J=7.2 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.58 (d, 1H, J=7.2 Hz), 8.36 (t, 1H, J=2.4 Hz), 9.20 (bs, 1H), 10.37 (bs, 1H), 12.45 (s, 1H); m/z [M++1] 296.1.
Reaction SMILES: [O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([CH:21]=[CH2:22])[CH:4]=[CH:5]2>CCO.[Pd]>[O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([CH2:21][CH3:22])[CH:4]=[CH:5]2
Reactant: C=Cc1ccc2c3c1OC1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc2c3c1OC1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Reaction time: 8 h
Yield: 63.8 %

Procedure:
1.2 g (4.06 mmol) of 4,5-epoxy-17-methyl-3-vinylmorphinan-6-one were dissolved in 150 ml of absolute EtOH. 1 g of 10% Pd on charcoal was added and the reaction mixture was hydrogenated in a Parr apparatus at 35 psi and at room temperature for 8 h. The catalyst was filtered off and the solvent was removed in vacuo, yielding 0.77 g of the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([CH:16]([OH:18])[CH3:17])[CH2:13][N:12]1[C:19]([O:21][CH2:22][C:23]1C=CC=C[CH:24]=1)=[O:20])=[O:10])[C:2]1C=CC=C[CH:3]=1.C>CO>[CH2:22]([O:21][C:19]([NH:12][CH2:13][CH:14]([CH2:15][NH:11][C:9]([O:8][CH2:1][CH:2]=[CH2:3])=[O:10])[CH:16]([OH:18])[CH3:17])=[O:20])[CH:23]=[CH2:24]
Reactant: CC(O)C1CN(C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Solvent: CO
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O
Reaction time: 17 h
Yield: 97.9 %

Procedure:
1,2-Bis(benzyloxycarbonyl)-4-(1-hydroxyethyl)pyrazolidine (100 g) in methanol (900 ml) was treated with activated charcoal at room temperatures for 30 minutes. After removing activated charcoal platinum oxide (22 g) was added under nitrogen atmosphere. The suspension was stirred under hydrogen atmosphere for 17 hours. After the starting material and mono(benzyloxycarbonyl) compound was disappeared. The catalyst was filtered off under nitrogen atmosphere. The cake was washed with water (300 ml) and combined aqueous metanol layer was evaporated under reduced pressure. The pH of the residue and tetrahydrofuran (500 ml) was adjusted to 8.0 with 4N aqueous sodium hydroxide and allyl chloroformate was added dropwise while keeping pH at 8.0-9.0 with 4N aqueous sodium hydroxide in an ice-bath. After stirring for 1 hour at pH 8.0-8.3, the reaction mixture was extracted three times with ethyl acetate (250 ml×1 and 100 ml×2). The combined organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate, and 10% sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue was calumn chromatographed on silica gel to give 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-ol (72.88 g).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]([OH:29])/[CH:9]=[CH:10]/[C:11]1[N:12]([CH3:28])[C:13](=[O:27])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3][C:4](O)=[O:5]>C1(C)C=CC=CC=1.C(O)(=O)C>[OH:1][CH:2]1[CH2:7][CH:8](/[CH:9]=[CH:10]/[C:11]2[N:12]([CH3:28])[C:13](=[O:27])[C:14]3[C:19]([C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:29][C:4](=[O:5])[CH2:3]1
Reactant: Cn1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cn1c(/C=C/C2CC(O)CC(=O)O2)c(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A stirred mixture of a 2:1 mixture of the erythro- and threo-diastereoisomers of (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoic acid (0.1 g; prepared as described in Example 2) in dry toluene (10 ml) and glacial acetic acid (2 drops) was heated at reflux for 1 hour. Further quantities of toluene (15 ml) and glacial acetic acid (2 drops) were added and the mixture was heated at reflux for a further period of 3.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to half volume. The resulting white solid was filtered off and washed with petroleum ether (b.p. 40°-60° C.), to give (E)-4-hydroxy-6-[2-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethenyl]-3,4,5,6-tetrahydro-2H-pyran-2-one (0.07 g), m.p. 190°-193° C. [Elemental analysis: C, 71.1; H, 5.52; N, 3.52%; calculated for C23H21NO4 : 0.75 H2O: C, 71.0; H, 5.8; N, 3.6%].
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5](=O)[NH:4][CH:3]=1.P(Br)(Br)([Br:22])=O.P(Br)(Br)(Br)=O.C(#N)C.C(=O)(O)[O-].[Na+]>C(#N)C.O.C1(C)C=CC=CC=1>[Br:22][C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(Br)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione (289.34 g @ 100%, 1 eq) and toluene (3 L) were charged to a flask and the slurry heated to reflux. Azeotroped water (53 ml) was collected and the slurry cooled to 25° C. The toluene was then removed under reduced pressure at <50° C. to give an off-white powder. This material was then added to acetonitrile (2.95 L) and the reaction mixture heated to 64-67° C. In a separate 2 L 3 necked flask, phosphorus oxybromide (368.4 g, 1.2 eq) was dissolved in acetonitrile (1.475 L). The POBr3/acetonitrile solution was then added to the original flask over 45 minutes at 64-67° C. The reaction mixture was then held at 64-67° C. for 4.5 hours and was then cooled to 20-25° C. Saturated sodium bicarbonate in water (10.3 L) was added over 30 minutes to quench the reaction. The mixture was then stirred for 6 hours at 20-25° C. The solid was then filtered off and the filter-cake washed with water (2×0.55 L) to give the title compound as a water-wet solid (486.4 g, 74.3% @ 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:32]>C(Cl)Cl.O>[ClH:32].[ClH:32].[NH2:11][CH2:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: NCCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-(4-hydroxyphenyl)-4-(isoquinolin-6-ylamino)-4-oxobutylcarbamate (E307) in CH2Cl2 was added HCl (4 N in dioxane) and 2 drops of H2O and the solution was stirred overnight at room temperature. The solvents were evaporated to give 4-amino-2-(4-hydroxyphenyl)-N-(isoquinolin-6-yl)butanamide dihydrochloride (E308).
Reaction SMILES: Cl.O.C[O:4][CH:5]=[CH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14]>O1CCOCC1>[CH3:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[CH2:6][CH:5]=[O:4]
Reactant: COC=Cc1c(C)cccc1C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C)c1CC=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
Concentrated HCl (35 mL, 420 mmol) was slowly added to water (55 mL) and then 2-(2-methoxyvinyl)-1,3-dimethylbenzene (11.2 g, 69.0 mmol) in dioxane (35 mL) was added in one portion. The biphasic mixture was heated to reflux for 16 h, cooled to room temperature and extracted with ethyl acetate (3×100 mL). After drying over sodium sulfate, filtering and removing the solvent under reduced pressure, the crude material was purified by bulb-to-bulb distillation (100° C., 93 mbar) to give 8.8 g (86%) of 2-(2,6-dimethylphenyl)acetaldehyde as a white solid. The product was confirmed by GC/MS and NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:15]([O:17]CC3C=CC=CC=3)=[O:16])[C:9]2=[O:25])=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:15]([OH:17])=[O:16])[C:9]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1CCCCN(c2ccc(F)cc2)C1=O
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCCCN(c2ccc(F)cc2)C1=O
Reaction time: 4 h
Yield: 39.8 %

Procedure:
A mixture of benzyl 1-(4-fluorophenyl)-2-oxoazepane-3-carboxylate (1 g, 3 mmol) and Pd/C (0.1 g, 10% wet) was stirred in MeOH (5 mL) under a H2 atmosphere. After 4 hours, the catalyst was removed by filtration through a pad of silica gel with MeOH. Solvent was evaporated to afford the product (0.3 g, 41% yield) as a white solid. LRMS (APCI pos) m/e 251.8 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:36])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:35])=[O:34])[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:36])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:18][CH2:19][OH:20])=[N:10][S:9]2(=[O:35])=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Agent: Cl
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To detach the protecting group, 20 mg of [5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were dissolved in 1 ml of methanol and, after addition of 0.05 ml of concentrated hydrochloric acid, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated by rotary evaporation and the residue purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution. Subsequently, this aqueous residue was extracted with ethyl acetate, and the combined organic phases were dried using a cartridge containing diatomaceous earth (Varian Chem Elut®) and concentrated by rotary evaporation. The residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (10.2 mg) with a molecular weight of 481.4 g/mol (C21H25BrN2O4S); MS (ESI): m/e=482 (M+H+).
Reaction SMILES: C(OC([NH:8][N:9]=[C:10]([C:19]1[C:20](OC2C=CC(F)=CC=2F)=[N:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[N:23][CH:24]=1)[NH:11][C@H:12]([CH3:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.Cl.C(OC(C)C)(=O)C>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[O:25][C:22]1[N:21]=[C:20]2[NH:8][N:9]=[C:10]([NH:11][C@H:12]([CH3:18])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:19]2=[CH:24][N:23]=1
Reactant: C[C@H](CS(C)(=O)=O)NC(=NNC(=O)OC(C)(C)C)c1cnc(Oc2ccc(F)cc2F)nc1Oc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: Cc1ccccc1
Product: C[C@H](CS(C)(=O)=O)Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of 1.02 kg of N′-[[2,4-bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-((R)-2-methanesulfonyl-1-methyl-ethylamino)-methylene]-hydrazinecarboxylic acid tert-butyl ester in toluene (6-8 l) and conc HCl. (500 ml) was stirred at room temperature overnight. The reaction mixture was diluted with iso-propyl acetate (3.5 L) and a saturated aqueous sodium bicarbonate solution was added. The resulting solid precipitate was collected by filtration, washed with aqueous sodium bicarbonate, water, then with methyl t-butyl ether, and dried under vacuum. The material was recrystallized from isobutanol to give 455 g of [6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-((R)-2-methanesulfonyl-1-methyl-ethyl)-amine. Mp=177.7-178.8° C., MS(M+H)=384.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[CH2:7]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:7]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:29][N:3]=[N:2][N:1]=2)=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCNc1ccc(-c2nnn[nH]2)cc1
Temperature: 120 °C

Procedure:
Sodium azide (0.98 g., 0.015 mole) and NH4Cl are added to a solution of p-hexadecylaminobenzonitrile (5.13 g., 0.015 mole) in dimethylformamide. The mixture is stirred and heated in an oil bath maintained at 120° C. for 42 hours. The reaction mixture is cooled and then poured into ice-water with vigorous stirring. The precipitate separated is filtered, washed thoroughly with water and dried. The dry precipitate is washed repeatedly with ether and dried; 1.7 g. of a pale brown powder is obtained as a homogeneous product, melting point 114°-116° C. (decomp.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1([C:21]([O:23]C(C)(C)C)=O)[CH2:11][C:10](=[O:12])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH2:8]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(C(C)C)CC)(C)C.[F:49][C:50]([F:63])([F:62])[C:51]1[CH:52]=[C:53]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[NH2:54]>Cl.O1CCOCC1.C(OCC)(=O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][C:7]1([C:21]([NH:54][C:53]2[CH:55]=[C:56]([C:58]([F:59])([F:60])[F:61])[CH:57]=[C:51]([C:50]([F:49])([F:62])[F:63])[CH:52]=2)=[O:23])[CH2:11][C:10](=[O:12])[N:9]([C:13]2[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:19])[CH2:8]1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1CC(Cc2ncc[nH]2)(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1N1CC(Cc2ncc[nH]2)(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
tert-Butyl 3-((1H-imidazol-2-yl)methyl)-1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxylate prepared in Step b above (460 mg, 1.2 mmol) was dissolved in 4 mL of 4 M HCl in dioxane and heated at 60° C. for 2 h. The solvent was evaporated to dryness and the residue suspended in THF (5 mL) was treated with carbonyl diimidazole (201 mg, 1.2 mmol) and diisopropylethyl amine (626 μL, 3.6 mmol) and heated at 40° C. for 1 h. The warm reaction mixture was treated with 3,5-bis(trifluoromethyl)aniline (550 mg, 2.4 mmol) and heating was continued for another 2 h. After cooling to room temperature the reaction mixture was diluted with 25 mL ethyl acetate and washed with water. The organic phase was dried, solvent evaporated and the residue was purified by flash chromatography (SiO2, 0-15% MeOH/DCM) to afford 260 mg of 3-((1H-imidazol-2-yl)methyl)-N-(3,5-bis(trifluoromethyl)phenyl)-1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide (42% yield). 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H), 2.19 (s, 3H), 2.52 (d, 1H, J=17 Hz), 3.28 (d, 1H, J=17 Hz), 3.38-3.42 (m, 3H), 3.59 (d, 1H, J=10.6 Hz), 4.20 (d, 1H, J=10.6 Hz), 1.60 (bs, 2H), 7.00-7.20 (m, 3H), 7.57 (s, 1H), 8.18 (s, 2H). LC-MS: Rt (retention time)=2.57 min, MS: (ES) m/z 525 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].[F:21][C:22]([F:26])=[C:23]([Cl:25])[Cl:24].O>C(#N)C>[Cl:24][CH:23]([Cl:25])[C:22]([F:26])([F:21])[O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: FC(F)=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)C(Cl)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 5.29 g (0.0200 mole) of 4-(4-(methylsulfonyl)phenoxy)phenol (Example 21) in 100 ml of acetonitrile was added 0.80 g (0.0200 mole) of NaOH. The mixture was stirred at room temperature for 1 hr and then cooled to 3° C. in an ice bath. To the cold slurry was slowly added 4.0 g (0.0300 mole) of 1,1-difluoro-2,2-dichloroethylene dissolved in 15 ml of acetonitrile and the reaction mixture stirred at 3°-5° C. for 3 hrs. To the cold mixture 150 ml of water was added which resulted in the product precipitating as an oil. The product was extracted from the mixture with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and solvent removed in vacuo, which gave 7.1 g (89.4% yield) of product. Purification was accomplished by column chromatography using silica gel as the support and chloroform as the eluent, which afforded purified 1 -(2,2-dichloro-1,1-difluoroethoxy)-4-(4-(methylsulfonyl)phenoxy)benzene, mp 67°-70° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][N:9]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 28c (3.1 g; 8 mmol) is suspended in acetonitrile (20 ml) under addition of N,N-diisopropyl ethyl amine (3.24 ml; 19 mmol). Methanesulfonylchloride (1.3 g; 11 mmol) is added and the mixture is stirred for 18 h at 25° C. The reaction mixture is evaporated to dryness and purified by silica gel chromatography. Yield: 3.5 g (102.5%), ESI-MS: m/z=450 [M−H]−
Reaction SMILES: [CH3:1][C@@H:2]1[C:8](=[O:9])[NH:7][C@H:6]([CH3:10])[CH2:5][CH2:4][N:3]1C(OCC1C=CC=CC=1)=O>[Pd].CO>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][C@@H:6]([CH3:10])[NH:7][C:8]1=[O:9]
Reactant: C[C@@H]1CCN(C(=O)OCc2ccccc2)[C@H](C)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCN[C@H](C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl (2R,5R)-2,5-dimethyl-3-oxo-1,4-diazepane-1-carboxylate (160 mg) and 10% palladium on carbon (32 mg) in methanol (15 mL) was stirred at room temperature overnight, filtered over Celite, and washed with 10% methanol in dichloromethane. The filtrate was concentrated under reduced pressure to yield the title compound. MS 143.1 (M+1).
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11](N3CCCC3)=[O:12])[CH2:10][C:5]=2[NH:4][CH:3]=1.ClC(Cl)C.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.P(Cl)(Cl)(Cl)=O>C(=O)([O-])[O-].[K+].[K+]>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:11]([CH:9]2[CH2:8][CH2:7][C:6]3[N:2]=[CH:3][NH:4][C:5]=3[CH2:10]2)=[O:12])=[CH:23]1
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1c[nH]c2ccccc12)C1CCc2nc[nH]c2C1
Reaction time: 7 h
Yield: 43.9 %

Procedure:
4 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride obtained in Example 5 were added to 40 ml of dichloroethane, and 2.74 g of indole and 4.4 ml of phosphorus oxychloride were added thereto. The mixture was stirred at 80° to 85° C. for 7 hours and then at room temperature overnight. To the mixture was added 40 ml of a cold potassium carbonate aqueous solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography using chloroform/methanol as an eluent to obtain 1.82 g of 5-[(indol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole as a foam-like substance. In 1 ml of methanol were dissolved 0.16 g of the resulting product and 0.06 g of fumaric acid, and 5 ml of acetonitrile was added to the solution. The formed crystal was collected by filtration to obtain 0.13 g of 5-[(indol- 3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.