Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([CH2:17][CH2:18]Br)[C:13]([O:15][CH3:16])=[O:14].O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2([C:13]([O:15][CH3:16])=[O:14])[CH2:18][CH2:17]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COC(=O)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C1(n2cc([N+](=O)[O-])cn2)CC1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (3.0 g) in N,N-dimethylacetamide (30 mL) was added sodium hydride (60% in mineral oil, 1.2 g) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added methyl 2,4-dibromobutanoate (6.9 g) in an ice bath, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.4 g).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:24]([N:26]4[CH2:30][CH2:29][C@@:28]5([C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=6[C:32](=[O:39])[O:31]5)[CH2:27]4)=[O:25])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[N:14]=1>O1CCOCC1>[S:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:24]([N:26]4[CH2:30][CH2:29][C@@:28]5([C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=6[C:32](=[O:39])[O:31]5)[CH2:27]4)=[O:25])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[N:14]=[CH:10]1
Reactant: Nc1nc(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)cs1
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5cscn5)cc4)CC3)C2)c2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Isoamyl nitrite (10.0 μL) was added to a solution of (1R)-1′-({1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (25.0 mg, 0.06 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixture was stirred at 80° C. for 2 hours. Then the solvent from the mixture was removed and the crude product was purified by prep-HPLC. LC-MS: 417.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([OH:33])=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:26])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(c1CNC(=O)OC(C)(C)C)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1CNC(=O)OC(C)(C)C)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A solution of 3 g (6.55 mmol) of 5-[(1-tert-butoxyformamido)methyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid in 65 ml of methylene chloride was cooled to 20° and treated with 1.1 ml (10.62 mmol) of benzyl alcohol. After the addition of 20 mg of 4-dimethylaminopyridine a solution of 1.5 g (7.27 mmol) of dicyclohexylcarbodiimide in 16 ml of methylene chloride was added dropwise, whereupon the mixture was warmed to room temperature and was stirred for 3 hours. The precipitated dicyclohexylurea was filtered off and washed with a small amount of methylene chloride. The filtrate was washed with sodium bicarbonate solution and water, dried over sodium sulphate and concentrated. The residue remaining was chromatographed on silica gel with hexane/ethyl acetate, whereby 2.9 g of benzyl 5-[(1-tert-butoxyformamido)methyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate were obtained as a colourless powder m.p. of 139°-141°; IR 3443, 2972, 2930, 1724, 1605, 1498 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH:6](/[CH:8]=[CH:9]/[O:10]C)[CH2:5][CH2:4][O:3]1.Cl>C1COCC1>[CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([CH2:8][CH:9]=[O:10])[CH2:5][CH2:4][O:3]1
Reactant: CO/C=C/C1CCOC(C)(C)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CC(CC=O)CCO1
Temperature: 20 °C
Yield: 95.2 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-[(E)-2-(methyloxy)ethenyl]tetrahydro-2H-pyran (2.93 g, 17.21 mmol) in THF (15 ml) was added 2N HCl (15 ml, 30.0 mmol) and the mixture was stirred at 20° C. After 1 hour the mixture was extracted with diethyl ether (3×25 ml); the combined ether extracts dried (Na2SO4), filtered and evaporated in vacuo (at 50 mbar and water bath at 15° C.) to give the title compound as a pale yellow oil (2.56 g).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: C1CCNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CN3CCCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde and pyrrolidine (Aldrich, St. Louis, Mo.). 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H); 8.71 (d, J=2.35 Hz, 1H); 8.36 (d, J=2.54 Hz, 1H); 8.20 (d, J=2.35 Hz, 1H); 8.13 (dd, J=8.80, 2.74 Hz, 1H); 6.76 (d, J=8.80 Hz, 1H); 6.33 (br. s., 2H); 3.94 (s, 3H); 3.58 (s, 2H); 2.57 (br. s., 4H); 2.54 (s, 3H); 1.80-1.90 (m, 4H). m/z (ESI, +ve ion) 392.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Product: Cc1cc(CCc2ccccc2)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 71, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with benzylbromide to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(2-phenylethyl)pyridine as an amber oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Yield: 95.1 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (5.0 g, 17 mmol) was combined with methyl 6-aminonicotinate (2.86 g, 1.10 eq) which gave methyl 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate (6.6 g) in 94% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.89 (s, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 8.22 (dd, J=8.9, 2.2 Hz, 1H), 6.67 (s, 1H), 4.77 (m, 1H), 3.86 (s, 3H), 3.06 (s, 6H), 2.42 (m, 2H), 2.00 (m, 4H), 1.68 (m, 2H); MS m/z 409.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S([CH:28]([N+]#[C-])[N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]2[O:13][CH:30]=[N:29][CH:28]=2)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: [C-]#[N+]C([N+]#[C-])S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(-c2cnco2)c1Cl

Procedure:
25 g (0.09 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate (Ex. A.1.), 17.6 g (0.09 mol) of tosylmethylene isocyanide and 6.2 g (0.045 mol) of finely pulverulent potassium carbonate are stirred together with 450 ml of methanol at reflux temperature for 5 hours. The solvent was subsequently stripped off, the residue was taken up in ethyl acetate, and the mixture was extracted with water. The ethyl acetate phase was dried using sodium sulfate and concentrated.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:19]=[CH:18][C:17]([C@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:22][CH:21]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(C(F)(F)F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.6 %

Procedure:
(2R,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (580 mg, 1.57 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 12 mL, 68.52 mmol) and the mixture stirred at room temperature for 17 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (341 mg, 70%). 1H NMR (600 MHz, cd3od) δ 1.68-1.79 (m, 2H), 2.10 (d, 1H), 2.21 (d, 1H), 2.98-3.10 (m, 2H), 3.35 (d, 1H), 3.99-4.07 (m, 1H), 5.64 (s, 1H), 7.60 (d, 2H), 7.66 (d, 2H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1150
Reaction SMILES: CN1CCOCC1.[NH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[NH:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[NH:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:15]([C:23]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)CN
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
1.01 g of N-methylmorpholine is added to a solution in 60 ml of methylene dichloride of 6.39 g of H-Phe-Gly-AHCP-Ile-AMPA [obtainable by subjecting H-Gly-OMe to a condensation reaction with BOC-Phe-OH to give BOC-Phe-Gly-OMe, saponifying the latter and subjecting the product to a condensation reaction with H-AHCP-Ile-AMPA to give BOC-Phe-Gly-AHCP-Ile-AMPA and splitting off the BOC group]. 2.43 g of 4-BOC-aminocyclohexanecarbonylic acid, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of methylene dichloride are added with stirring, the mixture is stirred for 14 hours at 0°-10°, the precipitated dicyclohexylurea is filtered off and the manner gives 4-BOC-aminocyclohexylcarbonyl-Phe-Gly-AHCP-Ile-AMPA, m.p. 141°-143°.
Reaction SMILES: [F:1][CH:2]([F:11])[S:3][CH2:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][CH:2]([F:11])[S:3][CH2:4][C:5](=[N:13][OH:14])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: NO
Reactant: CC(C)(C)C(=O)CSC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(CSC(F)F)=NO

Procedure:
A mixture of 1-difluoromethylthio-3,3-dimethyl-2-butanone (2.21 moles) from example 1, hydroxylamine hydrochloride (2.44 moles) and sodium carbonate (1.22 moles) in aqueous ethanol (1 liter of water and 2.3 liters of ethanol) was heated at its reflux temperature for 7.5 hours. This reaction mixture was poured into water, and the product was extracted into diethyl ether. The ether was washed with water and dried, then the ether extracts were evaporated under reduced pressure leaving a residue of 1-difluoromethylthio-3,3-dimethyl-2-butanone oxime. A pure sample, m.p. 92° to 95°C., was obtained by recrystallization from a mixture of diethyl ether and petroleum ether (b.p. 30° to 60°C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:27]=[CH:26][C:17]2[C:18]3[CH:19]=[CH:20][O:21][C:22]=3[CH2:23][CH2:24][O:25][C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:27]=[CH:26][C:17]2[C:18]3[CH:19]=[CH:20][O:21][C:22]=3[CH2:23][CH2:24][O:25][C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1OCCc1occc1-2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCCc1occc1-2
Reaction time: 18 h
Yield: 95.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.55 g) was added to a solution of methyl 8-amino-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (Intermediate 15, 0.47 g) and pyridine (3 mL) in DCM (5 mL) and the mixture was stirred for 18 hours. The mixture was evaporated to dryness and water and ethyl acetate were added. The organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino)-4,5-dihydro-3,6-dioxa-benzo[e]azulene-7-carboxylate (0.86 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH:6]1[CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:4].B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:32][C:2]([F:1])([F:33])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]1[CH:17]1[CH2:18][CH2:19][N:20]([S:23]([C:26]2[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=2)(=[O:25])=[O:24])[CH2:21][CH2:22]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCC(C3c4ccc(O)cc4CCN3C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,2,2-trifluoro-1-{6-methoxy-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethanone (0.036 g, 0.074 mmol) in CH2Cl2 (3 ml) under an atmosphere of N2 cooled to −78° C. was added boron tribromide as a 1.0 M solution in CH2Cl2 (0.3 ml, 0.3 mmol). The reaction mixture was stirred overnight slowly, while allowing it to warm to RT. MeOH (1 ml) was added to the reaction mixture and stirring was continued at RT for 10 minutes. Sat. NaHCO3 was added to the reaction mixture until the pH of the aqueous layer was 7. The mixture was then extracted with EtOAc (3×20 ml), the combined organics were washed with brine (1×20 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the desired product as an off white solid (0.028 g, 0.059 mmol, 80% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13](OCC)=[O:14])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.CC(C[AlH]CC(C)C)C.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH2:13][OH:14])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)cc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccccc2)nc1CO
Temperature: -15 °C
Reaction time: 1 h
Yield: 137.1 %

Procedure:
To a solution of ethyl 4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (100 mg, 434 μmol) in toluene (1 mL) cooled to −78° C. was added dropwise DIBAL-H (1M solution in toluene, 868 μL, 868 μmol) keeping the temperature below −68° C. The reaction mixture was stirred at −78° C. for 30 min and at −15° C. for 1 h. At that temperature, KHSO4 (10% aqueous solution, 10 mL) was added dropwise and the resulting reaction mixture was extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (1×30 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 112 mg crude material. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as yellow viscous oil (52 mg, 276 μmol, 63.6%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9]C)=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+]>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: COC(=O)[C@@H](N)CCSC
Agent: [Na+]
Agent: [OH-]
Product: CSCC[C@H](N)C(=O)O
Reaction time: 0.58 h
Yield: 68.4 %

Procedure:
Methyl L-methioninate (+)-hemitartrate ([α]D + 29.8°, 5.914 g., 18.9 mmole) was stirred with 5N-sodium hydroxide solution [2.514 g., 62.8 mmole, 3.32 equiv. sodium hydroxide in water (12.5 ml.)]. Most of the hemitartrate dissolved immediately but after 8 minutes a solid had precipitated (disodium (+)-tartrate). After 1 hour 35 minutes the pH of the mixture was adjusted from 12.3 to 5.8 (the isoelectric point of methionine) with concentrated hydrochloric acid -- solid was present all the time. The mixture was cooled in ice, filtered, and the solid washed with water (2 × 3 ml.), and dried over phosphorus pentoxide giving L-methionine (1.928 g., 68%), m.p. decomp. 210 to 215°, darkening began at 225° but the sample did not melt below 320°. An authentic sample of L-methionine decomposed at 225° to 230°, darkening and shrinking occurred at 230° but the sample did not melt below 330°, [α]D22 + 21.7° (c 1.007, 1N-HCl) -- 4 dm. tube, and [α]D22 + 21.4° (c 1.021, 1N-HCl) -- 1 dm. tube.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:34].FC(F)(F)S(O)(=O)=O>ClCCl>[I:34][C:9]1[C:5]2[NH:6][C:7](=[O:8])[C:2]([CH3:16])([CH3:1])[O:3][C:4]=2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: [IH2+]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(I)c2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a suspension of 2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 1(1), 1.00 g) in dichloromethane (50 mL) was added bis(pyridine)iodonium tetrafluoroborate (1.68 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were further added bis(pyridine)-iodonium tetrafluoroborate (0.84 g) and trifluoromethanesulfonic acid (1.2 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. The resultant residue was diluted with ethyl acetate, tetrahydrofuran and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous saturated sodium hydrogencarbonate solution, an aqueous 15% sodium thiosulfate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was triturated in n-hexane/ethyl acetate to give 5-iodo-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (0.90 g) as a pale brown powder.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH2:41][CH3:42])([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([CH3:40])[CH:34]=3)[CH2:31][CH3:32])=[CH:26][C:25]=2[CH3:43])=[C:21]([CH3:23])[CH:22]=1)=[O:17].C(OCC)C>CN(C)C=O>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:35]([CH3:40])[CH:34]=3)([CH2:31][CH3:32])[CH2:41][CH3:42])=[CH:26][C:25]=2[CH3:43])=[C:21]([CH3:23])[CH:22]=1)=[O:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2sc(C(=O)OC)cc2C)c(C)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(-c2sc(C(=O)OC)cc2C)c(C)c1
Reaction time: 0.2 h
Yield: 88285 %

Procedure:
t-Butyldimethylsilyl chloride (36 mg, 0.238 mmol) and imidazole (40.5 mg, 0.595 mmol) were added to a solution of 5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-4-methyl-thiophene-2-carboxylic acid methyl ester (Example 20-(1); 50.3 mg, 0.119 mmol) in N,N-dimethylformamide (0.2 mL) at room temperature, and the mixture was stirred at the same temperature for 0.2 hour. Diethyl ether was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=95/5 to ethyl acetate only) to give the title compound (56.4 g, 88.3%).
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:14][C:15]([C:17]1[N:18]=[C:19]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[N:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:21]=1)=[O:16])C1C=CC=CC=1.[Si](I)(C)(C)C.O>C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[CH:21]=[C:17]([C:15]([NH:14][C@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[OH:8])=[O:16])[N:18]=[C:19]2[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])=[CH:23][CH:24]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1OCc1ccccc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@H]1CCC[C@@H]1O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of N-[(1S, 2S)-2-(benzyloxy)cyclopentyl]-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide (Table entry 282, prepared according to the procedures described in Examples 13 and 14) (119 mg, 0.22 mmol) in CH2Cl2 (4 mL), TMSI (0.2 mL, 1.4 mmol) was added. The mixture was stirred at rt overnight, and diluted by water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc) to afford 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(1S, 2S)-2-hydroxycyclopentyl]-1H-imidazole-4-carboxamide (80 mg, 82% yield) as a white foam: LC-MS m/z 450.0 (MH+), retention time 3.24 min (method 1); Rf=0.45 (50% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 1.22-2.24 (6H, m), 3.97-4.15 (2H, m), 7.03-7.42 (7H, m), 7.86 (1H, s).