Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH2:17][C:18]1[C:27]2[N:28]=[C:29]([CH2:38][CH3:39])[N:30]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([OH:40])=[CH:21][C:20]=2[N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:38]([C:29]1[N:30]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:26]2[C:25]3[CH:24]=[CH:23][C:22]([O:40][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:21][C:20]=3[N:19]=[C:18]([NH2:17])[C:27]=2[N:28]=1)[CH3:39]
Reactant: ClCCN1CCOCC1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2n1CC1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCCN4CCOCC4)ccc3c2n1CC1CCOCC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
Cesium carbonate (1.41 g, 4.32 mmol) was added to a solution of 4-(2-chloroethyl)morpholine hydrochloride (348 mg, 1.87 mmol) and 4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol (471 mg, 1.44 mmol, prepared in Parts A and B of Example 553) in anhydrous DMF (25 mL). The reaction mixture was heated at 75° C. overnight, allowed to cool, and poured into 1% aqueous sodium carbonate (300 mL). The resulting mixture was stirred for two hours and then extracted with chloroform (4×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-40% methanol/dichloromethane (20:80) in dichloromethane). The resulting solid was recrystallized from acetonitrile and dried under vacuum to yield 393 mg of 2-ethyl-7-(2-morpholin-4-ylethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 230-232° C. Anal. calcd for C24H33N5O3: C, 65.58; H, 7.57; N, 15.93. Found: C, 65.48; H, 7.39; N, 15.91.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1(Br)[CH2:11][CH2:10][CH2:9][CH2:8]1.CN(C=O)C.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([C:25](=[O:27])[CH3:26])[CH:24]=1>O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:23]([C:25](=[O:27])[CH3:26])[CH:24]=1
Reactant: BrC1CCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)ccc1OC1CCCC1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 101 %

Procedure:
Potassium carbonate (6.55 g, 47.4 mmol), cyclopentyl bromide (8.25 g, 55.3 mmol) and DMF (5 ml) were added to a DMF solution (10 ml) of 5′-bromo-2′-hydroxyacetophenone (8.5 g, 39.5 mmol), and the resulting mixture was stirred at 60° C. for 4.5 hours. Potassium carbonate (3.0 g, 21.7 mmol) and cyclopentyl bromide (2.0 g, 13.4 mmol) were added to the resultant mixture, and stirred at 60° C. for 9 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure to thereby obtain 11.3 g of oily pale yellow 1-(5-bromo-2-cyclopentyloxyphenyl)ethanone (yield: 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:35]=[CH:34][C:28]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(NC(=O)Cc2ccc(C=CC(=O)O)cc2)c2ccccc2N2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C(NC(=O)Cc2ccc(CCC(=O)O)cc2)c2ccccc2N2CCCCC2)cc1

Procedure:
An amount of 0.91 gm (2 m mol) of 4-[N-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid was dissolved in 50 ml of methanol, and, after the addition of 0.5 gm of palladium (10% on charcoal), the mixture was catalytically hydrogenated at ambient temperature under a hydrogen pressure of 3 bar. After the hydrogen uptake ended, the catalyst was filtered off and recrystallized from a small amount of acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[C:14]([O-])([O-])=O.[K+].[K+].IC.O>CN(C)C=O>[CH3:14][O:12][C:11]([C:4]1[S:5][C:6]([CH:7]([OH:10])[CH2:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:13]
Reactant: CCC(O)c1sc(C(=O)O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCC(O)c1sc(C(=O)OC)cc1Cl
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A solution of crude 4-chloro-5-(1-hydroxy-propyl)-thiophene-2-carboxylic acid (0.262 g) in dimethylformamide (6.0 mL) is treated with K2CO3 (0.502 g, 3.63 mmol) and iodomethane (0.17 mL, 2.73 mmol) and stirred overnight. The reaction mixture is then poured into H2O (15 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are washed with brine (1×), dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 50% EtOAc to provide 4-chloro-5-(1-hydroxy-propyl)-thiophene-2-carboxylic acid methyl ester (87.6 mg, 15%-2 steps) as a yellow syrup. MS (ES): 216.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CC(C)([O-])C.[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(OC(C)C)(=O)C>O1CCCC1.O>[CH3:5][C:2]([NH2:1])([CH3:6])[CH2:3][O:4][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(N)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(N)COc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 118.6 %

Procedure:
A solution of 2-amino-2-methyl-1-propanol (488 g, 5.47 mol) in tetrahydrofuran (1.46 L) was added over 35 mins to a solution of potassium tert-butoxide (634 g, 5.65 mol) in tetrahydrofuran (2.95 L) at 2±3° C. The mixture was maintained at this temperature for a further 55 minutes before 4-fluoronitrobenzene (551 mL, 3.90 mol) was added over 1 hour 25 mins keeping the temperature below 10° C. The mixture was warmed to 20±3° C. and stirred for 2 hours. Water (1.95 L) and Isopropyl acetate (1.95 L) were charged to the mixture which was stirred, settled and separated. The organic phase was washed again with water (1.95 L) before 5M hydrochloric acid (1.95 L) was charged, keeping the temperature below 25° C. Isooctane (1.95 L) was added and the layers separated. 5M hydrochloric acid (322 mL) was added to the aqueous phase which was then reduced to approximately 3.9 L by vacuum distillation, causing spontaneous crystallisation, and stirred at room temperature overnight. Filtration, washing with water (2×488 mL) and drying in vacuo at around 48° C. afforded the title intermediate as a white solid (972.1 g, 72% th).
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].[CH3:12][NH2:13]>C1COCC1.C(O)C>[Br:11][C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:13][CH3:12])=[O:4])=[N:10][CH:9]=1
Reactant: CN
Reactant: COC(=O)c1ncc(Br)cn1
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1ncc(Br)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid methyl ester (5.0 g, 23.0 mmol) in THF (10 mL) was added 8 N solution of methyl amine in ethanol (11.5 mL). The reaction mixture was heated 20 min in a microwave oven, cooled down to room temperature and concentrated under pressure to give 5 g of 5-bromo-N-methylpyrimidine-2-carboxamide as a solid LCMS: 216, 218 (M+1).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[C:21]([Cl:26])[N:20]=1.CCOC(C)=O>CN(C)C=O>[CH:1]1([N:4]([C:23]2[CH:22]=[C:21]([Cl:26])[N:20]=[C:19]([Cl:18])[N:24]=2)[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OCCCNC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCCN(c1cc(Cl)nc(Cl)n1)C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
To a solution of 3-(cyclopropylamino)propan-1-ol (7 g, 60.8 mmol) and Hunig's base (31.8 mL, 182 mmol) in N,N-dimethylformamide (20 mL), was added 2,4,6-trichloropyrimidine (7.10 mL, 60.8 mmol), stirred for 3 h at 0° C. Then, EtOAc (150 mL) was added, and the organic phase was washed with water, brine, dried over Na2SO4, and concentrated. Purification via FC afforded the title compound (3.8 g).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][N:5]=1)[CH3:3].Cl[C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[F:35][C:32]1[CH:33]=[C:34]2[C:29]([CH2:28][CH2:27][N:26]2[CH:23]2[CH2:24][CH2:25][N:20]([C:17]3[N:18]=[N:19][C:14]([C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:6]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[CH:30][CH:31]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: CN(C)c1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 2-(N,N-dimethylamino)pyridine-5-boronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][CH:5]([C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[O:4][CH2:3][CH2:2]2.CO.[Cl-].[NH4+].[N-:22]=[N+:23]=[N-:24].[Na+]>O>[N:22]([CH:1]1[CH2:2][CH2:3][O:4][CH:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH:7]1[OH:8])=[N+:23]=[N-:24]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC2OC2CCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1C1CC(O)C(N=[N+]=[N-])CCO1
Temperature: 70 °C
Yield: 58.5 %

Procedure:
To a solution of 5-(4,8-dioxabicyclo[5.1.0]octan-5-yl)-1-methyl-4-nitro-pyrazole (1.04 g, 4.35 mmol) in 4:1 MeOH:water (30 mL) was added ammonium chloride (0.58 g, 10.88 mmol) and sodium azide (1.41 g, 21.75 mmol). The mixture was heated at 70° C. behind a blast screen for 16 hr. The MeOH was removed under reduced pressure and EtOAc (20 mL) added. The organic layer was washed with saturated aqueous NaHCO3 (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-60% EtOAc/isohexane) gave 5-azido-2-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol as a pale yellow gum (718 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.76 (dd, J=9.3, 3.2 Hz, 1H), 4.18-4.10 (m, 1H), 4.08-4.04 (m, 4H), 3.91 (ddd, J=9.4, 6.6, 6.2 Hz, 1H), 3.79 (ddd, J=12.6, 8.6, 3.5 Hz, 1H), 2.44 (ddd, J=15.3, 9.4, 3.8 Hz, 1H), 2.37-2.29 (m, 1H), 2.24 (d, J=3.2 Hz, 1H), 2.12 (ddd, J=15.3, 5.7, 3.2 Hz, 1H), 2.06-1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=S.[NH2:34][CH2:35][CH2:36][OH:37].C(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:34][CH2:35][CH2:36][OH:37])=[N:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: NCCO
Reactant: COc1cc2c(NC(=S)Nc3c(C)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(N=C(NCCO)Nc3c(C)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Mercuric(II) oxide (0.107 g) was added to a mixture of 1-(2-chloro-6-methylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]thiourea (0.118 g), 2-aminoethanol (0.03 ml), chloroform (5 ml) and methanol (5 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia gas in methanol as eluent. There was thus obtained the title compound (0.128 g); NMR Spectrum: (DMSOd6+CD3CO2D) 1.47–1.62 (m, 2H), 1.85–2.11 (m, 5H), 2.29 (s, 3H), 2.67 (s, 3H), 2.87 (t, 2H), 3.33 (d, 2H), 3.59 (t, 4H), 3.79 (s, 3H), 4.0 (d, 2H), 7.08 (s, 1H), 7.19–7.32 (m, 3H), 7.4 (d, 1H), 8.43 (s, 1H), 10.5 (br s, 1H); Mass Spectrum: M+H+ 513 and 515.
Reaction SMILES: [C:1]1(CC(N)=O)[CH:6]=CC=[CH:3][CH:2]=1.[CH:11]1([C:14]2[N:18]([CH3:19])[C:17]([CH:20]=[O:21])=[CH:16][N:15]=2)[CH2:13][CH2:12]1>>[CH2:11]([C:14]1[N:18]([CH3:19])[C:17]([CH:20]=[O:21])=[CH:16][N:15]=1)[C:13]1[CH:12]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: Cn1c(C=O)cnc1C1CC1
Product: Cn1c(C=O)cnc1Cc1ccccc1

Procedure:
2-Benzyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from 2-phenyl-acetamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22]O>>[C:1]1([S:7]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2cc(OCCSc3ccccc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCS(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-(2-phenylmercapto-ethoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.[NH2:17][C:18]1[CH:23]=[C:22]([OH:24])[C:21]([CH3:25])=[CH:20][CH:19]=1>C(OCCO)C>[OH:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)[CH:19]=[CH:20][C:21]=1[CH3:25]
Reactant: Cc1ccc(N)cc1O
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Solvent: CCOCCO
Product: Cc1ccc(Nc2c(C#N)cnc3c2sc2ccccc23)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A mixture of 300 mg (1.20 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and 160 mg (1.32 mmol) of 5-amino-o-cresol in 5 mL of 2-ethoxyethanol is heated at reflux temperature for 8 hours, then stirred at room temperature overnight. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to provide 220 mg (55%) of a light yellow solid, mp 260° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([N:7]([CH:8]1[CH2:9][CH2:10]1)[CH3:17])=[O:6]
Reactant: CI
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N(C)C2CC2)cc1Br
Temperature: 25 °C

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-N-cyclopropyl-4-methyl-benzamide (Intermediate 95, 6 g, 23.25 mmol) in anhydrous tetrahydrofuran (100 mL) under argon was treated with small portions of sodium hydride (1.6 g, 40 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to warm to ambient temperature and after 1 h, methyl iodide (3.11 mL, 50 mmol) was added and the reaction mixture was refluxed for 5 h. It was cooled to ambient temperature, poured into cold water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a dirty brown solid that was used as such for the next step (6.3 g, ˜100%).
Reaction SMILES: [Na].[CH3:2][C:3]([CH2:6][CH3:7])=[N:4][OH:5].[CH3:8][Si:9]([CH3:13])([CH3:12])[CH2:10]Cl>CN(C)C=O>[CH3:8][Si:9]([CH2:13][O:5][N:4]=[C:3]([CH2:6][CH3:7])[CH3:2])([CH3:12])[CH3:10]
Reactant: CCC(C)=NO
Reactant: C[Si](C)(C)CCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCC(C)=NOC[Si](C)(C)C
Yield: 70 %

Procedure:
To the above obtained dispersion of metallic sodium was added 34.8 g (0.4 mole) of methylethylketoxime and the reaction mixture was heated at 60° to 80° C. for about 180 minutes followed by removal of toluene under reduced pressure to give pasty sodium salt of methylethylketoxime. Then, this sodium salt of methylethylketoxime was dispersed in a mixture of 49.2 g (0.4 mole) of trimethylchloromethylsilane and 100 ml of N,N-dimethylformamide and heated at 70° to 80° C. for 3 hours with agitation. The reaction mixture after completion of the reaction was washed with water to remove sodium chloride formed as the by-product and N,N-dimethylformamide and the residue was extracted with diethyl ether followed by evaporation of the ether to give a crude product which was further distilled under reduced pressure to give 48.4 g of a liquid product boiling at 84° C. under 50 mmHg. This product is referred to as compound S-I hereinafter.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1([CH3:18])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][S:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[OH-].[K+]>>[CH3:18][C:5]1([CH2:4][C:3]([OH:19])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][S:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Agent: [K+]
Agent: [OH-]
Product: CC1(CC(=O)O)SCCc2c1[nH]c1ccccc21

Procedure:
This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Example 1 and 2 to afford the title compound, m.p. 147° - 149° C., nmr (CDCl3) δ 1.86 (S, 3H), 306 and 812 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), after recrystallization from benzene-hexane.
Reaction SMILES: [CH3:1][NH2:2].Cl.O[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>O>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([NH:2][CH3:1])[CH:14]=[CH:13]2)(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCC(=O)c1ccc2cc(O)ccc2c1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCC(=O)c1ccc2cc(NC)ccc2c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
MeNH2.HCl (11.0 g, 0.13 mol) was added to a mixture of 2-hydroxy-6-dodecanoylnaphthalene (8.0 g, 25 mmol), Na2S2O5 (12 g, 61 mmol), NaOH (5.2 g, 0.13 mol) and water (100 ml) in a high-pressure tube. The resulting mixture was stirred at 140° C. for 48 hours, followed by filtration to collect a solid. The solid was sufficiently washed with water and recrystallized from CH2Cl2-EtOH to give the title compound (5.6 g, yield: 67%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:17][C@@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (0.050 g, 0.184 mmol) in dichloromethane (0.3 mL) was added triethylamine (0.051 mL, 0.369 mmol) followed by 4-chlorobenzene-1-sulfonyl chloride (0.047 g, 0.221 mmol). The reaction was stirred at ambient temperature overnight. The crude material was purified using a 12 g silica gel cartridge eluting with 5-50% ethyl acetate/hexanes over 25 minutes to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.58 (s, 1H), 8.01-7.95 (m, 2H), 7.47-7.41 (m, 3H), 6.93 (d, J=7.3, 1H), 6.45 (d, J=8.5, 1H), 3.79-3.68 (m, 1H), 3.52-3.43 (m, 3H), 3.25 (dd, J=11.0, 4.1, 1H), 2.83-2.66 (m, 2H), 2.07-1.90 (m, 2H), 1.69 (dq, J=12.7, 7.9, 1H), 1.39-1.27 (m, 1H); MS (ESI+) m/z 446 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: C=CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 75.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and allyl bromide were reacted by the same way with the example 45-1 to obtain the titled compound (225 mg, yield: 75.1%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:3]([OH:19])[C:4]([N:6]1[CH2:17][C@@H:16]([Cl:18])[CH2:15][C@H:7]1[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[CH2:27]([O:34][C:35]([NH:37][C@@H:38]([CH2:42][CH2:43][S:44](=[O:47])(=[O:46])[NH2:45])[C:39](O)=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([NH:37][C@@H:38]([CH2:42][CH2:43][S:44](=[O:46])(=[O:47])[NH2:45])[C:39]([NH:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:3]([OH:19])[C:4]([N:6]1[CH2:17][C@@H:16]([Cl:18])[CH2:15][C@H:7]1[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])=[O:40])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NS(=O)(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCS(N)(=O)=O)NC(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
Following a procedure similar to that described in Example 66, but using 122 mg (0.32 mmol) of (4S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide [prepared as described in Preparation 21(b)] and 100 mg (0.32 mmol) of (S)-2-benzyloxycarbonylamino-4-sulfamoylbutyric acid, 169 mg of the title compound were obtained as a colorless powder, melting at 115°-122° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C[O-].[Na+].[Cl:7][C:8]([Cl:24])([Cl:23])[CH:9](Cl)[CH:10]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C(O)C>[Cl:7][C:8]([Cl:24])([Cl:23])[CH:9]([S:3][CH2:1][CH3:2])[CH:10]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCSC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
3.1 g (0.05 mol) of ethylmercaptan were added dropwise to a solution of 3.4 g (0.05 mol) of sodium methylate in 50 ml of absolute ethanol. The mixture was subsequently stirred at room temperature for 1 hour. A solution of 16.7 g of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one (Example 3) in 200 ml of ethanol was then added dropwise to this mixture, and the resulting mixture was subsequently stirred at room temperature for 6 hours. The inorganic salt was then filtered off and the filtrate was concentrated. After triturating in hexane, the residue crystallized. 8.9 g (50% of theory) of 1,1,1-trichloro-2-ethylmercapto-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one of melting point 101°-105° C. were obtained.