Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2OC)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(C)C)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
1-isopropyl-4-(2-methoxy-4-nitrophenoxy)piperidine (167 mg, 0.57 mmol) was dissolved in 20 mL of methanol and placed under a nitrogen atmosphere. A catalytic amount of 20% palladium hydroxide on carbon was added and a hydrogen balloon was connected to the reaction flask. The flask was flushed five times with hydrogen and stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction mixture was filtered and washed with methanol. The filtrate was evaporated under reduced pressure. Acetonitrile (1.0 mL) was added to the residue, swirled for 10 min, and decanted away from white film. The acetonitrile layer was evaporated under reduced pressure yielding 4-(1-isopropylpiperidin-4-yloxy)aniline as a brown oil (131 mg, 87%). LC/MS (m/z): 265.2 (MH+), Rt 0.33 minutes.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([S:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[OH:24])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])[CH3:5].[Na+].Cl[CH2:27][C:28]([O-:30])=[O:29].Cl>O1CCCC1.O>[CH3:16][C:13]([C:11]1[CH:10]=[C:9]([S:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[O:24][CH2:27][C:28]([OH:30])=[O:29])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[CH:12]=1)([CH3:14])[CH3:15]
Reactant: O=C([O-])CCl
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.33 g, 0.0138 mole) was added to a solution of trans-2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexanol (3.4 g, 0.0106 mole) in tetrahydrofuran (50 ml) at 0° C. After stirring the reaction mixture for 1.5 hours, the tetrahydrofuran was removed by rotary evaporation. Dimethyl sulfoxide (75 ml) was added followed by chloroacetic acid sodium salt (1.48 g, 0.0127 mole), and the reaction mixture was stirred at room temperature for 10 days. Water (100 ml) was added dropwise to the mixture followed by 10% hydrochloric acid (10 ml). The product was extracted twice with 200 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice with 200 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by chromatography on silica gel. The structure was supported by NMR and elemental analysis (378.6+1/4 mole H2O).
Reaction SMILES: C1([O:6][C:7](=[O:43])[C@@H:8]([NH:16][C:17](=[O:42])[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:40])[NH:38][OH:39])=[CH:23]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)CCCC1.[OH-].[Na+]>C1COCC1.CO>[OH:39][NH:38][C:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([CH2:19][CH2:18][C:17]([NH:16][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:43])=[O:6])=[O:42])=[CH:28][CH:27]=2)=[O:41])=[O:40]
Reactant: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)ccc2[nH]1)NO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)O)ccc2[nH]1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
Compound (100) (80 mg, 0.14 mmol) was dissolved in THF/MeOH (1 ml/0.5 ml) and 1.4 M NaOH (0.5 ml) added. The reaction was stirred at room temperature for 2 h. THF was removed by blowing a stream of N2 gas at the surface of the solution and the residual material purified by preparative HPLC to give compound (101) (34.9 mg), LCMS purity 95%, m/z 523 [M++H]+, 1H NMR (400 MHz, MeOD), δ:1.35-1.50 (4H, m, alkyl), 1.60-1.75 (4H, m, alkyl), 2.15 (2H, br t, CH2), 2.55 (2H, br t, CH2), 2.95 (3H, m, CH+CH2), 3.10 (1H, dd, CH), 4.65, (1H, m, NHCHCO), 7.00-7.15 (7H, m, Ar), 7.35-7.41 (2H, m, Ar)
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].II.[Cl:13][Si:14](Cl)([CH3:16])[CH3:15]>O1CCCC1.C(OCC)C>[Cl:13][Si:14]([CH3:16])([CH3:15])[C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH2:2])=[CH:5][CH:6]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: ClC=Cc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1ccc([Si](C)(C)Cl)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Two milliliters of chlorostyrene was added to 0.97 gram of magnesium turnings in 20 milliliters (ml) of dry tetrahydrofuran under argon. A crystal, about 5 milligrams of iodine, was then added, and the reaction mixture was heated at 65° C. with an air gun until the reaction started (approximately 15 minutes). Thereafter, an additional 2.33 milliliters of chlorostyrene was added slowly to the reaction mixture with a syringe over a period of 15 minutes. The reaction mixture was then refluxed for about 5 minutes at 67° C., and then allowed to cool to room temperature. Dichlorodimethylsilane (9.7 milliliters) was then carefully added with a syringe, (the reaction was exothermic) followed by stirring at 60° C. in an oil bath for 30 minutes. The reaction mixture was then cooled to room temperature, diluted with anhydrous diethylether (approximately 75 ml), and filtered to remove the insoluble magnesium salts. Subsequently, the solvent tetrahydrofuran was removed under reduced pressure and the resulting oil was distilled to yield 3.9 grams (55 percent) of the above product, which was characterized by NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 30 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
52.9 g (0.35 mol) of o-nitrobenzaldehyde was dissolved in 150 ml of methanol and an aqueous solution of 27.8 g (0.38 mol) of hydroxylamine hydrochloride in 35 ml of water was added over 30 minutes while maintaining the temperature at 30° C. The mixture was stirred at the same temperature for two hours and diluted with 300 ml of water. White crystals deposited were filtered, washed with water and dried. 53 g of o-nitrobenzaldoxime was obtained. Yield 91%; M.P. 95°-98° C.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(C)(=O)=O)CC2)n1
Yield: 97 %

Procedure:
Reaction of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine (460 mg, 1.0 mmol) with methanesulfonyl chloride (1 mL, 12.7 mmol) and K2CO3 (2.0 g, 14.5 mmol) in CH2Cl2 (10 mL) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide in 97% yield: mp (CH2Cl2/MeOH) 225-228° C.; 1H NMR (DMSO-d6) δ 7.88 (d, J=8.0 Hz, 1H), 7.68 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.52-4.45 (m, 2H), 3.97 (s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.50 (br m, 1H), 3.29-3.21 (m, 2H), 2.96 (s, 3H), 1.96 (br, 2H), 1.44-1.42 (m, 2H); Anal. Calcd. for C22H28F2N8O5S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.2; H, 5.2; N, 20.9%.
Reaction SMILES: [CH2:1](I)[CH3:2].CN(C=O)C.[Br:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>O>[Br:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[O:22][CH2:1][CH3:2]
Reactant: COC(=O)c1cc(O)c(Br)c(OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)OC)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 1.0-liter egg plant-type flaks, ethyl iodide (6.91 mL, 86 mmol) was added to a DMF (150 mL) solution of the previously-obtained methyl 4-bromo-3-hydroxy-5-methoxybenzoate and potassium carbonate (11.9 g, 86 mmol), and stirred overnight at room temperature. Water was added to the reaction solution, the formed precipitate was taken out through filtration and dried under reduced pressure to obtain the title compound as a colorless solid.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:7]([OH:10])([CH3:9])[CH3:8])=O.[OH-].[K+].O.ClCCl>CO>[NH2:5][C@H:6]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:7]([CH3:9])([OH:10])[CH3:8]
Reactant: CC(C)(O)[C@H](NC(=O)C(F)(F)F)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)[C@H](N)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
5.6 g of 2,2,2-trifluoro-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-2-methyl-propyl]-acetamide and 2.27 g KOH are suspended in 61.1 ml of methanol. The reaction mixture is stirred for 20 hours at 60° C. and then combined with water and dichloromethane, the organic phase is dried and evaporated to dryness. 3.2 g of the product are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 29.1 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50° C. for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). 1H NMR (CDCl3, HMDSO), δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1H, br s); 6.92–7.89 (10H, m).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)C.[BH4-].[Na+]>O>[I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)/C=C/I
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)/C=C/I
Reaction time: 2 h

Procedure:
A solution of 78.2 g. (0.310 moles) of 1-iodo-trans-1-octen-3-one (Example 724) in 150 ml. of absolute ethanol is added dropwise over 2 hours to a slurry of 6.49 g. (0.172 moles) of sodium borohydride in 50 ml. of absolute ethanol cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours with ice cooling and is then poured into 1 l. of water. The mixture is extracted into benzene and the organic phase is washed with saturated brine, dried (Na2SO4) and evaporated. The resulting oil is dissolved into 400 ml. of absolute ethanol and treated with 5 mole percent of p-carboxyphenylhydrazine at 70° C. for 1.5 hours to remove residual ketone. The mixture is cooled and evaporated and the residue is dissolved into 400 ml. of ether and is filtered. The filtrate is washed with dilute sodium bicarbonate solution and saturated brine, dried (Na2SO4), and evaporated to an oil. This oil is chromatographyed upon 2 Kg. of Florisil packed in hexane and the product is obtained upon elution with benzene Distillation of the product yields a colorless oil, b.p. 74°-76° C. (0.005 tor.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:40]3[CH2:45][CH2:44][C:43]([F:47])([F:46])[CH2:42][CH2:41]3)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:16][CH2:15]2)[C:10]1=[O:31].O.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:40]3[CH2:45][CH2:44][C:43]([F:47])([F:46])[CH2:42][CH2:41]3)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)N5CCC(F)(F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2ccc(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
To a solution of (R)-3-[3-chloro-4′-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one (0.15 g) in THF (3 mL), add water (3 mL) and TFA 1 mL). Stir the mixture at room temperature for 5 hours. Partition the reaction with ethyl acetate and sodium bicarbonate (sat. solution), separate the organic layer, extract the aqueous with ethyl acetate again, combine the organic solutions, dry over sodium sulfate, filter and concentrate. Purify the residue on silica gel column with ethyl acetate for 30 minutes and then switch to 8% methanol in dichloromethane to afford 0.06 grams (52%) of the desired product as white solid. MS (m/z): 532 (M+).
Reaction SMILES: C(OC(=O)N[C:8](=[O:40])[CH2:9][CH2:10][CH2:11][C@H:12]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.[BH4-].[Na+]>CC(O)C.O>[C:36]([O:35][C:33](=[O:34])[NH:32][C@@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][OH:40])[CH2:13][O:14][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(=O)CCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred solution of the material from Step 3 (128 g, 219 mmol) in 2-propanol (1800 mL) and water (180 mL) at room temperature was added sodium borohydride (8.28 g, 219 mmol). The reaction mixture was stirred at room temperature overnight. Additional 2 g of sodium borohydride was added and stirred at room temperature for an additional 4 hours. The reaction mixture was concentrated to ⅓ volume and diluted with EtOAc and 1 N NaOH (100 mL). The reaction mixture was partitioned, and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes (0 to 50%) to afford 65 g of the title compound. 1H NMR (CHCl3-d): δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H), 4.72-4.65 (b, 1H), 3.72-3.62 (m, 2H), 3.60-3.52 (m, 3H), 1.62-1.42 (m, 4H), 1.42 (s, 9H), 1.42-1.23 (m, 2H), 1.05 (s, 9H).
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])([CH3:3])[CH3:2].C([Li])(CC)C.[Cl-].[NH4+].[O:26]1CCC[CH2:27]1>>[CH3:12][C:8]1[O:9][C:10]([CH:27]=[O:26])=[CH:11][C:7]=1[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:18])[CH3:17]
Reactant: C1CCOC1
Reactant: Cc1occc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Product: Cc1oc(C=O)cc1CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10 g) in tetrahydrofuran (250 mL) was cooled to −78° C. with stirring, and then sec-butyllithium (1.3 M in cyclohexane; 37.25 mL) was added drop-wise over 10 mins. After stirring for 45 mins at −78° C., the cooling bath was removed for a period of 15 mins then re-introduced. A solution of N,N-dimethylformamide (14.4 mL) in tetrahydrofuran (25 mL) was added drop-wise and the resulting reaction mixture was stirred at −78° C. for a further 2 hours. The reaction mixture was allowed to warm to room temperature and then poured into saturated ammonium chloride solution (150 mL). This mixture was extracted with diethyl ether (2×350 mL), and the combined organic extracts were washed with water (500 mL) and brine (500 mL), dried, and concentrated in vacuo to give compound 33 as an amber coloured oil. LC/MS System A: Rt=4.86 mins.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[S:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:14])=[O:13].N1C=CC=CC=1>ClCCl>[N:1]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18]3)(=[O:13])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: c1ccc2c(c1)CCCN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (Aldrich), 5-chlorosulfonyl-2-oxindole and pyridine in dichloromethane was stirred at room temperature overnight. The reaction was concentrated and the residue recrystallized from methanol to vie 5-(3,4, -dihydro-2H-quinoline-1-sulfonyl)-1,3-dihydro-indol-2-one. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.74 (s, 1H, NH), 7.84–7.90 (d, 1H, SO2NH), 7.67–7.72 (m, 2H, 2×CH), 7.01–7.16 (m, 4H, aromatic), 6.95–6.97(d, 1H, CH), 4.28–4.29 (m, 1H), 3.58 (s, 2H, CH2), 2.59–2.65 (m, 2H), 1.75–1.77 (m, 2H), 1.53–1.61 (m, 2H). MS m/z 329 [M+1].
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]1[O:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][CH2:15][CH:14]1[OH:25].N1C=CC=CC=1>C(Cl)Cl>[C:2]([Cl:1])(=[O:4])[O:25][CH:14]1[CH2:13][O:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][CH2:15]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1COC(c2ccccc2)OC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)OC1COC(c2ccccc2)OC1
Temperature: -40 °C

Procedure:
Triphosgene (bis(trichloromethyl)carbonate (13.35 g, 45.0 mmol) was added under argon at room temperature to a solution of 1,3-O-benzylideneglycerol (18.02 g, 100.0 mmol) in dry CH2Cl2 (300 ml). The reaction mixture was cooled to −40° C. and a solution of pyridine (10.9 ml, 135.0 mmol) was added over 35 min under stirring. Upon completion of the addition the reaction mixture was stirred for 30 min at −40° C. Then it was allowed to warm to 0° C. over 60 min and subsequently warmed to rt over 3.5 h under stirring. The reaction product was used in the next step without any further purification
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][CH3:17])[CH2:9][CH2:8][C:7]2([CH3:19])[CH3:18])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH3:21]>C1COCC1>[CH2:16]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:13][C:12]=2[CH:14]([OH:15])[CH2:20][CH3:21])[C:7]([CH3:19])([CH3:18])[CH2:8][CH2:9]1)[CH3:17]
Reactant: CC[Mg]Br
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure C, 6-isopropyl-4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde (Intermediate 7, 5.78 g, 26 mmol) and a solution of ethyl magnesium bromide (2M, 35 ml, 65 mmol) in THF were reacted to give the title compound as a yellow oil after purification by column chromatography using 5% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([CH2:13][SH:14])[C@H:11]([C:15](O)=[O:16])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1[C@H](CS)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To 240 ml of a chloroform solution containing 30 g of (4R,5R)-1,3-dibenzyl-2-oxo-5-(mercaptomethyl)imidazolidin-4-carboxylic acid, 22.7 g of pyridine and 2.6 ml of trifluoroacetic acid was added dropwise 60 ml of a chloroform solution containing 17.4 g of dicyclohexylcarbodiimide at 5° C. over 30 minutes. After the solution was refluxed for 5 hours, it was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and concentrated, and after the procedure was repeated, 300 ml of ethyl acetate was added to the residue, and the mixture was stirred at 50° C. for 30 minutes. After cooling to 25° C., insoluble materials were filtered off. After the filtrate was concentrated, 85 ml of methanol was added to the concentrate and the mixture was dissolved under heating. After cooling the solution, precipitated crystal was collected by filtration, and washed with cold methanol. Precipitated crystal was dried by blowing air at 50° C. to give 21.3 g of (3aS,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione as colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:14])[CH2:12]Cl)[N:6]2[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:14])[CH2:12][N:33]3[CH2:34][CH2:35][N:30]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH:32]3[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCN1
Reactant: Nc1ncnn2c(C(=O)CCl)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCN1CC(=O)c1ccc2c(N)ncnn12
Reaction time: 17 h
Yield: 81 %

Procedure:
To a solution of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-chloroethanone (1.00 g, 4.75 mmol), K2CO3 (1.97 g, 14.2 mmol) and potassium iodide (79 mg, 0.47 mmol) in DMF (20 mL), was added 1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperazine (1.53 g, 4.79 mmol, prepared by the method of Naylor et al J. Med. Chem. 36, 2075). The reaction was allowed to stir for 17 hours. The mixture was partitioned between ethyl acetate (200 mL) and saturated, aqueous Na2CO3 solution (100 mL). The layers were separated and the organic was washed with brine, dried (Na2SO4), and evaporated. The crude material was purified by ISCO® chromatography using a gradient elution from 50% to 100% ethyl acetate in hexanes to obtain 1.9 g (81%) of the desired product LC-MS [M+H]+=495.6, RT=2.56 min.