Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[C:15]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[N:35]1([CH2:40][CH:41](O)[CH2:42][CH3:43])[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:35]1([CH2:40][CH:41]([O:13][C:14]2[C:15]([CH2:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]3)[CH2:42][CH3:43])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: CCC(O)Cn1ccnc1
Reactant: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Cn1ccnc1)Oc1ccc2c(c1CS(=O)(=O)c1ccccc1)CCCC2=O
Reaction time: 144 h
Yield: 29 %

Procedure:
Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10 min to a mixture of 6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-2-butanol (165 mg, 1.08 mmol), triphenylphosphine (260 mg, 0.99 mmol) and tetrahydrofuran (2 mL) under nitrogen. The resulting mixture was stirred for 6 d, whereupon it was concentrated. The residue was purified by dry-flash column chromatography (SiO2, 1-9% 2-propanol-dichloromethane) to give 6-[1-(1H-imidazol-1-ylmethyl)propoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a foam, 125 mg, 29% yield. NMR spectrum was consistent with structure. MS EI: M+• 438.1608 (M+• 438.1613).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:14]([CH2:19][OH:20])([CH2:17]O)[CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(OCC)OCC>O1CCCC1>[CH2:7]([C:14]1([CH2:15][OH:16])[CH2:17][O:20][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCC(CO)(CO)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(=O)OCC
Solvent: C1CCOC1
Product: OCC1(Cc2ccccc2)COC1
Temperature: 110 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A solution of potassium t-butoxide in tetrahydrofuran (1M, 24 mL) was added into a solution of 2-benzyl-2-(hydroxymethyl)propane-1,3-diol (90 g, 0.5 mol) and diethyl carbonate (55 g, 0.5 mol) in tetrahydrofuran (500 mL) under nitrogen. The reaction mixture was refluxed for 6 h and then heated to 110° C. to distill the solvent. Then the mixture was stirred at 155° C. for 24 h. The mixture was purified via silica gel chromatography (petroleum ether/ethyl acetate 10:1 to 2:1) to afford (3-benzyloxetan-3-yl)methanol (40 g, 0.226 mol, 49%) was a white solid.
Reaction SMILES: O[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:7][CH2:6]1.C(S(F)(F)([F:34])(CC)N)C>ClCCl>[F:34][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:7][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(O)c2ccccc2)CC1
Reactant: CCS(N)(F)(F)(F)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(F)c2ccccc2)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of 1 g of trans-2-[4-(2-hydroxy-2-phenyl-ethoxy)-cyclohexyl]-isoindole-1,3-dione in 100 mL of dichloromethane cooled to −78° C. under nitrogen atmosphere was added 1.2 g of diethyl-amino sulfur-trifluoride. The mixture was allowed to warm and stir for 24 h, then quenched with 25 mL of saturated sodium carbonate. After stirring for 15 min, the mixture was diluted with 25 mL of dichloromethane and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-30% ethyl acetate in hexane gave 0.7 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.7 (t, 1H), 7.4-7.3 (m, 5H), 5.6 (dd, 1H), 4.1 (m, 1H), 3.9-3.65 (complex m, 2H), 3.45 (m, 1H), 2.3 (dd, 2H), 2.2 (m, 2H), 1.8 (d, 2H), 1.4 (dd, 2H).
Reaction SMILES: [C:1](=O)([O:5]CC)[O:2][CH2:3][CH3:4].CCOCC.[H-].[Na+].[CH3:16][C:17]1([CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[O:21][CH2:20][CH2:19][O:18]1>CCCCCC.C(O)C>[CH2:3]([O:2][C:1](=[O:5])[CH2:26][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:17]1([CH3:16])[O:18][CH2:19][CH2:20][O:21]1)[CH3:4]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)CCCC1(C)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CCCC1(C)OCCO1

Procedure:
11.8 Grams (0.1 moles) of diethyl carbonate in 12.5 ml. of anhydrous ether was added to 4.55 g. (0.1 moles) of a 53 per cent dispersion of sodium hydride in mineral oil which was washed with anhydrous hexane and dried under nitrogen. This mixture was stirred under nitrogen and 8.6 g (0.05 mole) of the ketal ketone, 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone was added dropwise over a period of two hours. A gentle reflux was maintained throughout the addition and the refluxing was continued for an additional period of approximately 11/2 hours. The solution was then cooled with an ice bath, 20 ml. of anhydrous ether and 2 ml. of absolute ethyl alcohol was added and it was stirred for 45 minutes to destroy any unreacted sodium hydride. The suspension was diluted with an equal volume of ether and the ice cold suspension was then added to a rapidly agitated mixture of 6 ml. of glacial acetic acid and 200 ml. of ice water. The etheral layer was separated, and the aqueous layer was additional extracted twice with ether. The extract was washed with saturated sodium bicarbonate and with a saturated sodium chloride, dried with sodium sulfate, filtered and evaporated in vacuo to give the crude β-keto ester, 6-(2-methyl-1,3-dioxolan-2-yl)-3-oxo-hexanoic acid ethyl ester, b.p. 110°-112°C at 0.2 mm., Analysis calculated for C12H20O5 : C, 59.00; H, 8.25. Found: C, 58.92; H, 8.38.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH:23][N+:24]([O-])=O)[CH:17]=1>C(N)C1C=CC=CC=1>[CH2:22]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:23]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1cccc(Cl)c1
Solvent: NCc1ccccc1
Product: Clc1cccc(-c2cn(Cc3ccccc3)c3c2CNCC3)c1
Yield: 48.9 %

Procedure:
The title compound (193.3 mg) was prepared from 0.50 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 260 μL of benzylamine, and 0.45 g of 1-chloro-3-(2-nitro-vinyl)-benzene as in Example 9. MS (ESI): exact mass calculated for C20H19ClN2, 322.12. found, m/z 323.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.36-7.20 (m, 6H), 7.14-7.07 (m, 3H), 6.81 (s, 1H), 5.01 (s, 2H), 4.04 (s, 2H), 3.14 (t, J=5.8 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:15]([N+:20]([O-])=O)[CH:16]=[N:17]2)=[CH:12][CH:11]=1>O.C(O)(C)C>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:15]([NH2:20])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Temperature: 25 °C
Yield: 135.6 %

Procedure:
A solution of Na2S2O4 (193 g) in H2O (1 L) was added to a boiling solution of (7-bromo-3-nitroquinolin-4-yl)isobutylamine (32.0 g, 99 mmol) in isopropanol (1 L). Upon complete addition, the reaction mixture was cooled to room temperature and the bulk of the isopropanol was removed on a rotary evaporator. The resulting mixture was extracted with CH2Cl2 (3×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 39.5 g of the crude 7-bromo-N4-isobutylquinoline-3,4-diamine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[CH3:16].[CH3:17][OH:18].O.C([Li])CCC.C(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O.CCCCCC>[C:26]1([C:2]2[CH:15]=[CH:14][C:5]([CH:6]([CH2:17][OH:18])[O:7][CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)=[CH:4][C:3]=2[CH3:16])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: CO
Reactant: Cc1cc(COC2CCCCO2)ccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(CO)OC2CCCCO2)ccc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
2-(4-Bromo-3-methylbenzyloxy)tetrahydropyran (1.4 g, 5 millimol) was dissolved in tetrahydrofuran (5ml), and cooled to -20° C. with methanol-water. Under nitrogen atmosphere, thereto was added 15% hexane solution (5 ml) of n-butyllithium, and in this state, the mixture was stirred for 30 minutes. Next, benzaldehyde (0.6 ml, 6 millimol) was added, and stirred for 2 hours. During this procedure, inner-temperature was raised from -20° C. to 30° C. Then, water was added, and the mixture was extracted with ethyl acetae. After washing with water and saturated aqueous sodium chloride solution, the solvent was distilled away, and the residue was separated and purified by using a silica-gel column chromatography (ethyl acetatee:n-hexane=1:5 to 1:2) to give the title compound (0.9 g, 2.9 millimol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=3[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: COC(=O)COc1cc(C)ccc1CCl
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)COc1cc(C)ccc1COc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Yield: 79.1 %

Procedure:
By the method of Example 1, Step I, 2.0 g (0.0077 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step E) and 3.53 g (0.0151 mole) of methyl (2-chloromethyl-5-methylphenoxy)acetate were reacted in the presence of 1.60 g (0.0116 mole) of anhydrous potassium carbonate in 40 mL of N,N-dimethyl/-formamide, yielding 2.75 g of methyl [2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]acetate. The NMR spectrum was consistent with the proposed structure. NMR: 2.30 (s, 3H); 2.44 (s, 3H); 3.78 (s, 3H); 4.70 (s, 2H); 5.18 (s, 2H); 6.60-7.36 (m, 7H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][CH2:13][C:14]([O:16]C)=[O:15].[OH-].[Li+].Cl.CCOC(C)=O>C1COCC1.CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CCN1CCc2ccccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCN1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Dissolve methyl 3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (0.3 g, 1.29 mmol) in THF (12 mL) and MeOH (4 mL). Add lithium hydroxide (0.2 g, 8.23 mmol, in 4 mL H2O). Stir at ambient temperature for 2 hours. Evaporate the solvents from reaction mixture under reduced pressure. Adjust the pH to 5 with 2N HCl. Add EtOAc (60 mL); wash with brine; dry over Na2SO4; filter; and concentrate the filtrate under reduced pressure to provide the title compound (colorless oil, 0.27 g, 95.8%). MS (m/z): 220 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][C:21]=2[O:28][CH3:29])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].[H-].[Na+].[CH3:32]I>CN(C)C=O.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([CH2:26][O:27][CH3:32])[CH:23]=[CH:22][C:21]=2[O:28][CH3:29])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CI
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(CO)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(COC)ccc1OC
Product: Cl
Reaction time: 0.08 h

Procedure:
At 0° C., under an inert atmosphere, 320 mg of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-hydroxymethyl-2-methoxyphenyl)-N-propylamino]thiazole are dissolved in 0.7 ml of dimethylformamide. 70 mg of sodium hydride (50% in oil) are added. After 5 minutes, 0.24 ml of methyl iodide is added. After 12 hours at room temperature, the reaction mixture is diluted with ethyl acetate and then hydrolyzed. The organic phase is washed several times with water before being dried over sodium sulphate. After purification on a silica gel; the expected product is dissolved in dichloromethane. A 0.1 N solution of hydrochloric acid in isopropanol is then added. After evaporation under vacuum, the expected product is obtained in hydrochloride form; m.p.=71° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2[S:18]([NH:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[C:23]=1[CH3:28])(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CC(C)=O>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:8]3[NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2cccc3c(N)cccc23)c1C
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2cccc3c(NC(=O)C(C)C)cccc23)c1C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
Isobutyryl chloride (0.144 mL, 1.38 mmol) was added dropwise to a solution of Example 3 (0.350 g, 1.10 mmol) in pyridine (1 mL) and acetone (7 mL). The mixture was stirred for 2.5 hours and the acetone was removed under vacuum to leave a thick brown residue, which was added dropwise to half-saturated sodium hydrogen carbonate (30 mL). The pH of the resulting mixture was adjusted to 8-8.5 with saturated sodium hydrogen carbonate. The crude product was precipitated by acidifying the solution to pH 1.5 with 6N hydrochloric acid, filtered and dried. Recrystallization from methanol/water afforded 51% of a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>CCOCC>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:47])=[CH:49][CH:50]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with 100 ml. portions of water and dried over magnesium sulfate. The solvent is removed in vacuo and the solid is recrystallized in 50 ml. of diethyl ether to yield the product.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.O>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([S:12]([N:2]([CH3:3])[CH3:1])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1
Reactant: CNC
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
Dimethylamine (40% in H2O, 1 mL) was added to a solution of 3-methoxybenzenesulfonyl chloride (0.50 g, 2.4 mmol) and pyridine (1 mL) in THF (5 mL). The reaction mixture was allowed to stir at rt for 48 h, then was poured into H2O and extracted with EtOAc. The organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give an oil which was chromatographed (10-80% EtOAc in hexane) to give 0.400 g (76%) of the title compound. MS (ESI) 216 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])C.[BH4-].[Li+].Cl>O1CCCC1.CO>[OH:3][CH2:4][CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9]
Reactant: CCOC(=O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1cccs1)N(CCO)c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(2-thienylsulfonyl)glycine ethyl ester (100 mg) in tetrahydrofuran (10 mL) and methanol (2 mL) was added lithium borohydride (18.0 mg), and the mixture was stirred at room temperature for 4 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (70 mg, yield 76%) as white crystals.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH:3]([CH3:19])[CH:4]=[CH:5][CH:6]([CH:8]1[C:16]2([CH3:17])[CH:11]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH3:7].[CH3:22][Si:23]([CH3:30])([CH3:29])N1C=CN=C1.O>C(Cl)Cl>[CH3:7][CH:6]([CH:8]1[C:16]2([CH3:17])[CH:11]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH:5]=[CH:4][CH:3]([CH3:19])[C:2]([CH3:20])([O:1][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH3:21]
Reactant: CC(C=CC(C)C(C)(C)O)C1CCC2C(=O)CCCC21C
Reactant: C[Si](C)(C)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CC(C=CC(C)C(C)(C)O[Si](C)(C)C)C1CCC2C(=O)CCCC21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of 200.0 mg (0.679 mmol) of [1R-[1α-(1R*,2E,4S*),3aβ,7aα]]-octahydro-1-(5-hydroxy-1,4,5-trimethyl-2-hexenyl)-7a-methyl-4H-inden-4-one in 10 mL of dry methylene chloride was treated with 0.4 mL (2.726 mmol) of N-(trimethylsilyl)imidazole and the resulting mixture stirred at room temperature, under argon, for 18 hours. It was then treated with 1 mL of water, stirred for an additional 30 minutes then diluted with methylene chloride. The organic phase was separated, washed with water and brine, dried and evaporated to dryness. The residue obtained was purified by rapid filtration through a short silica gel column, eluted with hexane-ethyl acetate (5:1) to give 214.0 mg (84% yield) of pure [1R-[1α-(1R*,2E,4S*),3aβ,7aα]]-octahydro-1-(1,4,5-trimethyl-5-trimethylsilyloxy-2-hexenyl)-7a-methyl-4H-inden-4-one, as a thick, colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][C:24]=1[CH2:25][N:26]1[C@@H:30]([CH3:31])[C@@H:29]([C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[O:28][C:27]1=[O:46].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[F:45][C:42]([F:43])([F:44])[C:34]1[CH:33]=[C:32]([C@H:29]2[O:28][C:27](=[O:46])[N:26]([CH2:25][C:24]3[CH:47]=[C:48]([O:51][C:52]([F:53])([F:54])[F:55])[CH:49]=[CH:50][C:23]=3[NH:22][C:12]([C@H:9]3[CH2:8][CH2:7][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:11][CH2:10]3)=[O:14])[C@H:30]2[CH3:31])[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)Nc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of trans-4-(2-ethoxy-2-oxoethyl)-cyclohexanecarboxylic acid (1 g; 4.67 mmol) in anhydrous THF (25 mL) at 0° C. was treated dropwise with oxalyl chloride (1.02 mL; 11.68 mmol) followed by catalytic DMF (50 μL). The reaction was stirred at room temperature for 2 h, concentrated in vacuo, and the residue was redissolved in THF (25 mL). The resultant solution was cooled to 0° C. and treated with (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.58 g; 5.14 mmol) and triethylamine (0.716 mL; 5.14 mmol). The reaction was stirred at room temperature for 1 h, quenched with water and partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with EtOAc/hexanes, to afford ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}carbonyl)cyclohexyl]acetate as an off-white solid. LCMS=698.9 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.94 (s, 1 H), 8.23 (d, J=8.9 Hz, 1 H), 7.92 (s, 1 H), 7.73 (s, 2H), 7.27-7.24 (m, 1 H), 7.02 (s, 1 H), 5.71 (d, J=8.4 Hz, 1 H), 4.78 (d, J=15.5 Hz, 1 H), 4.19-4.12 (m, 3H), 4.07 (d, J=15.6 Hz, 1 H), 2.43-2.37 (m, 1 H), 2.21 (d, J=6.9 Hz, 2 H), 2.07-1.98 (m, 2 H), 1.93-1.83 (m, 3 H), 1.67 (q, J=12.6 Hz, 2 H), 1.26 (t, J=7.2 Hz, 3 H), 1.19-1.11 (m, 2 H), 0.88 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][CH2:36][N:35]([CH2:33][CH3:34])[C:11](=[O:13])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:1])([CH3:21])[CH3:20]
Reactant: CCNCCC(C)(C)C
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCC(C)(C)C)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 45 °C

Procedure:
To a mixture of 7.7 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1, 6.1 mg HOBt, and 10.2 mg EDC was added 0.5 mL dry DMF. Add 6.6 N-ethyl-3,3-dimethylbutan-1-amine hydrochloride from the Step A above followed by 16 μL DIEA. This solution was heated at 45° C. over night. It was purified directly on RP-HPLC using 65-80% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.38 min. (m/Z=424.3, 318.2, 402.3).