Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:22]([O-:25])(=[S:24])[CH3:23].[K+]>CN(C)C=O>[C:22]([S:24][CH:14]1[CH2:13][CH2:12][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15]1)(=[O:25])[CH3:23]
Reactant: CC([O-])=S
Reactant: CCOC(=O)c1csc(N2CCC(OS(C)(=O)=O)CC2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CCC(SC(C)=O)CC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-4-methanesulfonyloxypiperidine (76 mg, 0.23 mmol) (obtained as described in Reference Example 13(3)) in dimethylformamide (4.0 ml) was added potassium thioacetate (145 mg, 1.3 mmol) at room temperature, and the reaction mixture was then stirred in an oil bath (80° C.) for 8 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 4-acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidine (67 mg, yield 94%) as a pale brown solid.
Reaction SMILES: COC1C=C(OC)N=C(O[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=O)[O:18][CH:17]3[OH:22])N=1.[CH:23]([Mg]Cl)=[CH2:24].Cl>O1CCCC1>[CH:23]([CH:19]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:22])[O:18]1)=[CH2:24]
Reactant: C=C[Mg]Cl
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.6 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxyphthalide (see Example 84) are placed in 60 ml of absolute tetrahydrofuran at -45° C., and the solution is treated within 10 minutes with 18 ml of a 2M solution of vinylmagnesium chloride solution in tetrahydrofuran. The reaction solution is then stirred for approximately 16 hours at room temperature, a further 6 ml of vinylmagnesium chloride solution are added and the reaction solution is heated at reflux temperature for a further hour. When it has cooled, the reaction solution is acidified with 1N hydrochloric acid and freed of tetrahydrofuran in a rotary evaporator. The aqueous phase is then extracted with tert-butyl methyl ether, and the organic phase in washed and concentrated by evaporation under reduced pressure. Silica gel chromatography using ethyl acetate/n-hexane (2:3) as eluant yields pure 7-[4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-vinyl-phthalide, m.p. 94°-97° C.
Reaction SMILES: Br[C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:14].N12CCCN=C1CCCCC2>O1CCCC1>[OH:14][C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:12][CH3:13])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1(Br)CCc2cc(OC)ccc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(OC)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A solution of 10.2 g (0.033 mole) of 1,2,3,4-tetrahydro-2-bromo-6-methoxy-1-oxo-2-naphthalenecarboxylic acid, methyl ester in 100 ml of tetrahydrofuran under a nitrogen atmosphere was treated over 15 minutes with a solution of 10.0 ml (10.2 g; 0.067 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 20 ml of tetrahydrofuran. The mixture was stirred at room temperature for 16 hours, then added to 450 g of ice/water. Acidification with 6.0N hydrochloric acid precipitated the crude naphthalene ester product. The solid was filtered, washed with water, and recrystallized from aqueous methanol to yield 5.1 g (67% yield) of the final product, mp 109°-111°. This material was identical with that prepared by the procedure described in Example 11.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[NH:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:16]([NH:15][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 55.9 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (6.12 g), 3′-aminoacetanilide (5.80 g) and potassium carbonate (5.34 g) in toluene (50 ml) was refluxed for 5 hours. The mixture was cooled, and the solids were collected and washed with water, ethanol and isopropyl ether successively to give 2-(3-acetamidophenyl)amino-3-nitropyridine (5.88 g) as an orange solid.
Reaction SMILES: [N:1]#[N:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([NH:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C@@H:12]([CH3:14])[OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>N1C=CC=CC=1>[N:1]#[N:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([NH:17][O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[C@@H:12]([CH3:14])[O:13][S:27]([CH3:26])(=[O:29])=[O:28])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: c1ccncc1
Product: C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
N2 -(t Butyloxycarbonyl)-N-(Phenylmethoxy)-L-threonineamide (244 g) was dissolved in 1.2 liters of pyridine and the solution was cooled to 0° C. With stirring 120 grams of methanesulfonyl chloride was added dropwise at 0°-5° C. After 2.5 hours, the reaction mixture was poured into a mixture of 1500 ml of 2N hydrochloric acid and ice and concentrated HCl was added to adjust the pH of the mixture to 4. The title compound crystallized, and, after stirring for 1 hour, was filtered off, washed with water and petroleum ether. After drying at room temperature the yield was 356.4 grams, which contained a considerable amount of water, melting point 128°-130° C. dec.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:39])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.7 mmol) in THF (30 mL) was cooled to 5° C. 4-Methoxyphenyl isocyanate (0.4 g, 2.7 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and then concentrated. The residue was stirred with 1N HCl (30 mL) for one hour then filtered. The solid was slurried with hot methanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.8 g, 93%) as a white solid: mp 320-322° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.36-2.64 (m, 2H), 2.86-3.00 (m, 1H), 3.68 (s, 3H, OCH3), 4.35-4.57 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.6 and 13.0 Hz, 1H, CH), 6.61 (t, J=5.5 Hz, 1H, NH), 6.83 (d, J=8.9 Hz, 2H, Ar), 7.27 (d, J=8.9 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.40 (s, 1H, NH), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.58, 31.18, 46.20, 51.58, 55.11, 113.86, 119.70, 121.49, 128.27, 130.34, 131.62, 133.36, 135.76, 139.88, 154.08, 155.47, 168.10, 171.00, 172.84; Anal. calcd. for C22H22N4O5: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.61; H, 4.95; N, 13.59.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:23])[NH:9][C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:12][CH:13]=[N:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].IC.[C:26](=O)(O)[O-].[Na+]>O1CCCC1>[C:3]([O:7][C:8](=[O:23])[N:9]([CH3:26])[C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:12][CH:13]=[N:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1ccccc1-c1ncncc1NC(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ncncc1N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium hydride (75 mg, 1.87 mmol) was added to a stirring solution of (4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert-butyl ester (410 mmol, 1.44 mmol) in tetrahydrofuran (10 mL) under Argon atmosphere. After 10 min., iodomethane (117 μL, 1.87 mmol) was added. The reaction mixture was stirred for 16 hours and then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by removal of volatiles gave the crude product. Flash chromatography on silica gel (33% ethyl acetate in n-hexane) gave the product as a yellow solid (242 mg, 56%) which was pure enough for the next step.
Reaction SMILES: CO[C:3](=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].NCC[CH2:42][S:43]([OH:46])(=[O:45])=[O:44]>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][CH2:3][CH2:42][S:43]([OH:46])(=[O:45])=[O:44])=[O:37]
Reactant: NCCCS(=O)(=O)O
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Product: O=C(NCCCS(=O)(=O)O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 35, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 3-amino-1-propanesulfonic acid (commercially available, CAS RN 3687-18-1). Brown solid (18%). MS (ESI): m/z=605.102 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)[CH3:2].[Br:15]Br>ClCCl>[Br:15][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][NH:8][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCOc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: CCOc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 5-ethoxy-3-phenyl-1H-pyrazole (1.0 g, 5.31 mmol) in dichloromethane (20 mL), was added bromine (0.849 g, 5.31 mmol) dropwise at room temperature. The reaction was stirred for 2 h, washed with saturated NaHCO3 solution and concentrated under reduced pressure. The residue was triturated with 10% ethyl acetate/hexane to give the title compound as a yellowish solid (1.20 g). LCMS m/z=268.07 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=4.2 Hz, 3H), 4.39 (q, J=4.2 Hz, 2H), 7.45-7.85 (m, 5H), 12.4 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:12])[O:9][CH2:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)(O)[C:15]#[N:16].CN(C)C(=N)N(C)C.Cl>CC#N>[O:12]=[C:8]1[O:9][CH2:10][CH:11]([C:15]#[N:16])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C#N
Reactant: O=C1OCC=C1c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CC#N
Product: N#CC1COC(=O)C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
3-Phenyl-5H-furan-2-one (Description 2; 4.5 g, 0.028 mol), and acetone cyanohydrin (3.06 ml) were dissolved in CH3CN (80 ml) and cooled to −0° C. Tetramethylguanidine (3.5 ml) was added dropwise over 15 minutes and the reaction left to stand for a further 15 minutes. 0.5M HCl (100 ml) was added and the reaction mixture de-colourised and the product extracted with ethyl acetate (2×40 ml), washed with brine (2×30 ml) and dried over MgSO4. The solvent was removed in vacuo to afford a brown oil which was a mixture of the cis and trans isomers. Purification was carried out using flash column chromatography on silica gel eluting in increasing concentrations of ethyl acetate in hexane (0-60%) to yield the title compound (2.93 g, 56%). The only isolated product from the column was the more thermodynamically stable trans isomer.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1cc(O)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(O)ccc1C=NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of 27.4 g (0.18 mol) 4-hydroxy-2-methoxybenzaldehyde and 28.3 g (0.18 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. After cooling to room temperature, the precipitated solid was filtered off and dried under vacuum. Yield: 43.0 g (78.9%).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C@H:29]([OH:42])[CH2:30][O:31][C:32]4[C:40]5[NH:39][C:38](=[O:41])[NH:37][C:36]=5[CH:35]=[CH:34][CH:33]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[C:11](=[O:13])[N:12]=1)C.[OH-].[Na+]>>[OH:42][C@H:29]([CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:14]=[C:10]3[S:9][C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])=[N:12][C:11]3=[O:13])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)CCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 3-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionic acid ethyl ester(which was obtained in Example 8)by NaOH hydrolysis as a pale yellowish solid; MS (ES) m/z: 291.0 ((M+2H)2+, 100%); 581.0 (MH+, 30%); HRMS Calcd. for C28H33N6O6S (MH+): 581.2182. Found: 581.2195.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[OH:17].[CH2:18](I)[CH2:19][CH2:20][CH3:21]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)c1cc2ccccc2c(Br)c1O
Reactant: CCCCI
Product: CCCCOc1c(C(=O)OCC)cc2ccccc2c1Br

Procedure:
The intermediate was prepared from ethyl 4-bromo-3-hydroxynaphthalen-2-carboxylate and butyl iodide in almost quantitative yield and used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C(=O)c1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 52.1 g (197 mmol) of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (Example 1, Step A) and methyl acrylate (19.5 ml, 216 mmol) in 360 mL of THF was added 20 mL of a 1M solution of potassium tert-butoxide in THF slowly at 0° C. over a period of 20 min (reaction solution temp kept<10° C.). The reaction was allowed to warm to ambient temperature. After being stirred at rt for 1 h, the reaction was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 15% EtOAc/hexanes) provided the title compound as a colorless liquid. R is CH3.
Reaction SMILES: [O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C@@H:18]2[OH:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl>[C:31]([O:21][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:22])[C:20]3[C@:2]4([O:1][C:19]1=3)[O:24][C@H:3]4[C@@H:4]1[C@@H:14]2[CH2:13][CH2:12][C@@:11]2([CH3:23])[C@H:5]1[CH2:6][CH2:7][C@@H:8]2[CH2:9][CH3:10])(=[O:33])[CH3:32]
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a mixture of 0.084 g (0.189 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl )-1α,260 ;6α,7α-diepoxypregn- 4-en-3β-ol, 0.5 ml (6.18 mmoles) of dry pyridine and 5 ml of methylene chloride was gradually added 0.1 ml (1.06 mmoles) of acetic anhydride dropwise at a temperature of 0° C. and the solution was stirred at room temperature for 8 hours. The reaction mixture thus obtained was diluted with methylene chloride and washed with saturated aqueous copper (II) sulfate solution. The aqueous layer (washings) was extracted with methylene chloride and the extract was combined with the organic layer. The resulting mixture was washed with water and aqueous sodium chloride solution in that order and dired over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane: 1:10, v/v) to recover 0.083 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β -yl acetate (yield: 90%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Br-].[CH2:17]([Zn+])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: [Zn+]CCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1c(CCc2ccccc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A screw cap vial was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (500 mg, 2.016 mmol), tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.202 mmol), and THF (5.04 mL). The mixture was sparged with N2, then phenethyl-zinc(II) bromide (0.5 M in THF, 4.23 mL, 2.116 mmol) was added and the reaction stirred at 60° C. for 2 h. The reaction was then partitioned between EtOAc and water, and the organic layer washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography, eluting with a gradient of 0-15% EtOAc in hexane to give 4-chloro-5,7-difluoro-3-methyl-2-phenethylquinoline. Mass Spectrum (ESI) m/e=318.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:33]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH3:33])[CH:23]=3)[CH2:20][CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCN(c3cccc(CO)c3)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCc1cccc(N2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 0.4 g (1 mmol) of 4-{2-[4-(3-hydroxymethylphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester in 10 mL of dry dimethyl sulfoxyde is cooled at a temperature close to 5° C. and 40 mg (1 mmol) of sodium hydride (60% suspension) is added. The mixture is stirred for 30 minutes at room temperature then 140 mg (1 mmol) of iodomethane are added and stirring is maintained overnight at room temperature. The mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.3 g (73%) of crude 4-{2-[4-(3-methoxymethylphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester which is used without purification in the next step.
Reaction SMILES: [CH:1]1([C@@H:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C@H:5]2[C:16](OCC)=[O:17])[CH2:3][CH2:2]1.[Li+].[BH4-]>C1COCC1>[CH:1]1([C@H:4]2[C@H:5]([CH2:16][OH:17])[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C1CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](C2CC2)C1
Yield: 76.5 %

Procedure:
A mixture of 1-tert-butyl 3-ethyl(trans)-4-cyclopropylpyrrolidine-1,3-dicarboxylate (9.2 g, 13 mmol) and LiBH4 (1.37 g, 65 mmol) in dry THF (75 mL) was refluxed overnight. TLC (petroleum ether:EtOAc 5:1) indicated the reaction was complete. The reaction mixture was quenched by addition of water (75 mL) and extracted with EtOAc (75 mL). The organic layer was washed with brine (75 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:EtOAc=20:1 to 3:1) to give the title compound (2.4 g, 76%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ ppm 3.80-3.78 (d, 1H), 3.64-3.49 (m, 3H), 3.19-3.07 (m, 2H), 2.21 (s, 1H), 1.94-1.81 (d, 1H), 1.44-1.42 (d, 9H), 1.14-1.23 (m, 1H), 0.67-0.62 (m, 1H), 0.50-0.48 (d, 2H), 0.14-0.08 (m, 2H). m/z (APCI+) for C13H23NO3 186.0 (M−tBu+H)+.