Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)([OH:5])=O>C(OCC)C.O1CCCC1>[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)(=[O:5])[CH3:1]
Reactant: [Li]C
Reactant: O=C(O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyllithium in diethyl ether (250 ml) was added to a solution of 1-carboxymethyl-5-triphenylmethylaminopyrazole (25.95 g) in tetrahydrofuran (400 ml) under ice-cooling and the mixture was stirred for 6 hours at ambient temperature. The reaction mixture was added to a mixture of ice-cold water (500 ml) and diethyl ether (500 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetylmethyl-5-triphenylmethylaminopyrazole.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of thiophene-2-carbonyl chloride (40 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 7.8 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]([CH2:32][CH2:33][CH:34]=[O:35])([CH:29]([CH3:31])[CH3:30])[C:27]#[N:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F-].[K+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH:34]([OH:35])[CH2:33][CH2:32][C:26]([C:27]#[N:28])([CH:29]([CH3:30])[CH3:31])[C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C#N)(CCC=O)C(C)C)cc1OC
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Agent: [F-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(CC(C(O)CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-1-nitroethane (4, 135 g, 0.64 mol), 2-(3,4-dimethoxyphenyl)-2-(3-oxopropyl)-2-isopropylacetonitrile (7, 156 g, 0.57 mol) and KF (19.3 g, anhydrous, Aldrich) in 2-propanol (2.0 L) was heated to 50°-55° C. for about 40 hours. The mixture was then cooled to room temperature and the isopropanol removed in vacuo. The residue was dissolved in CH2Cl2 (1.6 L) and filtered through Celite (50 g). The filtrate was extracted with saturated aqueous NaHCO3 (2×500 mL), the organic layer evaporated, and the product recrystallized from ethyl acetate-hexane (1:1) to yield 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexan-3-ol (8, 205 g, m.p. 171°-173° C., MS m/e 486(M+)).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCn1cccn1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCn2cccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (3.1 g, 22.1 mmol) was dissolved in anhydrous DMF (150 mL), then potassium carbonate (9.1 g, 66.2 mmol) and 1-(bromomethyl)-1H-pyrazole (7.10 mg, 44.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-[(1H-pyrazol-1-ylmethyl)sulfanyl]pyrimidin-4-ol (365 mg, 7% yield for 3 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 5.93 (s, 2H), 6.11 (bs, 1H), 6.25 (t, J=2.1 Hz, 1H), 7.50 (d, J=1.4 Hz, 1H). 7.88 (d, J=2.0 Hz, 1H); LRMS (ES+) m/z 223 (100%, M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(C)C=CC=CC=1>CO>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0° C. was added(trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess(trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][N:14]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CNc1c(C)cccc1C)OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(CN(C(=O)c1ccccc1)c1c(C)cccc1C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
2.81 g (0.02 mol) of benzoyl chloride were added in drops in 20 minutes and at a temperature of 0°-5° C. to a solution of N-(2',2'-dimethoxy-ethyl)-2,6-dimethyl aniline (4.45 g; 0.02 mol) in ethyl ether (20 ml) containing triethylamine (2.76 ml; 0.02 mol). The reaction mixture was stirred at room temperature for 15 minutes. The resulting salt was filtered and the solution was washed with 8 ml of an aqueous solution of hydrochloric acid at 5% and then with water up to neutral pH. The organic phase was anhydrified with anhydrous NaSO4 and the solvent was evaporated, so obtaining 5.2 g of a white solid which, recrystallized from petroleum ether (25 ml) provided 4.5 g of product (purity=91% by GLC) with a yield of 65.5% (white solid, melting point=58°-59° C.).
Reaction SMILES: [Zn]([CH2:4][CH3:5])CC.[C:6]1([CH:12]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1>>[C:6]1([C@@H:12]([OH:13])[CH2:4][CH3:5])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: O=CC1=CCCCC1
Reactant: CC[Zn]CC
Product: CC[C@H](O)C1=CCCCC1
Yield: 90 %

Procedure:
The product was prepared by General procedure L using 0.28 mL (0.55 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 55 mg (0.50 mmol) cyclohexenecarboxaldehyde. The crude product was purified by column chromatography on silica (10% ethyl acetate in hexanes) to afford the title compound in 90% yield (104 mg, 0.39 mmol) as a colorless oil, [α]D20=−3.4 (c=0.005, CHCl3, 99% ee); 1H NMR (CDCl3, 500 MHz): δ 0.8 (t, 3H, J=7.5 Hz), 1.3 (br s, 2H), 1.5-1.6 (m, 4H), 1.8 (s, 1H), 2.0 (s, 4H) 3.84 (q, 1H, J=10.0 Hz), and 5.63 (s, 1 H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 10.1, 22.6, 23.3, 24.9, 27.6, 29.6, 78.1, 123.2, and 139.6 ppm; IR (neat) 3500, 2962, 2922, 2874, 2360, 1732, 1456, and 1260 cm−1. HRMS-CI m/z 123.1174 [(M−OH)+; calcd for C9H15: 123.1173].
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[CH:18][C:17]=2[F:33])[CH:12]=[CH:11][N:10]=1)(C)(C)C.C(OCC)C.[OH-].[Na+]>C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=2)=[C:17]([F:33])[CH:18]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
To a 4N solution of hydrochloric acid in ethyl acetate (30 ml) was added [4-(4-benzyloxycarbonylamino-2-fluorophenoxy)pyridin-2-yl]carbamic acid tert-butyl ester (510 mg) while stirring in an ice water bath. The reaction mixture was allowed to warm up to room temperature, followed by stirring for 16 hr. To the reaction mixture were added diethyl ether (10 ml) and a 5N aqueous solution of sodium hydroxide (1 ml), followed by stirring for 30 min. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2) and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue were added diethyl ether (4 ml) and hexane (6 ml) to suspend the precipitated solid. The solid was collected by filtration and dried under aeration to provide the titled compound as pale yellow powder (46.6 mg, 11.7%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7].[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 72.2 %

Procedure:
A mixture of methyl 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.25 mmol) in methanol (4.5 mL) and 1N sodium hydroxide aqueous solution (3.7 mL, 3.7 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and washed with water, dried in vacuo to afford 69 mg of 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 71.9%. LC-MS(M+1)=383.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=3[CH:25]([CH3:27])[CH3:26])=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH:25]([C:16]1[CH:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH3:34])=[O:12])([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2[nH]ncc12
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2c1cnn2C
Reaction time: 1.5 h

Procedure:
To a solution of Example 4C (0.468 g, 2.2 mmol) in DMF (6 mL) was added NaH (0.104 g, 2.6 mmol) and the mixture was stirred for 90 minutes. Dimethyl sulfate (Me2SO4, 0.22 mL, 2.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (1200 mL), washed sequentially with H2O (400 mL) and brine (400 mL), dried (Na2SO4), filtered, concentrated under reduced pressure, and purified by chromatography (75% diethyl ether/Hexanes to 100% diethyl ether) to provide the title compound. 1H-NMR (DMSO-d6) δ 8.81 (s, 1H), 8.04 (s, 1H), 7.64 (d, 1H), 7.60 (s, 1H), 7.55 (m, 2H), 7.25 (t, 1H), 7.14 (d, 1H), 6.81 (t, 1H), 4.49 (d, 2H), 3.99 (s, 3H), 3.30 (m, 1H), 1.25 (d, 6H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1)C(OCC)=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[F:17][C:16]1[C:11]([CH2:5][C:4]([OH:19])=[O:3])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ncc(F)cc1F
Temperature: 25 °C
Yield: 53 %

Procedure:
To a stirred solution of 2-(3,5-difluoro-pyridin-2-yl)-malonic acid diethyl ester (1 g, 3.56 mmol) (Preparation 264) in THF (15 mL) was added a solution of lithium hydroxide monohydrate (462 mg, 10.4 mmol) in water (4 mL) dropwise at 0° C. and the mixture heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, acidified (pH ˜3) with 2N hydrochloric acid and extracted with 20% isopropanol-dichloromethane (5×20 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM: MeOH 100:0 to 95:5) to afford the title compound as a solid in 53% yield, 336 mg.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37](O)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37]([NH:26][C@H:23]3[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]4[C:5]4[CH:6]=[C:7]5[CH:11]=[CH:10][CH:9]=[C:8]5[O:3][CH:4]=4)[CH2:25][CH2:24]3)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (79 mg, 65%), MS (ISP) m/z=489.3 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-(benzo[1,3]dioxol-5-yl)-acetic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[O:27]=[S:28]1(=[O:42])[C:33]2=[CH:34][CH:35]=[CH:36][C:37]3=[CH:38][CH:39]=[CH:40][C:31](=[C:32]23)[C:30](=[O:41])[NH:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:29]3[C:30](=[O:41])[C:31]4[CH:40]=[CH:39][CH:38]=[C:37]5[CH:36]=[CH:35][CH:34]=[C:33]([C:32]=45)[S:28]3(=[O:42])=[O:27])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: O=C1NS(=O)(=O)c2cccc3cccc1c23
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3C(=O)c4cccc5cccc(c45)S3(=O)=O)[C@H](C)[C@H]12
Yield: 58.2 %

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (64.8 mg, 0.174 mmol), 1,1-dioxo-2,3-dihydro-naphtho[1,8de][1,2]thiazin-3-one (34.5 mg, 0.145 mmol), and triphenylphosphine (46 mg, 0.174 mmol) in anhydrous tetrahydrofuran (2 mL) was cooled in an ice bath and stirred under a nitrogen atmosphere. Diisopropyl azodicarboxylate (0.034 mL, 0.174 mmol) was added and the resulting mixture was stirred at 0-5° C for 10 minutes. The mixture was concentrated under vacuum and the residue was purified by preparative layer chromatography on a 1 mm×20 cm×20 cm silica gel GF plate using 7:3 ethyl acetate-hexanes as the developing solvent. The product band was removed and eluted with ethyl acetate to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-(1,1,3-trioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-ylmethyl)-carbapen-2-em-3-carboxylate (49 mg) as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]([CH2:27][C:28]([F:31])([F:30])[F:29])[S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18].C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>ClCCl>[C:41]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]2[CH:6]=[CH:5][C:4]([CH2:15][N:16]([CH2:27][C:28]([F:31])([F:29])[F:30])[S:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:18])=[C:3]([F:2])[CH:8]=2)[CH2:10][CH2:11]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(C2CCNCC2)cc1F)CC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(CN(CC(F)(F)F)S(=O)(=O)Cc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To a solution of N-[[2-fluoro-4-(4-piperidyl)phenyl]methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide hydrochloride (100 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.62 mmol) in dichloromethane (1.5 mL) was added acetyl chloride (24 mg, 0.31 mmol) and the reaction was stirred at ambient temperature for 2 hours. The reaction was then concentrated and purified by preparative reverse phase HPLC to yield 33.3 mg of N-[4-(1-Acetyl-piperidin-4-yl)-2-fluoro-benzyl]-C-phenyl-N-(2,2,2-trifluoro-ethyl)-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.44-7.38 (m, 5H), 7.38-7.32 (m, 1H), 7.14-7.04 (m, 2H), 4.60 (s, 2H), 4.56-4.47 (m, 1H), 4.41 (s, 2H), 4.07-3.83 (m, 3H), 3.16-3.04 (m, 1H), 2.87-2.74 (m, 1H), 2.63-2.51 (m, 1H), 2.01 (s, 3H), 1.86-1.68 (m, 2H), 1.67-1.49 (m, 1H), 1.49-1.29 (m, 1H). LCMS (m/z) ES+ 487.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc2c[nH]c3ccccc23)cc1
Yield: 70.5 %

Procedure:
A solution of 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (12.6 g, 37.7 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol), (i-Pr)2NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C. After 8 hours the mixture is partitioned with CH2Cl2/H2O. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel to produce 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (13.1 g). Following the procedure described for the preparation of the hydroxamate compound in Example P1, 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (5.4 g, 11 mmol) is converted to N-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenamide (5.1 g,) and used without further purification. The hydroxamic acid (5.0 g, 13.3 mmol) is then dissolved in 95% TFA/H2O (59 mL) and heated to 40–50° C. for 4 hours. The mixture is evaporated and the residue purified by reverse phase HPLC to produce N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide as the trifluoroacetate salt (m/z 380 [MH+]).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:31])=[CH:25][CH:24]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C=Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=413.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 1-fluoro-4-isocyanato-benzene.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3](OC(=O)C(C)C)[CH3:4].[CH:14]1(C(O)=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][CH2:4][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Reactant: O=C(O)C1CCCCC1
Product: CSC(=O)OCCC1CCCCC1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing isobutyric acid with cyclohexanecarboxylic acid in Step B affords O-(cyclohexylethyl) S-methyl thiocarbonate (6) as an oil.