Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>O1CCOCC1>[CH3:12][C:8]1([CH3:13])[CH2:7][C:6]2=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CSc1sc(Br)c2c1C(=O)CC(C)(C)C2
Solvent: C1COCCO1
Product: CSc1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Yield: 56 %

Procedure:
1-Bromo-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (300 mg, 1 mmol) was dissolved in dioxane (25 mL), and 2-(tri-n-butylstannyl)pyridine (550 mg, 1.35 mmol) was added. The solution was degassed with nitrogen then tetrakis (tri-phenylphosphine)palladium (30 mg, 0.025 mmol) was added and the solution refluxed for 16 h. The solvent was then removed in vacuo and the residue triturated with a mixture of ethyl acetate and hexane (1:3). After filtration the solid product was washed with a little diethyl ether to give the title compound as a white solid (170 mg, 57%). mp 217-220° C. Found: C, 63.02; H, 5.64; N, 4.47%. C16H17NOS2 requires; C, 63.36; H, 5.61; N, 4.62%. 1HNMR (250 MHz, CDCl3)δ 1.08 (6H, s), 2.44 (2H, s), 2.65 (3H, s), 2.93 (2H, s), 7.18 (1H, m), 7.47 (1H, d, J=8 Hz), 7.71-7.77 (1H, m), 8.61-8.63 (1H, m). MS (ES+) 304 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br-:27].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][C:16]([Br:27])=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)c(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a stirred solution of (R)-2-benzyl-7-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (190 mg, 0.59 mmol) in dry CH2Cl2:methanol (4:2 mL), tetrabutylammonium tribromide (331 mg, 0.68 mmol) was added. The reaction was stirred for 1 h under Argon added more tetrabutylammonium tribromide (45 mg, 0.09 mmol). After 20 min removed solvent in rotavap and then diluted with dichloromethane (100 mL), washed with 5% Na2S2O3 (10 mL), saturated NaHCO3 (10 mL) and brine (15 mL). The organic layer was dried over MgSO4, and conc in vacuo and purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to yield 86 mg (36%) of the product as a faint brown oil. MS (ESI) 401, 403 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=3)=[C:18]([CH3:30])[CH:17]=2)=[C:12]([CH:31]([CH3:33])[CH3:32])[O:11][N:10]=1.Cl.CN(C)CCCN=C=NCC.[CH3:46][S:47]([NH2:50])(=[O:49])=[O:48]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:26][C:25]([C:27]([NH:50][S:47]([CH3:46])(=[O:49])=[O:48])=[O:28])=[CH:24][CH:23]=3)=[C:18]([CH3:30])[CH:17]=2)=[C:12]([CH:31]([CH3:32])[CH3:33])[O:11][N:10]=1
Reactant: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc(C(=O)O)s1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc(C(=O)NS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of 5-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-thiophene-2-carboxylic acid (250 mg, 0.5 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol), N,N′-dimethylamino pyridine (122 mg, 1.0 mmol) and methanesulfonamide (57 mg, 0.6 mmol) in dichloromethane (20 mL) is stirred at ambient temperature overnight. The reaction mixture is diluted with dichloromethane and washed with 1N HCl. The organic phase is concentrated under reduced pressure and purified by column chromatography (gradient: 0 to 20% EtOAc in hexanes with 0.1% AcOH) to give the title compound (160 mg, 55%). LC-ES/MS m/e 579 (M+1), 100%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C(C(=O)O)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
11.70 g (35.19 mmol) of tert-butyl [4-(acetoxymethyl)phenyl](cyclopentyl)acetate were dissolved in 108.5 ml of dichloromethane, the mixture was cooled to 0° C. and 39.2 ml of trifluoroacetic acid were added. The reaction mixture was stirred first at 0° C. for 1.5 h and then at RT for 1.5 h and then concentrated under reduced pressure. The residue was taken up in 50 ml of dichloromethane and the solution was washed four times with in each case 30 ml of water. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure and the residue was dried under high vacuum. This gave 9.83 g of the target compound as a crude product (about 90% pure, yield 91% of theory).
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[C:5](=[O:16])[CH2:6][CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[OH:20]O>CCO.[OH-].[Na+]>[CH:17]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:16])[CH2:6][CH:7]([C:14](=[O:20])[NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:19])[CH3:18]
Reactant: OO
Reactant: CC(C)N(C(=O)CC(C#N)c1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(C(=O)CC(C(N)=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropyl-3-cyano-3-phenylpropanamide (21.1 g, 82 mmol) was dissolved in EtOH (130 mL) and 2 M NaOH (100 mL). Hydrogen peroxide (30%, 20.2 mL, 200 mmol) was added and the mixture was stirred at ambient temperature for two hours. The resulting precipitate was filtered, washed with water and dried, yielding the title compound as white crystals, 15.6 g (69%): 1H NMR (CDCl3) δ1.09 (d, 3H), 1.19 (d, 3H), 1.31 (m, 6H), 2.51 (dd, 1H), 3.30 (dd, 1H), 3.41 (m, 1H), 4.02 (m, 1H), 4.18 (dd, 1H), 5.7 (br, 1H), 6.4 (br, 1H), 7.21-7.42 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:29][CH3:30].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:15]([CH2:29][CH3:30])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)CNc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC)c1cccc(OCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a solution of ethyl 2-((3-(benzyloxy)phenyl)amino)acetate (1.00 g) in DMF (10 mL) were added potassium carbonate (970 mg) and iodoethane (2.20 g), and the mixture was stirred at 120° C. for 4 hr. The mixture was allowed to cool to room temperature, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (960 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1.Cl[S:13]([N:16]=C=O)(=[O:15])=[O:14].C1(C)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][S:13](=[O:15])(=[O:14])[NH2:16])=[CH:7][CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1ccc(C(F)(F)F)cc1
Yield: 78.7 %

Procedure:
This compound was prepared according to the procedure used in Example 56. A mixture of 9.6 g (0.059 mole) of α,α,α-trifluoro-p-cresol, 5.7 ml (9.2 g, 0.065 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.2 g (70%) of white solid, mp 111°-112° C. (benzene).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](Cl)(C)=O>CO.CCOC(C)=O>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reaction time: 20 h

Procedure:
To a suspension of 3-methyl-2-nitro-benzoic acid (1.0 eq.) in MeOH (0.4 M) at 0° C. was added dropwise AcCl (3.0 eq.). The reaction mixture was stirred for 20 hr at reflux. The solvent was reduced in vacuo and the residue was dissolved in EtOAc and washed several times with sat. aq. NaHCO3 solution, brine and dried (Na2SO4). Evaporation of the solvent gave (A1) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 7.86 (1H, d, J=7.5 Hz), 7.53-7.42 (2H, m), 3.89 (3H, s), 2.36 (3H, s). MS (ES) C9H9NO4 requires: 195. found: 218 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Cl)=[CH:44][CH:43]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30]4)=[N:21][N:22]3[CH2:46][C:45]3[CH:48]=[CH:49][C:42]([Cl:41])=[CH:43][CH:44]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(CCC4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)cc3)c3cc(CCC4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A solution of 4-{2-[3-(l-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-ethyl}-piperidine-1carboxylic acid tert-butyl ester (0.25 g, 0.475 mmol) in dry DMF (5 ml) was treated with sodium hydride (0.021 g, 0.523 mmol, 60% dispersion in oil) and the mixture was stirred at 23° under nitrogen for 30 min. A solution of 4-chlorobenzyl chloride (0.080 g, 0.497 mmol; Aldrich) in DMF (5 ml) was added and the mixture was stirred at 23° for 20 h. The solvent was removed in vacuo, the residue treated with water and extracted with dichloromethane (3×30 ml); the extracts were evaporated in vacuo to give an orange gum. Purification by flash chromatography on silica gel (Merck 9385), eluant ether: cyclohexane:triethylamine (50:50:2 to 100:0:2), gave the title compound as a colourless gum (0.107 g, 35%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:7]1=[O:19]>CN(C)C=O>[N:1]([C@@H:6]1[CH2:12][CH2:11][CH2:10][C@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:7]1=[O:19])=[N+:2]=[N-:3]
Reactant: O=C1NC(c2ccccc2)CCCC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCC[C@H](c2ccccc2)NC1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium azide (8.73 g, 134 mmol) was added to a solution of 3-bromo-7-phenylazepan-2-one in N,N-dimethylformamide (40 mL) and the mixture heated to 60° C. After 2 h the reaction was allowed to cool to ambient temperature, concentrated, and diluted with water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water (3×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (30% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the racemic cis and trans compounds. The cis enantiomers were separated on a Chiralpak AD column eluting with 100% methanol to give the title compound (1.09 g). MS 231 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:8]([O:10][CH3:11])=[O:9])=[O:5].Cl.[CH3:24]N1C(=O)CCC1>O1CCOCC1.O>[CH:13]1([CH2:12][C@H:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:1]=[CH:24]2)[C:8]([O:10][CH3:11])=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccccc1N
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](CC1CCCCC1)n1cnc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of Compound 22 (1 g, 3.29 mmol) in 15 mL of NMP was added triethoxyorthformate (9.87 mmol), followed by 0.5 mL of 4M HCl in dioxane. The mixture was heated to 100° C. overnight, and then diluted with water and extracted with EtOAc. After removing the solvent, the residue was dissolved in MeOH and 7.9 mL of 2 M LiOH was added. The mixture was stirred for 4 hours and acidified with con. HCl to pH=4-5. The mixture was extracted with EtOAc and dried over MgSO4. Removing the solvent gave Compound 23. [M+H] calc'd for C17H20N2O3, 301; found, 301.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[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].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:42](=[O:43])[CH2:41][C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccc(F)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 4-fluorophenylacetic acid (0.37 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight and was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. The organic solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (0.64 g, 65%): mp, 214-216° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.53 (s, 2H), 4.72 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.10-7.16 (m, 2H), 7.29-7.34 (m, 2H), 7.62-7.65 (m, 1H), 7.78-7.81 (m, 2H), 8.67 (t, J=5.9 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.83, 41.17, 48.82, 114.77, 115.05, 121.89, 127.12, 130.81, 130.92, 131.51, 132.24, 132.28, 133.19, 134.67, 139.09, 159.42, 162.62, 166.90, 167.42, 169.78, 170.51, 172.73. Anal Calcd for C22H18FN3O5: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.05; H, 4.18; N, 9.85; F, 4.48.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:19])[CH2:14][CH2:15][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Methanesulfonyl chloride (21.91 g, 14.81 mL, 191.30 mmol) is added slowly (10 min) to a solution of 4-(4-bromophenyl)-4-piperidinol (50.00 g, 191.30 mmol) and triethylamine (29.04 g, 40.00 mL, 286.95 mmol) in tetrahydrofuran (575 mL) at 23° C. (internal temperature) under nitrogen atmosphere. The mixture is stirred at 23° C. for 30 min. 500 mL of 1 M aq hydrochloric acid are added and the mixture is stirred for 10 min. The mixture is extracted with ethyl acetate (2×500 mL) the organic layers are combined, dried over anhydrous sodium sulfate, filtered and the solvent is removed to obtain 60.0 g of the title compound as a white solid. MS m/e (79Br/81Br) 333, 335 (M+1).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[S:2].[K+].Br[CH2:14][CH2:15][CH2:16][Cl:17]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][S:2][S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClCCCBr
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)SCCCCl)cc1

Procedure:
Potassium thiotosylate (50.0 g, 221 mmol, 1.0 eq.) and 1-bromo-3-chloropropane (38.0 g, 241 mmol, 1.09 eq.) were stirred together in acetone (1 L) at room temperature for 72 hours. The mixture was then concentrated. Next, the mixture was partitioned between dichloromethane and water. The organic solution was washed with brine (2×), dried using MgSO4, concentrated and azeotroped with toluene to produce a pale yellow oil weighing 54 g (92%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH-].[K+].[N+:11]([CH2:13][C:14]([N:16]1[CH2:20][CH:19]=[CH:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[O:8][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:20][CH:19]=[CH:18][CH2:17]2)=[O:15])=[CH:3][CH:2]=1
Reactant: [C-]#[N+]CC(=O)N1CC=CC1
Reactant: O=Cc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccncc1)N1CC=CC1
Reaction time: 2 h
Yield: 53 %

Procedure:
SLA 07158 was prepared in accordance with method D using pyridine-4-carbaldehyde (0.293 mL, 2.40 mmol), KOH (0.13 g, 2.32 mmol) in methanol (10 mL) and 2-isocyano-1-(2H-pyrrol-1(5H)-yl)ethanone SLA 07178 (0.301 g, 2.20 mmol). The solution was stirred 2 h with continued cooling. After work-up and column chromatography on florisil (EtOAc), trans-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(2H-pyrrol-1(5H)-yl)methanone SLA 07180 was obtained (0.284 g, 53% yield) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.O1CCOCC1>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]1[C:14]([OH:16])=[O:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of (S)-4-(tert-butoxycarbonyl) piperazine-2-carboxylic acid (1.0 g, 4.34 mmol) in water (5 mL) was added solid NaHCO3 (0.73 g, 8.68 mmol) at room temperature. The reaction mixture was stirred at room temperature to get clear solution. Solution of CBZ-Cl (1.22 mL, 8.68 mmol) in 1,4-dioxane (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The aqueous layer was acidified with 0.5M aqueous HCl to pH 5 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.30 g) as white solid.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH2:9][CH2:10][CH:11]=[CH:12][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCC[Sn](C=CCCO[Si](C)(C)C(C)(C)C)(CCCC)CCCC
Yield: 95 %

Procedure:
A solution of Example 31A (1.08 g, 5.87 mmol), tri-(n-butyl)tin hydride (1.43 mL, 5.31 mmol), and AIBN (cat.) in benzene (10 mL) was stirred at 80° C. for 3 hours. Volatiles were removed under reduced pressure to provide the title compound as a colorless oil (>95% E-isomer). 1H NMR (300 MHz, CDCl3): δ 0.05 (s, 6H), 0.80-0.98 (m, 15H), 0.90 (s, 9H), 1.23-1.38 (m, 6H), 1.42-1.53 (m, 6H), 2.34-2.40 (m, 2H), 3.66 (d, J=6 Hz, 2H), 5.94-5.98 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:28])[C:24]([NH:26][NH2:27])=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C[O:32][CH2:31]C1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:24]3[O:25][C:31](=[O:32])[NH:27][N:26]=3)=[O:28])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Reactant: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate, intermediate 12, (289 mg, 0.72 mmol) in THF (8.5 mL) is added CD (139 mg, 0.86 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1M HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) and then lyophilized to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)butanoate (100 mg). HPLC retention time=1.67 minutes (condition A); MS (m+1)=430.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.1 Hz, 3 H) 2.52-2.70 (m, 2 H) 2.84 (dd, J=13.7, 8.4 Hz, 1 H) 2.90 (dd, J=13.7, 8.4 Hz, 1 H) 4.02 (q, J=7.1 Hz, 2 H) 4.42-4.58 (m, 1 H) 7.30 (d, J=8.1 Hz, 2 H) 7.37-7.43 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.57-7.66 (m, 3 H) 7.70 (t, J=1.9 Hz, 1 H) 8.98 (d, J=8.8 Hz, 1 H) 12.94 (s, 1 H).