Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[C:19]([CH3:21])[CH:20]=1>CCOCC>[CH3:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]3)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1

Procedure:
4-chloro-2-isopropylindene (10 g, 54 mmol) and NiCl2(PPh3) (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Dimethylphenylmagnesium bromide (54 mmol) as a Et2O solution was added under vigorous stirring and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 5.5 g (39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3([CH2:15][CH2:14]3)[CH2:12][N:11]([C:16](=[O:31])[C@H:17]([NH:21]C(=O)OCC[Si](C)(C)C)[CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:21][C@H:17]([CH:18]([CH3:20])[CH3:19])[C:16]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:32])[C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:31]
Reactant: CC(C)[C@@H](NC(=O)OCC[Si](C)(C)C)C(=O)N1CCC(O)(c2ccc(Cl)cc2)C2(CC2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)[C@@H](N)C(=O)N1CCC(O)(c2ccc(Cl)cc2)C2(CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A solution of 2-(trimethylsilyl)ethyl (2R)-1-(8-(4-chlorophenyl)-8-hydroxy-5-azaspiro[2.5]octan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate (754 mg, 1.567 mmol) in THF (10 mL) was treated with TBAF (1.0 M in THF) (6.27 mL, 6.27 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in-vacuo, and the residue was partitioned between EtOAc and saturated sodium bicarbonate. The layers were separated, and the organic phase was washed 2× with saturate sodium bicarbonate, once with water, and once with brine. The combined aqueous phases were extracted once with ethyl acetate, and the combined organic phases were washed with water and brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was taken up in acetonitrile (100 mL), and washed 3× with 20 mL of hexanes. The acetonitrile phase was concentrated in-vacuo to yield the title compound (420 mg, 1.247 mmol, 80% yield) as a colorless glass. MS (ESI+)=337.4, (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:28])([F:27])[C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:17]1[CH2:18][C@H:13]([C:12]([F:28])([F:27])[F:11])[CH2:14][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:16]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 4-chloro-3-nitropyridine (580 mg, 3.6 mmol), tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (800 mg, 3 mmol), isopropyl alcohol (5.0 mL) and DIPEA (1.0 mL, 6.0 mmol) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using CombiFlash® apparatus eluting with 50-100% EtOAc/hexanes. The purification gave 1.0 g (80% yield) of the sub-title compound as a yellow solid. LCMS calc. for C16H22F3N4O4(M+H)+: m/z=: 391.2. found: 391.1.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[NH2:13][C:14]1[C:15]([O:22][CH3:23])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:13]1[C:14]1[C:15]([O:22][CH3:23])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(N)c(OC)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1

Procedure:
1,3-Dioxo-2-(2,6-dimethoxypyridin-3-yl)-isoindoline (5) was prepared and isolated as follows. A mixture of phthalic anhydride (0.89 g, 6 mmol), 3-amino -2,6-dimethoxypyridine monohydrochloride (95%, 1 g, 5 mmol) and sodium acetate (0.49 g, 6 mmol) in glacial acetic acid (50 ml) was refluxed for 3 h. The solvent was removed under vacuum. The residue was dissolved in dichloromethane (200 ml) and washed with water (100 ml×3), dried over Na2SO4 and concentrated to give the crude product. The crude product was recrystallized with ethyl acetate to give 5 (1.345 g, 90%) as a pale pink crystals: mp 182-183° C.; 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.80-7.76 (m, 2H), 7.44 (d, J=8.1 Hz, 1H), 6.42 (d, J=8.1 Hz, 1H, 3.95 (s, 3 H), 3.91 (s, 3 H); 13C NMR (DMSO-d6) δ 166.5, 160.6, 156.1, 140.1, 132.8, 129.4, 121.4, 104.6, 99.3, 51.7, 51.5; MS (CI/CH4) 285 [M+1]+. Anal. Calcd for C15H12N2O4: C, 63.38; H, 4.25; N, 9.85. Found: C, 63.57; H, 4.18; N, 9.65.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:35])[C:19]([O:29][CH2:30][C:31](=[N:33][OH:34])[NH2:32])=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:36])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)(Cl)Cl>[C:4]([O:34][N:33]=[C:31]([NH2:32])[CH2:30][O:29][C:19]1[C:18](=[O:35])[C:17]2[C:22](=[CH:23][C:14]([NH:13][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:15]([F:36])[CH:16]=2)[N:21]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:20]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: NC(COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O)=NO
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)ON=C(N)COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O

Procedure:
40 μl of diketene was added dropwise under ice-cooling to a 8 ml chloroform solution of 800 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-N′-hydroxyethanimidamide, followed by stirring under ice-cooling for 6 hours. By evaporating the solvent under a reduced pressure, 180 mg of N′-(acetoacetyloxy)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}ethanimidamide was obtained.
Reaction SMILES: [CH3:1][C:2]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH:20]([Si:22]([O:27][CH3:28])([O:25][CH3:26])[O:23][CH3:24])=[CH2:21]>C1(C)C=CC=CC=1>[CH3:13][C:2]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:6]=1[CH2:21][CH2:20][Si:22]([O:27][CH3:28])([O:25][CH3:26])[O:23][CH3:24])=[O:4]
Reactant: CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Reactant: C=C[Si](OC)(OC)OC
Solvent: Cc1ccccc1
Product: CO[Si](CCc1cc(SC)ccc1C(=O)C(C)(C)N1CCOCC1)(OC)OC
Reaction time: 8 h
Yield: 54.7 %

Procedure:
11.18 g (40 mmol) of 2-methyl-1-(4-methylthiophenyl)-2-morpholino-1-propanone, 735 mg (0.8 mmol) of RuH2 (CO)(PPh3)3 and 7.3 ml (48 mmol) of vinyltr 60 ml of anhydrous toluene were degased with argon for 1/2 hour and boiled at reflux for 5 hours. After standing overnight, boiling was repeated for 4 hours, then 360 mg (0.4 mmol) of RuH2 (CO)(PPh3)3 and 2 ml (13 mmol) of vinyltrimethoxysilane were added, and the mixture was stirred at reflux for a further 5 hours. Concentration and chromatography (silica gel, CH2Cl2 /ethyl acetate) gave 3.04 g (18%) of a yellowish oil. 1H-NMR (CDCl3): 1.01 ppm (2H, mc, Et-H2); 1.22 ppm (6H, s, Pr-H3, CH3); 2.50 ppm (3H, s, -SCH3); 2.58 ppm (4H, mc, *morpholine--O--CH2); 2.69 ppm (2H, mc, Et-H1); 3.59 ppm (9H, s, Si(OCH3)3); 3.70 ppm (4H, mc, **morpholine--N--CH2); 7.03 ppm (1H, dd, Ph-H5, 3 JH5, H6 =8.4 Hz, 4JH3,h5 =2.0 Hz); 7.11 ppm (1H, d, Ph-H3); 8.47 ppm (1H, d, Ph-H6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1
Reactant: CNc1cccc(-c2ccc(/C=C/C(=O)OC)cc2OC)c1
Agent: [Pd]
Solvent: CO
Product: CNc1cccc(-c2ccc(CCC(=O)OC)cc2OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
100 mg (18% by mass) of 10% palladium-on-charcoal are added to a solution of 560 mg (1.88 mmol, 1 eq) of methyl (E)-3-(2-methoxy-3′-methylaminobiphenyl-4-yl)acrylate in 10 ml of methanol. The reaction mixture is stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction medium is filtered through Celite and then evaporated to dryness. 495 mg of methyl 3-(2-methoxy-3′-methylaminobiphenyl-4-yl)propanoate are obtained in oil form. Yield=88%
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:15]([OH:17])=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:18][C@@H:19]([CH2:36][CH3:37])[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)=[O:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CO>[C:4]([O:3][C:1]([NH:8][C@@H:9]([C:15]([NH:18][C@H:19]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)=[O:21])[CH2:36][CH3:37])=[O:17])[CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC[C@H](N)C(=O)NCc1cc(Cl)ccc1-n1cncn1
Agent: On1nnc2cccnc21
Solvent: CO
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)NCc1cc(Cl)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Boc-D-t-butyl-alanine (49 mg, 0.20 mmol), (2S)-2-amino-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]butanamide (66 mg, 0.20 mg), HOAt (27 mg, 0.20 mmol), EDC (57 mg, 0.30 mmol), and Et3N (28 μL, 0.20 mmol) in 1.0 mL of DMF was stirred at rt overnight. A small amount of MeOH was used to aid in dissolution. Solvent was removed in vacuo to give the title compound, which was carried on directly to deprotection. LCMS (M+H): 521.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=3)=[C:4]2[CH:3]=1.C([Li])CCC.[CH2:36]([S:38]SCC)[CH3:37].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:38][CH2:36][CH3:37])[N:5]2[N:8]=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=3)=[C:4]2[CH:3]=1
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Reactant: CCSSCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSc1cc(Cl)cc2c(-c3ccnc(Nc4ccccc4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-phenyl-2-pyrimidinamine (80 mg, 0.19 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (0.43 mL of 1.6M solution in hexane, 0.67 mmol) at −78° C. The resulting dark solution was stirred for 10 minutes, then quenched by the addition of ethyl disulfide (0.08 mL, 6.5 mmol). The reaction mixture was allowed to warm to room temperature, then water and ethyl acetate were added. The phases were separated and the ethyl acetate phase was washed with water, dried (magnesium sulfate), filtered and concentrated. The resulting residue was crystallized from acetonitrile to give N-{4-[5-chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinyl}-N-phenylamine (20 mg, 22%) as a solid. 1H NMR (CDCl3): δ 8.30 (d, 1H), 8.22 (d, 1H), 7.66 (m, 3H), 7.40 (t, 2H), 7.1–7.24 (m, 4H), 6.75 (d, 1H), 6.52 (d, 1H), 3.20 (q, 2H), 1.54 (t, 3H); 19F-NMR (CDCl3): δ −112.55; MS m/z 476 (M+1).
Reaction SMILES: C(O[C:4](=[O:17])[C:5]([CH3:16])([CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:18][S:19]([NH:22][C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[H-].[Na+].Cl>CN(C)C=O>[OH:17][C:4]1[C:5]([CH3:16])([CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])[CH:11]2[N:12]([CH2:13][CH2:14][CH2:15]2)[C:34](=[O:35])[C:33]=1[C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:32])(=[O:31])[N:29]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(C)(CCC(C)C)C1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)CCC1(C)C(O)=C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)N2CCCC21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,5-dimethyl-2-pyrrolidin-2-yl-hexanoic acid ethyl ester (266 mg, 1.1 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (367 mg, 1.1 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (274 mg, 1.43 mmol) in N,N-dimethylformamide (8 mL) was treated with N-methylmorpholine (289 mg, 2.86 mmol) and stirred for 1 h. The reaction was quenched with 1.0 M aqueous hydrochloric acid solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was dissolved in ethanol, treated with a 60% oil dispersion of sodium hydride (176 mg, 7.33 mmol) and heated to a vigorous reflux for 48 h. Upon cooling to 25° C., the reaction mixture was over ice in a 1.0 M aqueous hydrochloride solution. The resulting precipitate was collected by vacuum filtration to afford the crude product as a tan solid. The crude residue was purified by prep-HPLC to afford two separate diastereomers of the desired product, N-{3-[7-hydroxy-8-methyl-8-(3-methyl-butyl)-5-oxo-1,2,3,5,8,8a-hexahydro-indolizin-6-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide, as tan solids. Assignment of the relative or absolute configuration of the stereocenters was not attempted. Diasteromer 1 (122 mg, 22%): 1H NMR (400 MHz, CD2Cl2) δ: 0.84-0.90 (6H, m), 1.27 (3H, s), 1.84-2.20 (2H, m), 3.07 (3H, s), 3.50-3.58 (1H, m), 3.64-3.70 (1H, m), 3.90-3.95 (1H, m), 5.34 (2H, d, J=1.6 Hz), 6.83 (1H, s), 7.25-7.28 (1H, m), 7.54-7.58 (1H, m), 7.66-7.68 (1H, m), 14.22 (1H, s). LC-MS (ESI) calcd for C22H30N4O6S2 510.16, found 511.4 [M+H+]. Diasteromer 2 (67 mg, 12%): 1H NMR (400 MHz, CD2Cl2) δ: 0.93-0.97 (6H, m), 1.14 (2H, s), 1.22-1.45 (3H, m), 1.52-1.60 (1H, m), 1.83-2.19 (5H, m), 3.06 (3H, s), 3.42-3.59 (1H, m), 3.76-3.96 (2H, m), 5.34 (1H, s), 6.93-6.94 (1H, m), 7.27 (1H, d, J=8.8 Hz), 7.56-7.59 (1H, m), 7.66-7.69 (1H, m), 14.30 (1H, bs), 15.27 (1H, s). LC-MS (ESI) calcd for C22H30N4O6S2 510.16, found 511.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:32]3[CH2:34][CH2:33]3)[CH2:22][NH:23][S:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)(=[O:26])=[O:25])[C:11](=[O:35])[C@:10]([CH2:37][C:38]([O:40]C)=[O:39])([CH3:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CO.C1COCC1.[Li+].[OH-]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:32]3[CH2:33][CH2:34]3)[CH2:22][NH:23][S:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)(=[O:26])=[O:25])[C:11](=[O:35])[C@:10]([CH2:37][C:38]([OH:40])=[O:39])([CH3:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)c2cccs2)C2CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)c2cccs2)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetate (30 mg, 0.048 mmol; Example 263, Step D) in a mixture of water (0.16 mL), MeOH (0.16 mL), and THF (0.16 mL) was added 2 M aq. LiOH (48 μL, 0.095 mmol) at rt and the resulting solution was stirred at rt for 5 h. The reaction was quenched (sat. NH4Cl), extracted (2×EtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, gradient elution of 50% to 100% EtOAc in Hex and 30% iPrOH/DCM) provided the title compound as a white powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.S(Cl)(Cl)=O.Cl.[CH2:14]([NH2:16])[CH3:15].N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH2:14]([NH:16][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH3:15]
Reactant: CCN
Reactant: O=C(O)c1ccsc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of thiophene-3-carboxylic acid (20.0 g, 178 mmol), thionyl chloride (30 mL, 411 mmol), and catalytic DMF (5 drops) was stirred at RT overnight. This solution was concentrated under vacuum, and stripped several times from toluene to remove all traces of excess thionyl chloride. Ethyl amine hydrochloride (29.03 g, 356 mmol) was then added to a solution of this crude acid chloride dissolved in CH2Cl2 (50 mL). Pyridine (31.64 g, 400 mmol) was added, and after 1 h of stirring the reaction was washed with 10% HCl followed with water, dried (MgSO4), concentrated, and recrystallized from EtOAc/hexanes to give 14.9 g of N-ethyl-3-thiophenecarboxamide as a tan solid, a 76% yield. m.p. 115-117° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].NC1C(=O)C(=O)C=1NCC[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl.[OH-].[NH4+]>CCOCC.O>[N:25]1([CH2:24][C:20]2[CH:19]=[C:18]([SH:17])[CH:23]=[CH:22][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1c(NCCSc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Sc1cccc(CN2CCCCC2)c1
Yield: 180.9 %

Procedure:
To a suspension of lithium aluminum hydride (45.3 g, 1.19 moles) in 2200 mL of ether was added, dropwise under nitrogen, a solution of dithio bis-3,3'-N,N-di(piperidino)benzenecarboxamide (141.5 g, 0.32 mole) [prepared in Step B] in 2200 mL of ether and the mixture was stirred at ambient temperature for 20 hours. The mixture was decomposed by the addition of saturated sodium sulfate solution and filtered. The filter cake was stirred with 3000 mL of water and a solution of citric acid monohydrate (550 g, 2.62 moles) in 550 mL of water was added. The pH of the solution was adjusted to about 2 with 12N HCl and then to pH 8 with concentrated ammonium hydroxide. The solution was exhaustively extracted with ether to yield 120 g of product.
Reaction SMILES: [CH3:1][CH:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH2:6]([O:5][CH:2]([CH:3]1[CH2:4][O:30]1)[CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=CC(C)OCCCCCCCCCCCCCCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(C)C1CO1
Reaction time: 8 h

Procedure:
A mixture of 46.9 g of 1-[(1-methyl-2-propenyl)oxy]hexadecane, 32.19 g of m-chloroperbenzoic acid and 300 ml of methylene chloride was stirred overnight and then filtered. The filtrate was evaporated and the residue dissolved in petroleum ether:ether and washed with saturated aqueous sodium bicarbonate. The solution was dried, the solvent removed and the residue chromatographed via HPLC (two columns), eluting first with hexane to remove higher Rf impurities and then with 10% ether in hexane to elute the product, giving the desired compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7](O)[CH2:8][O:9][CH2:10][CH2:11]O.P(=O)(O)(O)O.[OH-].[Na+]>CS(C)=O.C1(C)C=CC=CC=1>[O:9]([CH2:10][CH2:11][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: OCCOCCO
Reactant: Cc1ncc[nH]1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1nccn1CCOCCn1ccnc1C
Reaction time: 16 h

Procedure:
2-Methyl imidazole (279 g; 3.4 moles), diethylene glycol (159 g; 1.5 mole), toluene (30 g), and 85% phosphoric acid (20 g; 0.17 mole) were charged in a flask equipped with a stirrer, a thermometer, and a distillation column, and the mixture was stirred at 240°~250° C. for 16 hours. Water produced during that time was distilled out by azeotropic distillation with toluene, and after fractionation the toluene was reflexed. The resulting product was incorporated with an aqueous solution of 48% sodium hydroxide (28.8 g; 0.35 mole) and subjected to distillation under reduced pressure of 1 mm Hg at 210°~215° C. to give a fraction of 239 g (yield, 68% based on diethylene glycol). Total amine value: 465 (theoretical value: 479). 'H--NMR (DMSO--d6, δppm)
Reaction SMILES: [H-].[Li+].[C:3]([OH:12])(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH3:13][Li]>CCOCC>[CH3:13][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: [Li]C
Reactant: C=CCCCCCC(=O)O
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCCCCC(C)=O
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
To a stirred mixture of 11.0 g lithium hydride in 800 ml of anhydrous ether, there was added dropwise 164 g of oct-7-enoic acid (prepared in Example 22 B-2) in 800 ml of anhydrous ether and the mixture was cooled to 0° C. and 650 ml of 2 M methyllithium in ether was added dropwise and then allowed to warm to room temperature and stir for 4.5 hr. This mixture was quenched by pouring the slurry into rapidly stirred 10% aqueous hydrochloric acid (1.2 liter) and wet ice. The resulting mixture was extracted with ether (3×700 ml). The continued ether extracts were washed with 10% aqueous sodium hydroxide and then with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to yield 118.9 g of the title compound having the following physical characteristics: