Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[S:16]1[CH:20]=[C:19]([CH:21]=[O:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]1=2.[Cl-].[NH4+]>O1CCCC1>[S:16]1[CH:20]=[C:19]([CH:21]([OH:22])[CH2:14][C:13]#[N:15])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CCC(O)c1csc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
To a stirring solution of diisopropylamine (0.93 mL, 6.58 mmol) in tetrahydrofuran (8 mL) at −78° C. under nitrogen was added a solution of n-butyllithium (2.75 mL, 6.88 mmol, 2.5 M in hexane). After the addition was complete, the mixture was stirred at −78° C. for 10 minutes and removed cooling bath for 5 minutes. The mixture was cooled back to −78° C., acetonitrile (0.31 mL, 5.98 mmol) was added and the reaction mixture was then stirred at −78° C. for 30 minutes. Benzo[b]thiophene-3-carbaldehyde (1 g, 5.98 mmol) in tetrahydrofuran (4 mL) was added and the resulting solution was allowed to warm to ambient temperature. After 18 hours at ambient temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (20 mL), washed with water (10 mL) followed by saturated aqueous sodium chloride (10 mL). The organic layer was concentrated and purified by column chromatography (80 g silica gel cartridge) eluting with ethyl acetate/hexane (30%-50%) to give the product as a light yellow oil (1.2 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26]>CO.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[N:25][OH:26])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=O)cc2)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=NO)cc2)CC1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)benzaldehyde (3.16 g, 9.89 mmol) and hydroxylamine hydrochloride (1.27 g, 18.3 mmol) in 9:1 MeOH/pyridine (30 mL) was heated at reflux for 18 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1M HCl (3×), water, sat. CuSO4 (2×), water, sat. NaCl, dried (MgSO4) and concentrated, giving 3.19 g (96%) of the oxime; mp: 140.1°-141.8° C.; 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.14 (bs, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.71 (bt, J=12.4 Hz, 2H), 1.95 (m, 1H), 1.80 (bd, J=12.4 Hz, 2H), 1.45 (s, 9H), 1.26 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:12])[CH2:6][NH:7][C:8](=[O:11])[CH2:9][NH2:10])[CH3:3].C(N(CC)CC)C.O.O.[C:22]([O:26][C:27]([NH:29][C@H:30]([C:38](O)=[O:39])[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCCN=C=NCC)C>O1CCCC1>[CH2:2]([O:4][C:5](=[O:12])[CH2:6][NH:7][C:8](=[O:11])[CH2:9][NH:10][C:38](=[O:39])[C@H:30]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CCOC(=O)CNC(=O)CN
Agent: CCN=C=NCCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 90.9 %

Procedure:
To a solution of 289.4 mg (1.47 mmol) of glycyl-glycine ethyl ester hydrochloride in anhydrous tetrahydrofuran (5 mL), 155.9 mg (1.54 mmol) of triethylamine, 451.5 mg (1.47 mmol) of N-t-butoxycarbonyl-β-cyclohexyl-L-alanine dihydrate, 205.3 mg (1.52 mmol) of 1-hydroxybenzotriazole hydrate, and 292.7 mg (1.53 mmol) of 1-[3-(dimethylaminomethyl)propyl]-3-ethylcarbodiimide hydrochloride were added sequentially with stirring under ice cooling. After the mixture was stirred for 1 hour, the reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure, chloroform (30 mL) was added to the residues, and the solution was washed sequentially with 0.5M hydrochloric acid (3×5 mL), water (3×5 mL) and 5% aqueous sodiumhydrogen carbonate solution (3×5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 570 mg of a crude product was obtained. The crude product was purified by column chromatography on alumina (alumina 2g, chloroform), to give 552.8 mg of N-t-butoxycarbonyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester (yield 91%) as a colorless crystalline powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:13]1([CH:19]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]([NH:22][C@H:23]2[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[CH2:25][CH2:24]2)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:2]([F:12])([F:11])[F:1])[CH:10]=1)[CH2:6][N:28]1[CH2:29][C@H:30]2[C@H:23]([NH:22][C:20](=[O:21])[CH:19]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:24][CH2:25][C@H:26]2[CH2:27]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: O=C(N[C@@H]1CC[C@H]2CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting 3,5-bis(trifluoromethyl)benzaldehyde for 3-(trifluoromethyl)benzaldehyde and 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide from Example 74 for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.16 (d, J=7.1, 1H), 7.99 (s, 3H), 4.50-4.42 (m, 1H), 3.69 (d, J=13.9, 1H), 3.54 (d, J=13.9, 1H), 2.92 (dd, J=2.7, 9.0, 1H), 2.65-2.56 (m, J=10.2, 15.6, 2H), 2.55-2.50 (m, 1H), 2.31 (d, J=4.2, 2H), 2.10 (dq, J=5.9, 11.8, 1H), 2.03 (t, J=7.4, 1H), 1.99-1.83 (m, 5H), 1.80 (d, J=12.4, 2H), 1.75-1.64 (m, J=12.4, 18.4, 5H), 1.63-1.56 (m, J=8.7, 2H), 1.44 (td, J=7.6, 21.0, 3H), 1.31-1.16 (m, 4H), 1.16-1.04 (m, 4H); MS (ESI+) m/z 559 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(F)cc1

Procedure:
Using the procedure of Example 56, a mixture of 11.2 g (0.1 mole) of 4-flurophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 50 ml of toluene gave, after recrystallization from benzene, 15.0 g (79%) of the title compound as a white solid, mp 82.5°-85.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[N:22]([CH2:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:21]1=[O:35].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH2:43][C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45])[C:23](=[O:27])[N:22]([CH2:28][C:29]([O:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:21]1=[O:35]
Reactant: CC(C)OC(=O)CBr
Reactant: CC(C)OC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)Cn1c(=O)n(CC(=O)OC(C)C)c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A mixture of isopropyl 3-{2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]-pyridazin-1-ylidene)amino]phenyl}tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.85 g, 1.62 mmol), potassium carbonate (0.27 g, 1.95 mmol) and isopropyl bromoacetate (0,353 g, 1.95 mmol)in N,N-dimethylformamide is stirred overnight at room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an orange gel. Flash column chromatography of the gel using silica gel and an ethyl acetate/hexanes solution (2:3) gives the title product as a yellow gel (0.3 g) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].CO[C:24]([C@@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl.C(N(CC)CC)C.Cl>CN(C)C=O>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:33]2[C:17](=[O:18])[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=4[S:13](=[O:15])(=[O:14])[N:12]=3)=[C:24]([OH:25])[CH:26]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]23)=[CH:40][CH:39]=1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)C3CCCCCC3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.1 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.299 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.5 mL). cis-2-(4-Fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (0.084 g, 0.299 mmol) was added followed by a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.314 mL, 0.314 mmol). The mixture stirred at 25° C. for 1.5 h. Triethylamine (0.122 mL, 0.897 mmol) was added and the mixture stirred at 50° C. for 16 h. Upon cooling, the mixture was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The product was extracted into ethyl acetate (100 mL). The organic layer was filtered to remove the N,N′-dicyclohexylurea precipitate and then further washed with 1.0 M aqueous hydrochloric acid solution (50 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; column 1: 50-70% ethyl acetate in hexanes; column 2: 1-5% methanol in dichloromethane) afforded the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.049 g, 0.087 mmol, 29%), as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.23-1.38 (3H, m), 1.46-1.73 (6H, m), 1.93-2.02 (1H, m), 2.72-2.80 (1H, m), 2.98 (3H, s), 3.03 (1H, s), 4.07 (1H, d, J=14.9 Hz), 5.01 (1H, d, J=15.5 Hz), 7.12 (2H, t, J=9.1 Hz), 7.18-7.25 (1H, m), 7.33-7.37 (3H, m), 7.43 (1H, s), 7.51-7.56 (1H, m), 9.81 (1H, s). LC-MS (ESI) calcd for C25H27FN4O6S2 562.14, found 563.2 [M+H+].
Reaction SMILES: [CH3:1][C@@:2]1([OH:14])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]1([CH3:13])[CH3:12].[C:15](Cl)(=[O:17])[CH3:16]>>[CH3:1][C@@:2]1([O:14][C:15](=[O:17])[CH3:16])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]1([CH3:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CC(C)=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Product: CC(=O)O[C@]1(C)CC[C@@H](CC=C(C)C)C1(C)C

Procedure:
Using the procedure of Example 15, 2 g of (1R,S) 1,2,2-trimethyl-3-(3-methyl-2-butenyl)-cyclopentanol and 3 ml of acetyl chloride were reacted and the product was chromatographed over silica gel and was eluted with a 95-5 cyclohexane-ethyl acetate mixture to obtain 1.5 g of (1R,S) 1,2,2-trimethyl-1-acetyloxy-3-(3-methyl-2-butenyl)-cyclopentane.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16](=O)[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1>CO.CCOCC>[O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16](=[N:20][OH:21])[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1cccc(Oc2ccccc2)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(/C=C/c1cccc(Oc2ccccc2)c1)=NO
Reaction time: 1 h
Yield: 96 %

Procedure:
The product from step (a) (10.0 g) and hydroxylamine hydrochloride (7 g) were taken up in methanol (50 ml), pyridine (15 ml) was added and the mixture stirred for 1 hour. The mixture was then stripped, redissolved in ether, washed with 2N aqu. HCl and satd. aqu. NaCl, dried over MgSO4, and stripped to give the desired product (10.2 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1[C:14]1[C:15](=[O:28])[NH:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1[C:14]1[C:15]([O:28][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (800 mg, 2.11 mmol) in dichloromethane (20 ml) under an inert atmosphere of nitrogen, was added TEA (958 mg, 9.47 mmol) followed by addition of Tf2O (1.19 g, 4.22 mmol) dropwise at −60° C. After stirring 5 min at this temperature, the reaction was quenched by the addition of water (100 ml), extracted with dichloromethane (2×30 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (0.9 g, 83.4%).
Reaction SMILES: [CH3:1][C@H:2]([C@H:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].[Cl-].[Cl:12]C=[N+](C)C>ClCCl>[CH3:1][C@H:2]([C@H:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[C:3]([Cl:12])=[O:4]
Reactant: C[N+](C)=CCl
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)O
Agent: [Cl-]
Solvent: ClCCl
Product: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Reaction time: 1.5 h

Procedure:
To a solution containing 1.0 g (6.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 10 mL of dichloromethane was added 1.1 g of chloromethylene dimethyl-ammonium chloride (8.3 mmol). The resulting solution was stirred under nitrogen for 1.5 hours. The solvent was subsequently evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. To a solution containing 2.5 g (14.6 mmol) of potassium monoethyl malonate in 50 mL of acetonitrile was added 1.7 g (17.3 mmol) of magnesium chloride and 1.2 g (11.4 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction was cooled to 0° C. and a solution of the (2R,3R)-2,3-dimethyl-hexanoyl chloride in acetonitrile (20 mL) was slowly added followed by the addition of triethylamine (0.4 g, 0.4 mmol). The reaction was heated to 40° C. and stirred at that temperature for 6 hours. The reaction mixture was cooled to 25° C., quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 1.3 g (87.8% yield) of the titled compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]([CH3:42])([CH3:41])[CH2:14][CH:15]1[C:19]2([C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH:17]([C:38]([OH:40])=O)[NH:16]1)(=[O:10])[CH3:9].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:67][C:68]1[CH:75]=[CH:74][C:71]([C:72]#[N:73])=[CH:70][CH:69]=1>>[Cl:28][C:24]1[CH:23]=[C:22]2[NH:21][C:20](=[O:29])[C@:19]3([C@@H:18]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=4[F:37])[C@H:17]([C:38](=[O:40])[NH:67][C:68]4[CH:75]=[CH:74][C:71]([C:72]#[N:73])=[CH:70][CH:69]=4)[NH:16][C@H:15]3[CH2:14][C:13]([CH3:42])([CH3:41])[CH2:12][O:11][C:8](=[O:10])[CH3:9])[C:27]2=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)OCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 40.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 103 (0.25 g, 0.4 mmol), was reacted with diisopropylethylamine (0.47 g, 3.6 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.19 g, 1.6 mmol) to give acetic acid rac-3-[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-5′-(4-cyano-phenylcarbamoyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidin]-2′-yl]-2,2-dimethyl-propyl ester as a light yellow foam (Yield 0.1 g, 40%).
Reaction SMILES: Cl.Cl.[O:3]1[CH2:7][CH2:6][C@H:5]([C@:8]2([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH2:4]1.[CH3:32][CH:33]1[C:38](=O)[CH2:37][CH2:36][O:35][CH2:34]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][CH:33]1[C@H:38]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@:8]([C@H:5]3[CH2:6][CH2:7][O:3][CH2:4]3)([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)=[O:15])[CH2:9]2)[CH2:37][CH2:36][O:35][CH2:34]1
Reactant: CC1COCCC1=O
Reactant: N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCC[C@H]1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methyltetrahydro-4H-pyran-4-one (52.1 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (9.1 mg, 12%). MS calculated for C26H37F3N4O3; (M+H) 511.3; found 511.3.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[CH:27]=[CH:26][C:25]=1[O:33][C:34]([F:37])([F:36])[F:35]>>[Cl:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])[CH:27]=[CH:26][C:25]=1[O:33][C:34]([F:37])([F:36])[F:35]
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)c(Cl)c1
Yield: 68 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 2-chloro-4-isocyanato-1-trifluoromethoxy-benzene (intermediate 17) gave the titled compound in 68% yield as light brown foam. MS: 547.19 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-:25]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([F:25])(=[O:22])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:18][CH2:19][S:20]([F:25])(=[O:22])=[O:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)CCCCCc1ccc(OCc2ccccc2)cc1
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=S(=O)(F)CCCCCCCc1ccc(OCc2ccccc2)cc1
Product: O=S(=O)(F)CCCCCc1ccc(OCc2ccccc2)cc1
Yield: 251.7 %

Procedure:
5-(4-Benzyloxy-phenyl)-pentanesulfonyl fluoride (13.4) was synthesized as described in 13.1 using, 12.4 (0.3 g, 0.87 mmol) and NH4F (0.06 g, 1.64 mmol) in dry acetone (40 mL). Purification by flash column chromatography on silica gel gave the title compound (0.266 g, 91% yield) as a white solid (m p 66-68° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:35])([CH3:34])[CH3:32])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)(C)CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)C)(C(=O)OCC(C)(C)C)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethylpropanol according to the procedure of Example 1 as an off-white foam (HCl salt); 1H NMR (CDCl3) δ 0.924 (s, 18H), 1.45 (d, 2H), 1.75 (s, 2H), 2.80 (m, 1H), 3.17 (m, 1H), 3.45 (m, 1H), 3.98 (s, 4H), 5.45-5.55 (bd, 1H), 5.63-5.67 (bs, 1H), 6.75-6.80 (m, 2H), 6.80-6.89 (m, 2H), 7.25-7.35 (m, 3H), 7.440 (s, 1H), 8.75 (bs, 1H), 10.10 (bs, 1H); IR (KBr) 3355 cm-1 (--OH), 1767 cm-1 (C=O); MS (ES) m/z 562.3 (MH+); [α]D25 -23° (c, 1.0, CHCl3). Anal. Calcd. for C30H40ClNO7 : C, 60.20; H, 6.90; N, 2.34; Cl, 11.85. Found: C, 59.74; H, 6.97; N, 2.23; Cl, 11.60.