Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:20]([NH2:25])(=[O:24])[CH:21]=[CH:22][CH3:23].O1CCOCC1>C/C(/O)=C/C(C)=O.C=C.C=C.[Rh].O>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C@H:22]([CH3:23])[CH2:21][C:20]([NH2:25])=[O:24])=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC=CC(N)=O
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CC(N)=O)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Acetylacetonatobis(ethylene)rhodium(I) (0.3 mmol), (S)-(−)-2,2′-Bis(diphenyl-phosphino)-1,1′-binaphthalene (0.045 mmol), 4-(trifluoromethyl)phenylboronic acid (2 mmol), K2CO3 (0.5 mmol), and but-2-enoic acid amide (1 mmol) are added into a 25-mL round-bottomed flask containing a magnetic stirrer bar, a septum inlet, and a reflux condenser. The flask is flashed with argon and then charged with 1,4-dioxane (3 mL) and de-ionized H2O (0.5 mL). The reaction mixture is stirred for 16 hours at 100° C. The (R)-3-(4-trifluoromethylphenyl)butyramide is extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Chromatography over silica gel gives the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.[Cl-].[NH4+]>CN(C=O)C>[CH3:21][C@H:17]([N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:22])[C:18]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:20]
Reactant: C1COCCN1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 2.5 h

Procedure:
(2S)-2-((3S)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (84.5 g) was dissolved in DMF (2 l) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (161 g) was added, followed by N,N-diisopropylethylamine (92 m)) and morpholine (46 ml). The mixture was stirred under nitrogen for 2.5 h, and saturated aqueous ammonium chloride was added. The mixture was stirred for 15 min then partitioned between water and ethyl acetate. The separated organic phase was washed with lithium chloride (10% by weight), followed by saturated sodium bicarbonate and brine. The organic layer was dried (over sodium sulphate) and concentrated under reduced pressure to give the title compound (65 g) as a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)NCCO)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(NCCO)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-hydroxyethyl)thiophene-2-carboxamide (62.6 mg) in acetonitrile (10 mL) were added sodium iodide (48.6 mg) and chloro(trimethyl)silane (0.164 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (49.0 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[N:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=O)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@](C)(C=NO)Cc1ccccc1

Procedure:
A solution of (R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanal (80 mg, 0.30 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol) and triethylamine (0.125 mL, 0.9 mmol) in 3.4 mL ethanol was heated to reflux temperature overnight. Additional hydroxylamine hydrochloride (25 mg, 0.36 mmol) and triethylamine (0.125 mL, 0.9 mmol) were added and the reaction continued at reflux temperature for 4.5 h. Concentration and flash chromatography (0-25% EtOAc/hexanes) gave (R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanal oxime. 1H NMR (CDCl3) δ 7.95 (bs, 1H), 7.52 (bs, 1H), 7.25 (m, 3H), 7.10 (d, J=6.7 Hz, 2H), 5.01 (s, 1H), 3.14 (m, 2H), 1.46 (s, 9H), 1.42 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@H:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CCO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@H:21]([OH:22])[CH2:23][N:35]3[CH2:34][CH2:33][N:32]([C:26]4[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=4[CH3:24])[CH2:37][CH2:36]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2C[C@H]2CO2)C1
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2C[C@H](O)CN2CCN(c3cc(Cl)ccc3C)CC2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
(S)-1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (37 mg, 0.98 mmol) and 4-(2-methyl-5-chlorophenyl)piperazine (36 mg, 0.17 mmol) were combined in EtOH (0.4 mL) and heated to 70° C. After 18 h the mixture was allowed to cool, diluted with CH2Cl2 and purified by preparative TLC (silica, 8% MeOH/CH2Cl2) to give 35 mg (61%) the title compound. HPLC (reverse phase conditions): tR=4.41 min. MS (electrospray): m/z calculated for C28H3435Cl79BrN5O2 [M++H], 586.16, found 586.2. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.56 (d (partially obscured), J=8.5, Hz, 2H), 7.53 (s, 4H), 7.48 (d, J=8.5 Hz, 2H), 7.08 (br d, J=8.5 Hz, 1H), 6.95 (m, 2H), 4.85 and 4.73 (A and B of AB quartet, Jab=15.6 Hz, 1H), 4.62 (s, 1H), 4.20 (m, 2H), 4.04 (m, 2H), 3.90-3.71 (m, 2H), 2.92-2.53 (m, 11H), 2.21 (s, 1.5H), 2.16 (s, 1.5H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[CH2:21]([N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1)[CH3:22].C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([N:23]1[CH:27]=[C:26]([C:2]2[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1cc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)cn1
Temperature: 100 °C
Yield: 80.8 %

Procedure:
To a solution of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.33 g, 3.73 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (995 mg, 4.48 mmol) in 1,2-DME (20 mL) were added Pd(Ph3P)4 (0.22 g, 0.19 mmol) and 2.0 M aqueous K2CO3 (5.6 ml, 11.2 mmol). The reaction mixture was degassed by bubbling N2 for 15 min then heated at 100° C. overnight. The resultant maroon reaction mixture was cooled and diluted with H2O then extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (30% to 80% EtOAc/hexanes) to afford 1.12 g (81%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a light orange-brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)(O)[O-].[Na+]>CCO>[Cl:8][C:6]1[CH:7]=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([C:15]3[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:21][CH2:22]2)[N:3]=[C:4]([CH2:9][O:10][CH3:11])[N:5]=1
Reactant: COCc1nc(Cl)cc(Cl)n1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCc1nc(Cl)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 25 °C

Procedure:
Combine 4,6-dichloro-2-methoxymethyl-pyrimidine (800 mg, 4.14 mmol), 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (960 mg, 4.14 mmol), sodium bicarbonate (500 mg), and EtOH (50 mL). Reflux for 4 hours, let cool to room temperature, vacuum filter, and evaporate the mother liquor. Purify the residue by column chromatography eluting with 20:1 DCM/MeOH to obtain 4-chloro-2-methoxymethyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CN(C)/[CH:16]=[C:17](/[C:23](=[O:32])[C:24]1[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=1F)\[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([N:1]2[C:25]3[C:24](=[CH:29][C:28]([I:30])=[CH:27][CH:26]=3)[C:23](=[O:32])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16]2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn([C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
(S)-3-Amino-1-N-Boc-pyrrolidine (1 g, 5.36 mmol) was added to the solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 14.3 mL, 4.88 mmol) and heated at 50° C. for 3 h. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (8 mL) and potassium carbonate powder (1.0 g, 6.83 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (40 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×, 30 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 hour. The suspension was filtered and the solid dried to give 1.76 g (71% yield) of (R)-ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[NH:22][CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:7]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:29])[CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:9])[CH:7]=1
Reactant: CI
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CC(=O)N(C)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Solutions of the individual diastereoisomers of tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate (0.31 g, 0.80 mmol [peak 1 from Examples 192, step 3]; 0.31 g, 0.80 mmol [peak 2 from Examples 192, step 3]) in DMF (4 mL) at 0° C. were each treated individually with sodium hydride dispersed in mineral oil (80 mg, 2.0 mmol). The ice bath was removed and the reaction mixtures were stirred for 30 min and heated at 60° C. for 30 minutes. The reaction mixtures were cooled down to 0° C., treated with methyl iodide (0.060 mL, 0.96 mmol) in DMF (2 mL, 26 mmol), and stirred at room temperature for 16 hours. The reaction mixtures were cooled to 0° C., quenched with saturated ammonium chloride, and extracted with EtOAc. The organic extract was concentrated to give a crude oil which was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give diastereoisomer from peak 1 (28 mg, 9%, retention time: 2.52 min) and diastereoisomer from peak 2 (56 mg, 18%, retention time: 2.51 min). Peak 1: LCMS for C20H29ClN2O4Na (M+Na)+: m/z=419.2. Found: 419.1. Peak 2: LCMS for C20H29ClN2O4Na (M+Na)+: m/z=419.2. Found: 419.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(-n2cnc(C)c2)nc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
1-(6-chloro-pyridin-3-yl)-ethanone (7.00 g, 45.16 mmol) and 4-methylimidazole (11.11 g, 135.50 mmol) were combined in DMSO (35 ml), before addition of K2CO3. The mixture was heated at 110° C. for 22 h with rapid stirring. The reaction was then cooled to room temperature and poured into ice water (400 ml) with vigorous stirring for 15 min. The resulting precipitate was collected on a filter and washed generously with water. The resulting material was dried in vacuo to yield 19 as a tan solid (6.1 g, 67%). LC/MS: [M+1]+=202.2. C11H11N3O=201.2. 1H NMR (DMSO-d6) 300 MHz δ2.18 (3H, s), 2.63 (3H, s), 7.72 (1H, s), 7.87 (2H, d, J=9.0 Hz), 8.41 (2H, d, J=9.0 Hz), 8.51 (1H, s), 8.98 (1H, s).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:26][O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2COCC2C=NC=CC=2)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2COCC2C=NC=CC=2)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:36][C:2]([F:1])([F:35])[C@@:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2COCc2cccnc2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COCc2cccnc2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2COCc2cccnc2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COCc2cccnc2)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-((3-pyridinylmethoxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CDCl3) δ 8.40-8.38 (m, 1H), 7.67-7.65 (m, 1H), 7.60-7.58 (m, 1H), 7.52-7.46 (m, 3H), 7.45-7.39 (m, 1H), 7.22-7.18 (m, 2H), 6.88-6.86 (m, 2H), 4.45-4.35 (m, 2H), 4.26-4.22 (m, 1H), 3.91-3.77 (m, 3H), 3.73-3.69 (m, 1H), 3.41-3.27 (m, 2H), 2.84-2.79 (m, 1H), 2.69-2.60 (m, 1H), 1.74 (s, 3H). m/z (ESI, +ve ion) 542.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=4.93 μM; GK-GKRP EC50 (LC MS/MS)=4.93 μM.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)/[CH:10]=[CH:11]/[CH3:12]>>[CH2:9]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])/[CH:10]=[CH:11]/[CH3:12]
Reactant: C/C=C/CBr
Reactant: Oc1ccccc1S
Product: C/C=C/CSc1ccccc1O
Yield: 97 %

Procedure:
This compound was prepared from 2-mercaptophenol and (E)-2-butenyl bromide in 97% yield according to the general procedure for 16p in Example VII. Colorless oil; 1H NMR (CDCl3): δ 1.61 (d, J=0.8 Hz, 3H), 3.26 (d, J=7.40 Hz, 2H), 5.26-5.33 (m, 1H), 5.43-5.50 (m, 1H), 6.73 (s, 1H), 6.87 (dt, J=1.35 Hz, J=7.40 Hz, 1H), 6.99 (dd, J=1.10 Hz, 8.25 Hz, 1H), 7.27 (dt, J=1.65 Hz, J=7.40 Hz, 1H), 7.43 (dd, J=1.65 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 17.79, 39.40, 114.69, 118.57, 120.59, 125.77, 128.88, 131.27, 136.65, 157.28.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:5]([N:13]=O)[C:4]([CH3:15])=[N:3]1>[Pd].CCOC(C)=O>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:15])[C:5]=1[NH2:13]
Reactant: Cc1nn(C)c(NCC(C)(C)C)c1N=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(NCC(C)(C)C)c1N
Temperature: 23 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
(2,5-Dimethyl-4-nitroso-2H-pyrazol-3-yl)-(2,2-dimethyl-propyl)-amine (3.44 g, 16.36 mmol), 400 mg of 10% Pd/C and 60 mL EtOAc were placed under a balloon of H2 and stirred at 23° C. After 4 h, the reaction mixture was filtered through Celite and evaporated to an orange oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (20/1), gave a yellow solid. Recrystallization from hot hexanes/EtOAc gave 2.86 g (14.57 mmol, an 89% yield) of the title compound as an off-white crystalline solid. mp: 65-69° C.; 1H NMR (300 MHz, CDCl3): δ 1.00 (s, 9H), 1.65 (brs, 2H), 2.13 (s, 3H), 2.77 (brs, 2H), 2.89 (brs, 1H), 3.62 (s, 3H); IR (KBr, cm−1): 3347-3204 brs, 2952s, 2903w, 1599m, 1528m, 1495m, 1477m, 1378m, 1316m; MS (ES) m/z (relative intensity): 197 (M++H, 100). Anal. Calcd. for C10H20N4: C, 61.19; H, 10.27; N, 28.54. Found: C, 56.19; H, 10.56; N, 26.37
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:14][C@H:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH2:12][N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:42][CH2:43][CH3:44]>CC(N(C)C)=O.O>[N:1]1([C:7]([C@@H:9]2[CH2:14][C@H:13]([N:15]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])[CH2:42][CH2:43][CH3:44])[CH2:12][N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])C[C@@H](C(=O)N2CCOCC2)C1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN([C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h

Procedure:
tert-Butyl (3R,5S)-3-(morpholin-4-ylcarbonyl)-5-{[(2-nitrophenyl)sulfonyl]amino}piperidine-1-carboxylate (4.68 g) was dissolved in DMA (20 ml), cesium carbonate (9.18 g) and 1-iodopropane (1.83 ml) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7-10:0) was concentrated under reduced pressure to give the object product (4.02 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:12].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:25](=[O:27])[CH3:26])=[O:12]
Reactant: CC(=O)Cl
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1sc2c(c1C(=O)c1ccco1)CCCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
To a stirred solution of (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-furan-2-yl-methanone (Example 4, 200 mg, 0.8 mmol) in dichloromethane (5 mL), cooled to 4° C. with an ice-water bath, was added triethylamine (0.12 mL, 0.88 mmol), followed by acetyl chloride (0.062 mL, 0.88 mmol). The mixture was warmed to room temperature, stirred for 12 hours, diluted with dichloromethane (5 mL), and washed with 5% aqueous HCl (5 mL), followed by saturated aqueous NaHCO3 (5 mL). The organic phase was dried (Na2SO4), filtered, and evaporated, and the residue precipitated with ethyl acetate and petroleum ether. Yield: 69%; IR (KBr) cm−1: 3448, 3118, 2931, 1677, 1606, 1529, 1466, 1432, 1267, 1063, 774; 1H NMR (CDCl3): 61.67 (m, 2H), 1.86 (m, 2H), 2.26 (s, 3H), 2.38 (t, 2H, J=6.0 Hz), 2.72 (t, 2H, J=7.4 Hz), 6.58 (m, 1H), 7.12 (d, 1H, J=3.4 Hz), 7.63 (s, 1H), 10.7 (s, 1H); yellow solid, mp: 126-127° C. (petroleum ether).
Reaction SMILES: [N:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10]([NH:13][C:14](C)([CH3:16])[CH3:15])(=[O:12])=[O:11])=[N+]=[N-].[BH4-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[NH2:1][C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10]([NH:13][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:12]
Reactant: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N=[N+]=[N-]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)NS(=O)(=O)c1sc(Cl)cc1N
Temperature: 5 °C
Reaction time: 72 h
Yield: 39.5 %

Procedure:
A solution of the product of Example 311B (0.739 g) in toluene (20 mL) and hexadecyltributylphosphonium bromide (0.128 g, 0.25 mmol) at 0° C. was treated dropwise with a solution of sodium borohydride (0.109 g, 2.9 mmol) in water (0.80 mL). The reaction was stirred at 25° C. for 18 hours and at 5° C. for 72 hours. The reaction was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide, water, and brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 1:1 hexanes/dichloromethane to 100% dichloromethane to give the title compound (0.252 g, 23%). 1H NMR (300 MHz, CDCl3)δ ppm 6.36 (s, 1 H) 4.93 (br s, 2 H) 4.60 (br s, 1 H) 1.30 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: BrCCC1CCOCC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(CCC4CCOCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with 4-(2-bromo-ethyl)-tetrahydro-pyran (described in US 2004220214) gave the title compound. ES-MS m/e (%): 493.2 (M+H+).