Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:38]([O:40][CH3:41])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:38]([O:40][CH3:41])=[O:39])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.50 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide and 0.12 ml of pyridine were dissolved in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. 0.12 ml of methyl chloroformate and a few crystals of 4-dimethylaminopyridine were added in succession and the mixture was left to come to room temperature and then stirred for 1 hour. The mixture was diluted with dichloromethane and then washed in succession with 5% aqueous sodium hydrogen carbonate solution, water, 2M aqueous hydrochloric acid and water and then dried over magnesium sulphate. The solvent was evaporated to give 0.54 g of methyl (E)-3-[2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]-2-isobutylcarbazate in the form of a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].O[CH:14]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:14]([C:37]1[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=1)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-[3-(1-{5-hydroxy-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]-2-methylpropanamide: ESMS m/e: 639.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH2:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1C[O:35][CH2:34][CH2:33]1.C(Cl)(=O)C>C(N(CC)CC)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH:29][C:34](=[O:35])[CH3:33])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol) and THF (5 mL) is added acetyl chloride (50 mg) and triethylamine (50 mg). The solution is stirred at rt for 10 min before being partitioned between EtOAc and water. The organic layer is washed further with brine. The organic layer is then dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound. MS (ESI) m/z 470.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.61 (d, J=1.01 Hz, 1 H), 8.34 (d, J=9.09 Hz, 1 H), 8.05 (s, 1 H), 7.93 (d, J=3.54 Hz, 1 H), 7.89 (d, J=7.83 Hz, 1 H), 7.56 (t, J=7.96 Hz, 1 H), 7.39-7.45 (m, 2 H), 7.09 (dd, J=8.97, 2.40 Hz, 1 H), 6.88 (s, 1 H), 6.73 (d, J=3.79 Hz, 1 H), 4.40 (s, 2 H) 2.01 (s, 3 H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH:14]3[CH:12]([O:13]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:17]([CH2:19][NH2:20])[OH:18]>C(O)(C)C>[OH:13][C@H:14]1[C@H:12]([NH:20][CH2:19][CH2:17][OH:18])[CH2:11][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[CH2:15]1
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)N2CC3OC3C2)cc1
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)[C@H](NCCO)C2)cc1
Temperature: 25 °C

Procedure:
643.7 g (2.65 mol) of 3-(toluene-4-sulphonyl)-6-oxa-3-aza-bicyclo[3.1.0]hexane are refluxed for 16 hours with 318.5 ml of ethanolamine in 4 l of isopropanol. After TLC checking, a further 35.1 ml (altogether 5.86 mol) of ethanolamine are added to the mixture and it is boiled again until the next morning. The mixture is filtered off with suction whilst hot and the filtrate is concentrated to 3.5 ltr in a rotary evaporator. After seeding and stirring at room temperature, 3.5 l of diisopropyl ether are added and the mixture is stirred at 0° C. for 6 hours. The precipitated crystallizate is filtered off with suction, washed with 250 ml of a mixture of isopropanol/diisopropyl ether (1:1) and twice with 300 ml each of diisopropyl ether and dried overnight in a high vacuum.
Reaction SMILES: C(N1C=C(C(=O)C=C(O)C(OC)=O)C(=O)N(CC2C=CC=CC=2)C1=O)C1C=CC=CC=1.[F:32][C:33]([F:70])([F:69])[C:34]1[CH:68]=[CH:67][C:37]([CH2:38][N:39]2[CH:44]=[C:43]([C:45](=[O:53])[CH:46]=[C:47]([OH:52])[C:48]([O:50]C)=[O:49])[C:42](=[O:54])[N:41]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=3)[C:40]2=[O:66])=[CH:36][CH:35]=1>>[F:70][C:33]([F:32])([F:69])[C:34]1[CH:68]=[CH:67][C:37]([CH2:38][N:39]2[CH:44]=[C:43]([C:45](=[O:53])[CH:46]=[C:47]([OH:52])[C:48]([OH:50])=[O:49])[C:42](=[O:54])[N:41]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][CH:57]=3)[C:40]2=[O:66])=[CH:36][CH:35]=1
Reactant: COC(=O)C(O)=CC(=O)c1cn(Cc2ccc(C(F)(F)F)cc2)c(=O)n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccc(C(F)(F)F)cc2)c(=O)n(Cc2ccc(C(F)(F)F)cc2)c1=O
Yield: 68.2 %

Procedure:
The title compound was synthesized using a similar procedure to that described in Example 2, except that methyl 4-(1,3-dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[1,3-bis(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3d). The title compound was recrystallized from hexane and ethyl acetate (3:1). The yield was 68.2%. Mp. 176-178° C. 1HNMR (DMSO-d6): 14.98 (br, s, 1H), 14.02 (br, s, 1H), 8.99 (s, 1H), 7.72 (d, 2H, J=8.0 Hz), 7.66 (d, 211, J=8.5 Hz), 7.59 (d, 2H, J=8.5 Hz), 7.57 (s, 1H), 7.51 (d, 2H, J=8.0 Hz), 5.26 (s, 2H), 5.09 (s, 2H). 13CNMR (DMSO-d6): 185.8, 169.3, 163.1, 159.9, 151.3, 150.2, 141.2, 140.5, 128.4 (q, J=31.5 Hz), 128.3, 128.2, 127.9 (q, J=31.7 Hz), 125.4 (q, J=3.8 Hz), 125.2 (q, J=3.8 Hz), 124.2 (q, J=272.3 Hz), 124.1 (q, J=271.8 Hz), 108.0, 100.7, 52.6, 43.9. FAB-HRMS: [M+H]+ Calcd. for C24H17F6N2O6 543.0991. Found 543.1003.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[NH:10][CH:11]([CH2:31]OS(C1C(C)=CC=CC=1)(=O)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][S-:45].[Na+]>C(O)C.CO>[CH2:1]([O:8][C:9](=[O:43])[NH:10][CH:11]([CH2:31][S:45][CH3:44])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)OCC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CSCC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-toluenesulfonyloxymethylethylcarbamic acid benzyl ester 2.4 g, 3.99 mmol) in ethanol (40 ml), a solution of sodium methanethiolate (560 mg, 7.99 mmol) in methanol (4 ml) was added and stirred at 40° C. for 3 hours. The mixture was evaporated under reduced pressure to remove the solvent, mixed with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=5:1), giving the titled compound (1.63 g, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].Cl>C1COCC1.CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:18]2[CH2:23][CH:22]([O:24][CH3:31])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:16])=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COC1CCC(C(=O)O)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid (0.10 g, 0.26 mmol) and 1:1 THF-N-methylpyrrolidin-2-one (1 mL) was treated with NaH (0.031 g, 0.78 mmol, 60% dispersion in mineral oil). After stirring for 10 min, the mixture was warmed to room temperature, stirred for 20 min and treated with iodomethane (0.016 mL, 0.26 mmol). After stirring fro 3 h, the mixture was treated with an additional 0.010 g of NaH and 0.015 mL of iodomethane. The resulting mixture was stirred for 24 h, acidified with 1M HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by radial chromatography (1:1 to 2:1 ethyl acetate hexane containing 1% of acetic acid, 2 mm silica gel plate) afforded 0.077 g (75%) of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid as a colorless syrup:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.[Cl-].[NH4+]>ClCCl.O1CCCC1>[Br:25][C:10]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:7]=[CH:6]2
Reactant: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl 2-(6-hydroxy-1H-indazol-1-yl)-1-methylethylcarbamate (0.90 g, 2.98 mmol) in dichloromethane (10 mL) and tetrahydrofuran (5 mL) was added N-bromosuccinimide (0.59 g, 3.38 mmol) at room temperature. After 16 h, a saturated aqueous solution of ammonium chloride (25 mL) was added and this mixture was extracted with ethyl acetate (3×60 mL). The combined extracts were washed with brine (10 mL), dried (magnesium sulfate), and evaporated. The residue was purified by chromatography (silica, 30% to 50% ethyl acetate in hexane) to give (1.1 g, 91%): 1H NMR (CDCl3) δ 7.86 (1H, d, J=8.8 z), 7.80 (1H, s), 7.37 (6H, m), 6.18 (1H, brs), 5.24 (1H, brs), 4.95 (2H, s), 4.80 (2H, m), 4.34 (1H, m), 1.26 (3H, d, J=6.8 Hz); MS (ES) m/z 404, 406 (M+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:34]#[N:35].O>CN1CCCC1=O>[C:34]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:35]
Reactant: N#C[Cu]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(C#N)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 3 %

Procedure:
A mixture of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl ]1-[5-(4-fluorophenyl)2-methylthiazol-4-yl]methanone, E66 (216 mg, 0.42 mmol) and copper(I)cyanide (76 mg, 0.84 mmol) in N-methylpyrrolidinone (15 ml) was heated at reflux for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (2×). Solid sodium chloride was added to the aqueous layer which was further extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was Chromatograped (silica gel, 10-100% ethyl acetate-hexane then 1-20% methanol-ethyl acetate). Further purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid) afforded the title compound as a pale brown amorphous solid (5.3 mg, 3%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])=[O:14])[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])#[N:2].C(N[C:32]1[CH:37]=CC=[CH:34][CH:33]=1)C>>[C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(=[O:17])=[O:18])=[O:14])[C:6]([N:8]([CH2:9][CH3:10])[C:11]1[CH:34]=[CH:33][CH:32]=[CH:37][CH:12]=1)=[O:7])#[N:2]
Reactant: CCN(CC)C(=O)C(CCC#N)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCNc1ccccc1
Product: CCN(C(=O)C(CCC#N)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (1.00 g) obtained in Example 153 (3) and N-ethylaniline (379 μL). This was purified by silica gel column chromatography to give the title compound (687 mg) as a white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:47])([F:48])[F:49])[CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2ccc([N+](=O)[O-])cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (332 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200–400 mesh, 90/10 hexane s/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as an off-white solid: mp 109–110° C.; EI-HRMS m/e calcd for C21H22F3N3O3S (M+) 453.1334, found 453.1334.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(=O)(=O)C(C)C)cc3)ccnc2n1

Procedure:
The product from Example 6 (120 mg, 0.274 mmol) was reacted with isopropyl sulfonyl chloride (43 mg, 0.30 mmol), N,N-diisopropylethylamine (43 mg, 0.33 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (40 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.75 (d, J=8.54 Hz, 1H) 8.20 (d, J=6.71 Hz, 1H) 7.58 (d, J=8.54 Hz, 1H) 7.26 (d, J=7.93 Hz, 1H) 7.17-7.21 (m, 2H) 7.08 (d, J=9.16 Hz, 2H) 6.95 (d, J=8.54 Hz, 2H) 6.15 (d, J=6.71 Hz, 1H) 3.43-3.51 (m, J=13.43, 1H) 2.79 (t, J=7.63, 7.63 Hz, 2H) 2.20 (s, 3H) 1.61-1.67 (m, 2H) 1.21 (d, J=6.71 Hz, 6H) 0.78 (t, J=7.32 Hz, 3H); MS (ESI+) m/z 508 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@@H:30]2[CH2:32][C@H:27]1[CH2:28][NH:29]2)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CC#N>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@@H:30]2[CH2:32][C@H:27]1[CH2:28][N:29]2[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: ClCc1ccc(Oc2nc3ccccc3s2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a stirred solution of 2-(4-chloromethyl-phenoxy)-benzothiazole (15.3 g, 55.3 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (13.2 g, 66.4 mmol) in CH3CN (200 mL) was added triethylamine (Et3N) (11.5 mL, 82.9 mmol). The resulting solution was stirred at rt for 24 h and then concentrated. The crude residue was then partitioned between CH2Cl2 (800 mL) and saturated (satd.) aqueous (aq.) NaHCO3 (200 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (10% to 40% ethyl acetate (EtOAc) in hexanes) afforded the title compound as a white foam (17.2 g, 71%). MS (ESI): mass calcd. for C24H27N3O3S, 437.18; m/z found, 438.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=7.1 Hz, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.38 (m, 1H), 7.32-7.24 (br m, 3H), 4.40 (br m, 0.5H), 4.26 (br m, 0.5H), 3.76 (br d, J=9.7 Hz, 2H), 3.63 (br d, J=10.5 Hz, 0.5H), 3.50 (br m, 1H), 3.46 (m, 0.5H), 3.18 (br m, 1H), 2.93 (br d, J=8.8 Hz, 0.5H), 2.88 (br d, J=9.4 Hz, 0.5H), 2.73 (br d, J=9.2 Hz, 0.5H), 2.55 (br d, J=9.2 Hz, 0.5H), 1.87 (br t, J=8.8 Hz, 1H), 1.74 (br d, J=9.3 Hz, 0.5H), 1.68 (br d, J=9.3 Hz, 0.5H), 1.47 (s, 9H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)cc1

Procedure:
A mixture of 1-(4-methoxyphenyl)piperazine dihydrochloride (5.30 g, 20 mmole), 2-chloro-5-nitropyridine (3.2 g, 20 mmole) and potassium carbonate (4.14 g, 30 mmole) in DMF (20 ml) was heated at 120° for 66 hours. The reaction mixture was cooled, diluted with water and the resulting precipitate collected by filtration. To this solid was added methanol (200 ml) and the mixture was heated under reflux for 0.17 hour. After cooling, the solid was collected by filtration and dried to yield the desired product, m.p. 165°-6° (4.0 g, 64%), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([C:34](=[O:36])[CH3:35])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[F:21][C:22]1[CH:23]=[C:24]([C:34](=[O:36])[CH3:35])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([C:4](=[O:5])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[F:1])[CH2:30][CH2:29]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A solution of 2-Fluoro-5-nitro-benzoyl chloride (CAS: 7304-32-7; Feng, Y.; Burgess, K.; Chem. Europ. J.; EN; 5; 11; 1999; 3261-3272) (0.054 g, 0.261 mmol) in dioxane (1 ml) was treated with triethylamine (0.073 ml, 0.522 mmol) and then with a solution of 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (CAS: 189763-57-3; WO9714690) (58 mg, 0.261 mmol) in dioxane (1 ml). The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The crude oil was taken in water. The aqueous layer was extracted 3 times with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude gum was purified on silicagel (eluent: heptane/ethylacetate 0%-20% (10 minutes) to provide the title compound (69 mg, 68%) as a light yellow solid, MS (m/e): 390.2 (MH+, 100%)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][C:36]([CH3:38])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([CH:36]([CH3:38])[CH3:35])[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (29.6 mg, 0.06 mmol), acetone (0.044 mL, 0.60 mmol) and NaB(OAc)3H (69 mg, 0.33 mmol) in DCM was added 1 drop of HOAc and was stirred at rt for 16 hr. The mixture was diluted with DCM and was washed with NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated. The crude was purified by reverse phase HPLC to afford the title compound. MS: (MH)+534.