Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([O-:11])=[O:10].[Na+].[F:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[CH:20]=[C:21]([C:24]([F:27])=[CH:25][CH:26]=1)[CH2:22]Br>CN(C)C=O>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([O:11][CH2:22][C:21]1[C:24]([F:27])=[CH:25][CH:26]=[C:19]([O:18][C:17]2[CH:28]=[CH:29][CH:30]=[C:15]([F:14])[CH:16]=2)[CH:20]=1)=[O:10]
Reactant: Fc1cccc(Oc2ccc(F)c(CBr)c2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cc(Oc2cccc(F)c2)ccc1F
Yield: 69.3 %

Procedure:
6.9 g (0.03 mol) of sodium 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylate were dissolved in 150 ml of dimethylformamide and heated, with 8.0 g (0.027 mol) of 3-(3-fluorophenoxy)-6-fluorobenzyl bromide, for 4 hours at 120° C. After completion of the reaction, the dimethylformamide was distilled off in vacuo and the residue was taken up in 200 ml of methylene chloride. This solution was then extracted by shaking twice with 150 ml of water, the organic phase was dried over sodium sulphate and the solvent was stripped off in vacuo. The last remnants of solvent were removed by brief incipient distillation at 70° C. (bath temperature)/1 mm Hg. 8.0 g (71% of theory) of 3-(3-fluorophenoxy)-6-fluorobenzyl 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylate were obtained as a yellow oil having a refractive index nD24 of 1.5395.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[NH4+].[Cl-]>C1COCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1,4-Dibromobenzene (2 g, 8.48 mmol) was taken up in THF (35 mL) and cooled to −78° C. before adding n-BuLi (3.39 mL, 8.48 mmol) dropwise. After stirring at −78° C. for 30 minutes, oxetan-3-one (0.611 g, 8.48 mmol) was added and the reaction was warmed to room temperature for 1 hour at which time water and saturated NH4Cl were added and the products were extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (6-50% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](O)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[Cl-].ClC=[N+:16](C)C.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+]>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: C[N+](C)=CCl
Reactant: Cc1cc(S(=O)(=O)O)ccc1N
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(S(N)(=O)=O)ccc1N

Procedure:
For example, commercially available 2-aminotoluene-5-sulfonic acid was allowed to react with Villsmeyer reagent (N-(chloromethylene)-N-methylmethanaminium chloride), that is either commercially prepared or is generated in situ from a mixture of N,N-dimethylformamide and oxalyl chloride. The intermediate compound was then allowed to react with ammonium hydroxide in tetrahydrofuran to afford 4-amino-3-methylbenzenesulfonamide (Scheme IV).
Reaction SMILES: [F:1][C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1.N[C:27]1[S:31][C:30]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2F)=[N:29][C:28]=1[C:40]([NH:42][C:43]1[CH:44]=[N:45][N:46]([CH3:57])[C:47]=1[CH:48]1[CH2:54][CH2:53][C@@H:52]([NH2:55])[C@@H:51]([F:56])[CH2:50][O:49]1)=[O:41]>>[NH2:55][C@H:52]1[C@H:51]([F:56])[CH2:50][O:49][C@H:48]([C:47]2[N:46]([CH3:57])[N:45]=[CH:44][C:43]=2[NH:42][C:40]([C:28]2[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([F:1])[C:37]=3[F:38])[S:31][CH:27]=2)=[O:41])[CH2:54][CH2:53]1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](N)[C@@H](F)CO1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,3-difluorophenyl)thiazole-4-carboxylic acid (Intermediate 119) gave 306. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.59 (s, 1H), 8.28-8.21 (m, 1H), 7.87 (s, 1H), 7.68-7.58 (m, 1H), 7.44-7.36 (m, 1H), 4.88 (dd, J=10.5, 3.5 Hz, 1H), 4.67-4.49 (m, 1H), 4.41-4.29 (m, 1H), 4.20-4.03 (m, 2H), 3.79 (s, 3H), 3.45-3.35 (m, 1H), 2.15-2.05 (m, 1H), 1.91-1.73 (m, 3H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.C(O)C>[Pd].CO>[NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A mixture of 21 gm (89.9 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 10% palladium on carbon pre-wet with 30 mL ethanol in 180 mL methanol were hydrogenated at 65 p.s.i for 3 days. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The residual solid was slurried in 120 mL ethyl acetate, filtered, and washed 3×30 mL ethyl acetate. The remaining solid was dried under reduced pressure to provide 19 gm (92%) the title compound as a light brown solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5][CH:4]=[C:3]1[C:20]([OH:22])=[O:21].C(Cl)(=O)C(Cl)=O.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([O:22][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH:30]=1)=[O:21]
Reactant: O=C(O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C=C(OC(=O)c2cnc(-c3ccccc3)n(-c3ccccc3)c2=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinecarboxylic acid (i.e. Step B product (B) or the product from Step B1) (1.40 g, 4.8 mmol) in dichloromethane (30 mL) was added oxalyl chloride (1.21 g, 9.61 mmol) at 0° C. followed by catalytic amount (2 drops) of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stir for 1 h. Then the reaction mixture was concentrated under reduced pressure. To the resulting residue was added dichloromethane (30 mL), 1,3-cyclohexanedione (646 mg, 5.76 mmol), followed by triethylamine (976 mg, 9.60 mmol), and the reaction mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product as a white solid (1.1 g).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=1)=[C:2]=[O:3].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([NH:27][CH3:28])=[CH:25][CH:24]=1>O1CCOCC1>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:8]1[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=[C:4]([NH:1][C:2](=[O:3])[N:27]([CH3:28])[C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=2)[N:9]=1
Reactant: CNc1ccc(Br)cc1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
2-Isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (750 mg, 2.4 mmol) was dissolved in anhydrous dioxane (15 mL). To this solution was added 4-bromo-N-methylaniline (440 mg, 2.36 mmol) and the resulting solution was stirred under an N2 atmosphere at room temperature. After ca. 12 h an LCMS analysis of the reaction indicated mostly desired product (91%). The reaction was partitioned between EtOAc and water, the organics separated and the aqueous layer extracted with EtOAc (3×50 mL). Organic extracts were combined, washed with water (2×) and once with brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil. The oil was partially purified by column chromatography (silica, hexane/EtOAc) and then recrystallized (EtOAc/cyclohexane) to afford 41 as a white solid (346 mg, 29% yield): m.p. 110-111° C. Anal Calcd for C16H13BrF6N4O3: C 38.19, H 2.60, N 11.13. Found: C 38.42, H 2.66, N 11.20. 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 7.55 (d, 2H, J=4.5 Hz), 7.26 (d, 2H, J=4.5 Hz), 6.14 (s, 1H), 4.99 (q, 4H, J=4.4 Hz), 3.28 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C>[NH2:24][CH2:23][CH2:22][CH2:21][S:20][C:15]1[C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN3C(=O)c4ccccc4C3=O)c2CC1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN)c2CC1
Temperature: 65 °C
Yield: 97.1 %

Procedure:
Suspend 3-tert-butoxycarbonyl-7-chloro-6-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.20 g, 2.39 mmol) in ethanol (53.2 mL), add hydrazine (0.150 mL, 4.78 mmol) and heat at 65° C. for 2 h. Cool to ambient temperature, filter from precipitate, and concentrate in vacuo to provide the 6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (861 mg, 97%). MS (APCI+) m/z: 371 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][CH2:16][CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=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>[CH2:15]([O:14][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][CH3:18])[CH:21]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11])[CH2:16][CH3:17]
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCO[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCO[C@@H](Cc1ccc(-c2cccc(NC)c2)cc1)C(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
38 mg (0.033 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 100 mg (0.33 mmol) of methyl (S)-3-(4-bromophenyl)-2-(propyloxy)propionate and 90 mg (0.39 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 1 ml of dimethylformamide. 0.2 ml of a 2M potassium phosphate solution is added and the reaction mixture is stirred at 90° C. for 2 hours. The reaction is halted by the addition of 10 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 76 mg of methyl (S)-2-propyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=70%.
Reaction SMILES: C(N1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19]([OH:21])=O)=[O:15])C1C=CC=CC=1.[CH2:30]([NH2:32])[CH3:31].O[NH-].O=[N-]>>[CH2:30]([N:32]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([C:18](=[O:22])[C:19]([NH:16][CH2:14][CH3:9])=[O:21])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:31]1[CH:24]=[CH:23][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: CCN
Agent: [N-]=O
Agent: [NH-]O
Product: CCNC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
Coupling of 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenyl-butanoic acid with ethylamine and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: C([O:8][C:9]1[CH:46]=[CH:45][C:12]([O:13][CH2:14][C@@H:15]([OH:44])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:43]=[CH:42][C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:34]([NH:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][NH:17][CH2:16][C@H:15]([OH:44])[CH2:14][O:13][C:12]3[CH:45]=[CH:46][C:9]([OH:8])=[C:10]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:11]=3)=[CH:43][CH:42]=2)[CH2:26][CH2:27]1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: [H][H]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1
Yield: 38.6 %

Procedure:
4-(4-{2-[((2S)-3-{4-(Benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]ethyl}anilino)-N-octyl-1-piperidinecarboxamide (0.15 g, 0.207 mmol) was dissolved in ethanol (70 mL) and 10% palladium on carbon (0.043 g) added. The solution was shaken in a Parr apparatus at 50 psi hydrogen atmosphere for 16 hours, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.052 g, 0.08 mmol).
Reaction SMILES: CN(C)[CH:3]=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:12][C:13]1[N:14]([Si](C(C)C)(C(C)C)C(C)C)[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[CH:3]([C:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:12])[NH:14][CH:15]=1)=[O:4]
Reactant: CCOC(=O)c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1C
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C=O)c[nH]c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
N,N-dimethylformamide (5.5 mL, 71 mmol) in dichloromethane (126 mL) at 0° C. was treated dropwise with oxalyl dichloride (6 mL, 71 mmol). The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 1 hour. The mixture was again cooled to 0° C. and treated with a mixture of Example 1a (20 g, 64.6 mmol) in dichloromethane (126 mL). The reaction mixture was stirred at 0° C. for 2 hours and then at ambient temperature for 48 hours. The reaction mixture was again cooled to 0° C. and slowly quenched with 4 N aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated with a mixture of 9:1 hexanes/ethyl acetate, filtered, and dried under high vacuum to give 8.67 g (74%) of the title compound.
Reaction SMILES: [OH:1][C:2]1([C:20]#[C:21]/[C:22](/[C:29]([F:32])([F:31])[F:30])=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]([CH3:18])([C:14]([F:17])([F:16])[F:15])[CH2:12][C:5]2(OC(C)C(C)[O:6]2)[CH:4]=[C:3]1[CH3:19].O>CC(C)=O.Cl>[OH:1][C:2]1([C:20]#[C:21]/[C:22](/[C:29]([F:30])([F:31])[F:32])=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]([CH3:18])([C:14]([F:17])([F:16])[F:15])[CH2:12][C:5](=[O:6])[CH:4]=[C:3]1[CH3:19]
Reactant: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
Ethyl (2E)-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluormethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]-3-(trifluoromethyl)pent-2-en-4-ynoate (110 mg, 0.23 mmol) was dissolved in acetone (5 ml) under argon in a round-bottom flask, and 5 drops of conc. hydrochloric acid were added. The resulting reaction solution was stirred at room temperature for 4 h and then water was added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E)-5-[1-hydroxy-2,6-dimethyl-4-oxo-6-(trifluoromethyl)cyclohex-2-en-1-yl]-3-(trifluoromethyl)pent-2-en-4-ynoate (70 mg, 71% of theory) was isolated in the form of a colorless viscous oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.72/6.71 (s, 1H), 5.98/5.97 (s, 1H), 4.28/3.93 (q, 2H), 3.28 (br. s, 1H, OH), 3.00 (d, 1H), 2.66 (d, 1H), 2.21/2.18 (s, 3H), 1.49/1.37 (s, 3H), 1.32/1.09 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:14][N:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]1)[CH2:10][C:9]2=[O:27].Cl>CC(O)=O>[C:17]1([CH2:16][CH2:15][N:13]2[CH2:14][C:11]3([CH2:10][C:9](=[O:27])[C:8]4[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=4)[O:23]3)[CH2:12]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2
Yield: 94.7 %

Procedure:
(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (350 mg, 0.93 mmol) was hydrolyzed with AcOH (6 ml) and aqueous 20% HCl solution (6 ml) following the procedure described in Example 31, Step B, giving (E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (320 mg, hydrochloride salt) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[O:9])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: COCCN
Product: COCCNC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-methoxyethylamine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:46]([S:48]([CH3:51])(=[O:50])=[O:49])=[CH2:47]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([O:40][CH2:47][CH2:46][S:48]([CH3:51])(=[O:50])=[O:49])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(OCCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a stirred solution of [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-(4-hydroxy-piperidin-1-yl)-methanone (94.8 mg, 0.152 mmole, example 101) was added sodium hydride (9.3 mg, 0.232 mmole, 60%, Aldrich) followed by methyl vinyl sulfone (0.04 mL, 0.448 mmole, Aldrich). The mixture was allowed to stir at room temp for 2.5 h before quenched with aqueous ammonium chloride and extracted with dichloromethane. The organic extracts were washed with brine and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, eluting a gradient of 1-10% methanol in methylene chloride) to give the title compound (93.4 mg, 84% yield). HR-MS (ES, m/z) calculated for C37H47Cl2N4O5S [(M+H)+] 729.2639, observed 729.2641.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C.[OH-].[Na+]>O.[Fe]>[N:9]1([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A stirred suspension of 4-(4-nitrobenzyl)morpholine (500 mg) (prepared according to a modified procedure described by Leffler and Volwiler, JACS, 1938, 60, 896) in water (4.15 mL) was treated with glacial acetic acid (0.5 mL). The reaction mixture was heated to gentle reflux and then treated with iron powder (500 mg) over 10 minutes. After stirring at reflux for a further 10 minutes the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with water (10 mL) and then basified to pH 12 with a 4 M aqueous solution of sodium hydroxide. The aqueous was extracted three times with diethyl ether (1×40 mL, 2×10 mL). The combined organic extracts were dried over magnesium sulfate and then evaporated to give the title compound (370 mg) as a white solid, m.p. 96–97° C. MS: 193 [MH]+.