Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C@H:23]([O:44][CH3:45])[C@@H:24]([CH3:43])[C:25]([NH:27][C@H:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>ClCCl>[CH3:45][O:44][C@@H:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][NH:18]1)[C@@H:24]([CH3:43])[C:25]([NH:27][C@H:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCNCC
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of #120 (2.87 g, 4.68 mmol, 1.00 eq.) in 20 mL of dichloromethane, diethylamine (10 mL, 95 mM, 20.5 eq.) was added. The reaction was allowed to stir at room temperature for 2 hours. Another (10 mL, 95 mmol, 20.5 eq.) of diethylamine was added and the reaction was allowed to stir at room temperature for 3 more hours. Reaction was concentrated in vacuo and placed underneath high vacuum producing #121 (1.8 g, quant.) yellow white oil solid mix. LC-MS (Protocol Q): m/z 391.1 [M+H+] retention time=1.05 minutes.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[NH:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11](SC)=[CH:10][CH:9]=2)[N:7]=1.O[O:28][S:29]([O-:31])=O.[K+].O1CCC[CH2:34]1.O>CO>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:4]=[C:3]([C:2]([F:26])([F:25])[F:1])[NH:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([S:29]([CH3:34])(=[O:31])=[O:28])=[CH:10][CH:9]=2)=[CH:17][C:18]=1[CH3:24]
Reactant: O=S([O-])OO
Reactant: COc1ccc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(SC)cc2)cc1C
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(S(C)(=O)=O)cc2)cc1C
Yield: 75 %

Procedure:
The title compound was synthesized according to the procedure of Example 41, Step 4 using the product of Step 3 (1 g, 2.6 mmol) and Oxone®(4 g, 6.6 mmol) in methanol (20 ml), tetrahydrofuran (10 ml) and water (5 ml). The crude product was purified by chromatography on silica gel using 50% ethyl acetate in toluene as the eluent to give 610 mg (75%) of the desired product as a crystalline solid: mp 265-267° C. Anal. Calc'd. for C19H17N2F3O3S (MW 410.41): C, 55.60; H, 4.18; N, 6.83; S, 7.81. Found: C, 55.69; H, 4.28; N. 6.70; S, 8.07.
Reaction SMILES: [CH3:1][C:2]1[N:12]2[C:13]3[C:8]([O:9][CH2:10][CH:11]2[CH2:14][OH:15])=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][C:2]1[N:12]2[C:13]3[C:8]([O:9][CH2:10][CH:11]2[CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1
Reactant: Cc1nc2cccc3c2n1C(CO)CO3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc4nc(C)n2c34)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Methyl-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-3-yl)-methanol (2.0 g, 9.8 mmole) was dissolved in pyridine (35 mL), p-toluenesulfonyl chloride (4.0 g, 20.9 mmole) was added and the resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue partitioned between 400 mL each of methylene chloride and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude residue was column chromatographed on silica gel using methylene chloride to elute 2.6 g of the title compound. 1H NMR (DMSO-d6): δ 7.60 (d, 1H); 7.20 (m, 3H); 7.05 (t, 1H); 6.65 (d, 1H); 4.75 (d, 1H); 4.57 (dd, 1H); 4.10 (m, 3H); 2.58 (s, 3H); 2.47 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[ClH:18].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][CH2:16][C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1
Reactant: CCc1cc(-c2ccc(C=O)s2)c(C)[nH]c1=O
Reactant: NCc1ccccc1Cl
Product: CCc1cc(-c2ccc(CNCc3ccccc3Cl)s2)c(C)[nH]c1=O
Product: Cl
Yield: 98 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-carbaldehyde is reacted with 2-chlorobenzylamine as described in Method A, Example 123 to give the title compound as a yellow solid (98% yield). LC/MS: RT 2.22 min; m/e 373 (M+H); 1H NMR (CD3OD, δ, ppm): 7.70 (2H, m), 7.0-7.58 (7H, m), 4.53 (2H, s), 4.28-4.47 (4H, d), 3.55 (1H, m), 2.62 (2H, q), 2.46 (3H, s), 4.46 (4H, d), 1.20 (3H, t).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2([N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:5][N:4]=1)[CH3:2].[CH2:25](Br)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+].[I-].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[C:27]1([CH2:26][CH2:25][N:11]2[CH2:10][CH2:9][C:8]([C:6]3[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=3)([N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH2:12]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCc1ccccc1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCN(CCc2ccccc2)CC1

Procedure:
A mixture of 4-(ethyl-1,3,4-oxadiazolyl)-4-(N-phenylpropionamido)piperidine (900 mg, 2.74 mmol), phenethyl bromide (507 mg, 2.74 mmol, NaI (490 mg, 3.3 mmol), Na2CO3 (2.0 g) in acetonitrile (50 ml) was refluxed for 72 hours. It was filtered and concentrated in vacuo. The residue was treated with CH2Cl2 (100 ml) and filtered again. The filtrate was concentrated in vacuo and the resulting residue was chromatographed (SiO2, EtOAc/Hex 1:1) to give the product (904 mg, 2.1 mmol) as a colorless oil: IR (neat) 1660 cm-1 ; NMR (60 MHz, CDCl3) δ 0.87 (t, 3H, CH3CH2CON), 1.37 (t, 3H, oxadiazolyl CH3), 1.60-3.15 (m, 16H), 7.23 and 7.50 (2bs, 10H, phenyl H's). ##STR33##
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=O)=[C:26]([F:33])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28]#[N:30])=[C:26]([F:33])[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(C(N)=O)c(F)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine and trifluoroacetic anhydride were added to a dioxane solution of 4-tert-butyl-2-fluorobenzamide and stirred at room temperature for 3 hours. By post-treating the reaction liquid, 4-tert-butyl-2-fluorobenzonitrile was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[C:6]([F:22])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](Cl)=[O:43])[C:37]2=[O:45])=[CH:32][CH:31]=1>CCOC(C)=O.O.C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[C:6]([F:22])=[CH:5][C:3]=1[NH:4][C:42]([C:38]1[C:37](=[O:45])[N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH:41]=[CH:40][CH:39]=1)=[O:43]
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3F)ccn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.2 %

Procedure:
A mixture of Example A2 (0.324, 1.073 mmol) and K2CO3 (0.178 g, 1.288 mmol) in EtOAc (1.4 mL) and H2O (2.15 mL) was stirred vigorously for 5 min, treated with a solution of Example A3 (0.108 g, 0.429 mmol) in EtOAc (1.4 mL) and stirred at RT for 2 h. The layers were separated, the aqueous layer extracted with DCM and the combined organics were dried over Na2SO4 and concentrated to dryness. The residue was combined with K2CO3 (0.265 g, 1.920 mmol) in DCM (1.4 mL) and H2O (2.1 mL), stirred vigorously for 5 min, treated with a solution of Example A3 (0.403 g, 1.60 mmol) in DCM (1.4 mL) and stirred at RT overnight. The layers were separated, the aqueous layer extracted with DCM and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (400 mg, 72%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 8.60 (dd, J=7.3, 2.2 Hz, 1H), 8.55 (dd, J=12.6, 7.2 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.15 (dd, J=6.6, 2.2 Hz, 1H), 7.97 (s, 1H), 7.62-7.56 (m, 3H), 7.41 (m, 2H), 7.25 (d, J=2.4 Hz, 1H), 6.76-6.71 (m, 2H), 3.84 (s, 3H); MS (ESI) m/z: 518.1 (M+H+).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:35]3[CH:36]=[N:37][C:38]([CH:39]=O)=[C:34]3[CH2:33][N:32]([CH3:41])[C:31](=O)[C:30]=2[CH:43]=1.[O:44]1CCCC1>>[Cl:2]/[CH:3]=[CH:39]\[C:38]1[NH:37][C:36](=[O:44])[N:35]2[C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:43][C:30]=3[CH2:31][N:32]([CH3:41])[CH2:33][C:34]=12
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1Cc2c(C=O)ncn2-c2ccc(F)cc2C1=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Product: CN1Cc2cc(F)ccc2-n2c(c(/C=C\Cl)[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
25 g of an equimolar mixture of chloromethyltriphenylphosphonium chloride and sodium amide was stirred at room temperature in 120 ml of tetrahydrofuran for 20 minutes. 12.9 g (50 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde was then added thereto and the mixture was stirred at room temperature for 1 hour and at the boiling temperature for 10 minutes. The mixture was cooled, filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1) and recrystallization from acetonitrile there was obtained 3-[(Z)-2-chlorovinyl]-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-one of melting point 220°-221°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[S:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([CH3:20])[S:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][C@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:39])[F:40])=[C:33]([O:41][CH2:42][CH:43]2[CH2:44][CH2:45]2)[CH:32]=1)[CH2:28][C:27]1[C:26]([Cl:46])=[CH:25][N+:24]([O-:47])=[CH:23][C:22]=1[Cl:21])=[O:18])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccsc1C(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccsc1C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 68.1 %

Procedure:
To a solution of 3-(N-(tert-butoxycarbonyl)-N-methylsulfamoyl)-thiophene-2-carboxylic acid (Int. 34) (150 mg, 0.467 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (196 mg, 0.467 mmol), EDC (268 mg, 1.400 mmol) and DMAP (28.5 mg, 0.233 mmol) were added and the mixture was reacted at RT overnight. The solvent was removed and the crude was purified by flash chromatography on silica gel (DCM/MeOH=95/5) affording (S)-4-(2-(3-(N-(tert-butoxycarbonyl)-N-methylsulfamoyl)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl)ethyl)-3,5-dichloropyridine 1-oxide (Int. 35) (230 mg, 0.318 mmol, MS/ESI+722.8 [MH]+).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:13]=[CH:12][NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:14]([C@@H:18]1[CH2:22][C:21](=[O:23])[O:20][C:19]1=[O:24])[CH:15]([CH3:17])[CH3:16]>O1CCCC1>[CH3:16][CH:15]([CH3:17])[CH2:14][C@H:18]([CH2:22][C:21](=[O:23])[N:11]1[CH:12]=[CH:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1)[C:19]([OH:24])=[O:20].[CH3:16][CH:15]([CH3:17])[CH2:14][C@H:18]([C:19]([N:11]1[CH:12]=[CH:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1)=[O:24])[CH2:22][C:21]([OH:23])=[O:20]
Reactant: c1ccc(-c2cc[nH]c2)cc1
Reactant: CC(C)C[C@@H]1CC(=O)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CC(=O)O)C(=O)n1ccc(-c2ccccc2)c1
Product: CC(C)C[C@H](CC(=O)n1ccc(-c2ccccc2)c1)C(=O)O
Reaction time: 0.25 h
Yield: 5.3 %

Procedure:
Sodium hydride (12 mg of 60% dispersion in oil, 0.3 mmol) was added to a stirred solution of 3-phenylpyrrole (43 mg, 0.30 mmol) in tetrahydrofuran (1.0 ml) under nitrogen. The mixture was stirred for 15 minutes then added via cannula to a stirred solution of the (3R)-3-isobutyldihydrofuran-2,5-dione (0.2 mmol) in tetrahydrofuran (1.0 ml) at 0° C., then stirred for 5 hours. The majority of solvents were removed in vacuo then water (10 ml) added. The aqueous layer was extracted with ethyl acetate (5 ml) then saturated aqueous sodium chloride solution (5 ml) added and the aqueous layer extracted with an additional portion of ethyl acetate (5 ml). The aqueous layer was acidified using hydrochloric acid (1M) to pH=1 then the product extracted into ethyl acetate (2×5 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica gel eluting with a gradient of methanol:dichloromethane 1:99→3:17. Appropriate fractions were combined and the solvents removed in vacuo to leave a mixture (approximately 1:1) of (2R)-4-methyl-2-[oxo-2-(3-phenylpyrrol-1-yl)ethyl]pentanoic acid and (3S)-5-Methyl-3-(3-phenyl-pyrrole-1-carbonyl)-hexanoic acid (1.6 mg, 2%) as an oil. TLC (two spots, Rf=0.8 and Rf=0.75, methanol:dichloromethane 1:9), analytical HPLC two unresolved UV peaks with Rt=19.020 and 19.127 mins, HPLC-MS (two unresolved UV peaks with Rt=9.724 and 9.861 mins, 300.2 [M+H]+, 621.3 [2M+Na]+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25]>ClCCCl>[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([CH2:12][C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]#[N:25])=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6]
Reactant: Cn1cccc1CC#N
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)c1ccc(Cc2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a suspension of 17.5 g. (0.131 mole) aluminum chloride in 60 ml. 1,2-dichloroethane is added 24 g (0.131 mole) p-isopropylbenzoyl chloride. The resulting mixture is added slowly and dropwise to a chilled solution (0° C.) of 15.7 g. (0.131 mole) 1-methylpyrrole-2-acetonitrile in 100 ml. of 1,2-dichloroethane. After the addition is complete, the mixture is stirred at room temperature for twenty minutes and heated at reflux for three minutes. The reaction mixture is then cooled and poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over magnesium sulfate; and the solvent evaporated. The product, 5-(p-isopropylbenzyl)-1-methylpyrrole-2-acetonitrile, is isolated from the residual oil by column chromatography. The column is packed with acid washed alumina and eluted with benzene, ether and ethylacetate. The product is found in the first compound-bearing fraction which absorbs ultraviolet light at approximately 250 mμ. It is purified by recrystallization twice in ether: pentane. m.p. 59-64° C. Anal. Calcd. for C17H18N2O: N, 10.53%. Found: N,10.71%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][S:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OO)=[O:32].OO>C(O)(C(F)(F)F)=O.C(Cl)Cl.[OH-].[Na+]>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:24][CH2:25][S:26](=[O:32])[CH2:27][CH2:28]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)C(F)(F)F
Reactant: c1cc(C2(CN3CCSCC3)CCOCC2)ccc1OCCCN1CCCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 4-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-thiomorpholine (200 mg, 0.494 mmol) in TFA (0.67 ml) at 5 to 10° C. was added dropwise a solution of trifluoro-peracetic acid [4M solution prepared by the addition of 27.5% H2O2 (0.94 ml) to TFA (1.56 ml)] and stirred at 5 to 10° C. for 1 hour. The reaction mixture was diluted with DCM (5 ml) and NaOH (5M solution, 4 ml) was added to attain pH14. The mixture was extracted with DCM ((2×5 ml), the combined DCM extracts were washed with saturated aqueous brine (10 ml), dried over MgSO4, filtered and concentrated in vacuo. The isolated yellow oil was purified by column chromatography on silica eluting with DCM(95):MeOH(4):NH3(I) to give the title compound as a yellow oil (165 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.87 (d, 2H), 4.02 (t, 2H), 3.81-3.69 (m, 2H), 3.59-3.43 (m, 2H), 2.99-2.82 (m, 2H), 2.76-2.2.59 (m, 6H), 2.53 (br s, 4H), 2.46 (s, 2H), 2.31-1.73 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:17])=[CH:6][C:7]=1[F:8].[Cl:17][C:3]1[C:2]([Cl:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Oc1cc(Cl)c(F)cc1Cl
Product: Oc1ccc(F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %
Yield: 42 %

Procedure:
3-Chloro-4-fluorophenol (500 mg, 3.4 mmol) was dissolved in acetonitrile (25 mL) and trifluoroacetic acid (500 mL) was added, followed by addition of N-chlorosuccinimide (456 mg, 3.4 mmol). The reaction was stirred at ambient temperature for 3 days and the volatiles were then removed in vacuo. The crude product was purified by chromatography on silica gel with EtOAc:isohexane (1:19, v/v) as eluent to afford of 3,6-dichloro-4-fluorophenol (261 mg, 1.4 mmol, 42%) and 2,3-dichloro-4-fluorophenol (153 mg, 0.8 mmol, 25%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]1([C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)O)[OH:28].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:23][C:22]([F:24])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:28][C:27]3[CH:29]=[CH:31][CH:32]=[CH:33][C:34]=3[O:26]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: FC(F)(F)Oc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 71.2 %

Procedure:
A solution of 4-(4-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 247) (373 mg, 1.0 mmol), catechol (440 mg, 4.0 mmol) and p-TsOH.H2O (380 mg, 2.0 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 44 hours. Standard work-up and purification gave 4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (260 mg, 71%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(C)C.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH:33]2[CH2:35][CH2:34]2)=O)=[CH:27][CH:26]=1>O1CCCC1.CCCCCC>[CH:33]1([C:31]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:36])[F:37])=[CH:26][CH:27]=2)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:35][CH2:34]1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(C(F)(F)F)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
A stirred solution of 4.1 grams (0.04 mole) of diisopropylamine in 100 ml of tetrahydrofuran was cooled to -78° C., and 17.4 ml (0.04 mole) of 2.3 M n-butyllithium in hexane was added during a 15 minute period. Upon completion of addition, the reaction mixture was stirred at -78° C. for 15 minutes. After this time, 6.4 grams (0.04 mole) of ethyl (trimethylsilyl)acetate was added during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at -78° C. for 30 minutes, and 8.5 grams (0.04 mole) of cyclopropyl (4-trifluoromethylphenyl) ketone was added during a 5 minute period. After this time the reaction mixture was stirred at -78° C. for one hour, at -25° C. for one hour, and finally at ambient temperature for two hours. The reaction was then quenched with aqueous 5% hydrochloric acid. The mixture was then extracted with diethyl ether, and the combined extracts were dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 6.0 grams of ethyl 3-cyclopropyl-3-(4-trifluoromethylphenyl)propenoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1([CH2:20][N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]=[C:22]2[CH3:46])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[OH:13][C:14]1([CH2:20][N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]=[C:22]2[CH3:46])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CCCc1nc(C)n(CC2(O)CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(CC2(O)CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.57 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.7 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 18%).