Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6]CC)=O.[O-]CC.[Na+].Br[CH:14]([CH:20]([CH3:22])[CH3:21])C(OCC)=O.[NH4+].[Cl-].Cl>C(O)C>[CH3:14][CH:20]([CH:22]1[CH:4]([OH:6])[CH2:3][CH2:2][S:1]1)[CH3:21]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: CCOC(=O)CCS
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: CC(C)C1SCCC1O
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Ethyl 3-mercaptopropionate (22.46 g) was dissolved in absolute ethanol (60 mL) and the solution was cooled to -20° C. To it was added sodium ethoxide solution in ethanol (62.5 mL of 21%). A solution of ethyl 2-bromoisovalerate (35 g) in absolute ethanol (60 mL) was added slowly. The reaction mixture was stirred for 2 hours while the reaction temperature was allowed to warm to room temperature. Saturated NH4Cl (150 mL) was added to the reaction mixture and organic layer was separated. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. Sodium (0.88 g) was dissolved in absolute ethanol (40 mL) at 0° C. and the solution was concentrated. The residue was dissolved in toluene and the product from the previous reaction, Compound 10, (7.78 g) was added. The reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and 1N HCl was added to the reaction mixture until the pH became acidic. The crude product was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine, were dried over Na2SO4 and concentrated. The residue, Compound 11, was heated with 10% H2SO4 (40 mL) at 100° C. overnight. The crude product was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue (2(S,R)-(methylethyl)-tetrahydrothiophen-3-one), compound 12, was dissolved in methylene chloride (60 mL) and the solution was cooled to 0° C. Diisobutylaluminumhydride (25 mL, 1M) in methylene chloride was added dropwise. The reaction mixture was stirred for one hour at 0° C. The reaction was quenched by the dropwise addition of water until no gas evolved. 1N HCl (50 mL) was added and the crude product was extracted with methylene chloride (50 mL×3). Combined organic layers were washed with saturated NaHCO3, brine and dried over Na2SO4. Concentration and purification by column chromatography, eluting with 20% ethyl acetate in hexane gave Compound 13, as an oil (1.72 g):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=O)[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[S:41])[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.250 g, 0.575 mmol) in toluene (5 mL) and DME (5 mL) was added Lawesson reagent (0.372 g, 0.920 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.095 g, 36.6%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 6.90 (d, J=8.8 Hz, 1H), 6.67 (brs, 1H), 6.38 (m, 1H), 6.31 (s, 1H), 4.85 (d, J=15.2 Hz, 2H), 4.14 (m, 4H), 3.87 (m, 2H), 1.64 (d, J=7.2 Hz, 3H), 1.59 (s, 3H), 1.42 (s, 9H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](OC2C=CC=CC=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)C2C(=CC=CC=2)[NH:8]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN1C(=O)CCC1>[OH:1][C:2]1[C:3]([C:19]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)[C:3]2[C:2](=[CH:18][CH:6]=[CH:5][CH:4]=2)[NH:8]1
Reactant: Nc1ccccc1
Reactant: O=C(Oc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 178.4 %

Procedure:
The phenyl 2-hydroxy-11H-benzo(a)carbazole-3-carboxylate obtained from Example I (5 grams, 14 millimoles), aniline (27.5 grams, 280 millimoles) and 15 milliliters of N-methyl pyrrolidinone were charged in a 100 milliliter 3-neck flask equipped with a magnetic stirrer and a nitrogen inlet. The resulting mixture was stirred and was heated to reflux at an oil bath temperature of ~250° C. under a nitrogen atmosphere. After 3 hours, TLC analysis revealed that all the starting phenyl ester was consumed. The mixture was cooled to room temperature and was poured into a 1 liter beaker containing 400 milliliters of ice cold 5 percent HCl. The yellow precipitate obtained was isolated by filtration. After washing with water (~200 milliliters) and ~20 milliliters of methanol and vacuum drying, 5.0 grams of crude product resulted. This product was then recrystallized from a mixture of DMF/MeOH/H2O (~30 milliliter each) yielding 4.4 grams (88 percent) of 2-hydroxy-11 H-benzo(a)carbazole-3-carboxanilide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:20]=[C:19]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(N(CC)C(C)C)(C)C.[CH:37]1[C:50]2[C:41](=[CH:42][C:43]3[C:48]([C:49]=2C(Cl)=O)=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[CH:39][CH:38]=1.ClCCl.CO>CO.[Pd].ClCCl>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:19]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([C:42]3[C:43]4[C:48]([CH:49]=[C:50]5[C:41]=3[CH:40]=[CH:39][CH:38]=[CH:37]5)=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:7])[CH2:13][CH2:12]2)[CH2:20]1)=[O:27])[CH3:24]
Reactant: CCN(CC)C(=O)C1=CN(C2CCN(C(=O)OC(C)(C)C)CC2)CCCC1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)C1CCCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
4-(6-diethylcarbamoyl-2,3,4,5-tetrahydro-azepin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.079 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon (10% w/w) (˜30 mg) added. The mixture was shaken under a hydrogen atmosphere (50 psi) for 3 h . The catalyst was removed by filtration through Celite® and the solvent evaporated under vacuum. The residue was dissolved in ethyl acetate (10 mL) under nitrogen, cooled to −78° C. and hydrogen chloride was passed in for a few minutes. The solution was allowed to warmed at room temperature then evaporated to dryness overnight in a stream of dry nitrogen. The residue was dissolved in anhydrous dichloromethane (4 mL), N,N-diisopropylethylamine (5 eq, 70 mL) was added followed by a suspension of anthracene-9-carbonyl chloride (Intermediate 3, 0.088 mmol) in dichloromethane (0.175 mL). The thin layer chromatography (9:1 dichloromethane-methanol) showed a new UV spot at Rf 0.40. After 30 minutes, the solution was washed with a mixed sodium hydrogen carbonate/sodium hydroxide solution, dried over anhydrous sodium sulfate, evaporated and the residue purified by chromatography on silica gel eluting with a 1%-2.5%-5%-10% methanol-dichloromethane gradient to give the title compound (20.4 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[N:12]=[C:11](SC)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:15].[Cl-]>CO>[C:1]([O:5][C:6]([C@H:8]1[N:12]=[C:11]([NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC1=N[C@H](C(=O)OC(C)(C)C)CC1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCC(N)=N1

Procedure:
To a solution of (S)-2-methylsulfanyl-3,4-dihydro-5H-pyrrole-5-carboxylic acid t-butyl ester (0.42 g, 1.95 mmol) in 4.0 mL anhydrous MeOH was added anh NH4Cl (0.11 g, 2.05 mmol). The reaction mixture was heated to reflux for 2 h, concentrated in vacuo, and the residue was taken up in CH2C2. The white solids were filtered, and the filtrate was concentrated to provide (S)-2-amino-3,4-dihydro-5H-pyrrole-5carboxylic acid t-butyl ester.HCl (0.41 g, 94%) as a light yellow solid 1H NMR (CDCl3) δ 1.49 (s, 9H), 2.24 (m, 1H), 2.52 (m, 1H), 3.06-3.08 (m, 2H), 4.44 (m, 1H), 9.81-9.8 (m, 2H). MS calcd for C9H16N2O2 +H 185, found 185.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])([C:14]([F:18])([F:17])[CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])([C:14]([F:18])([F:17])[CH2:15][O:16][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Reaction time: 0.83 h

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (13.6 g) and triethylamine (11.4 ml) in chloroform (136 ml) cooled to 0° C. was added methanesulfonyl chloride (7.8 ml), and the mixture was stirred for 50 minutes. To the mixture was added 5% aqueous potassium bisulfate solution, and the mixture was extracted with ethyl acetate. The separated organic layer was sequentially washed with 4M aqueous sodium hydroxide solution twice and saturated aqueous sodium chloride solution once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the titled compound (17.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1[N:14]=[C:15]([Sn](CCCC)(CCCC)CCCC)[S:16][CH:17]=1>CN(C=O)C.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>[CH3:12][C:13]1[N:14]=[C:15]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[S:16][CH:17]=1
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2nc(C)cs2)c1
Temperature: 90 °C

Procedure:
A mixture of commercially available methyl 2-bromoisonicotinate (2.750 g; 12.70 mmol), 4-methyl-2-(tributylstannyl)thiazole (4.942 g; 12.70 mmol), copper iodide CuI (242 mg; 1.27 mmol), and Pd(PPh3)4 (1.471 g; 1.27 mmol) in anh. DMF (55 ml) was heated to 90° C., under nitrogen, for 18 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the separated solids were washed with AcOEt. The organic layer was washed with water and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 2-(4-methylthiazol-2-yl)isonicotinate as a yellow solid. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 234.94 g/mol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(OCC)C.Cl[C:19]([O:21][C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[O:20].O>N1C=CC=CC=1.C(Cl)Cl>[C:22]([O:21][C:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:20])([CH2:25][CH3:26])([CH3:24])[CH3:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCC(C)(C)OC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1

Procedure:
To a solution of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (14 g.) in a mixture of pyridine (40 g.) and methylene chloride (300 ml.) was gradually added diethyl ether solution of t-pentyl chloroformate (70 ml.) containing 0.35 mole of t-pentyl chloroformate over 10 minutes at -20° C. with stirring, and the mixture was stirred for 2 hours at the same temperature and further stirred for 0.5 hour at 0° C. After the reaction, the reaction mixture was poured into water (200 ml.), and then the organic layer was separated. The organic layer was washed with 2N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn and then dried over magnesium sulfate. The solvent was distilled off from the organic layer to give dark brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (12 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[N:17]=3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C1COCC1>CO.[Pd]>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[C:18]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:17]=[C:16]([C:12]2[CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[CH:15]=[CH:14][CH:13]=2)[N:21]=1
Reactant: O=[N+]([O-])c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a stirred suspension of 2-(3′-nitro-biphenyl-3-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (1.6 g, 3.27 mmol) in MeOH (40 mL) was added at room temperature Pd—C (10%, 0.16 g) and THF (40 mL). The mixture was stirred at room temperature under H2 atmosphere for 2 h, the catalyst was removed by filtration and the obtained solution evaporated. The crude product was further purified by crystallization from diethyl ether/hexane to yield the title compound as an off-white solid (1.28 g, 85%). MS (ISP) 460.2 [(M+H)+]; mp 156.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][C:4]=1[F:15].N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][C:4]=1[F:15])[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:22](=[O:24])[CH3:23]
Reactant: COc1cc2c(CCN)c[nH]c2cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc2c(CCNC(C)=O)c[nH]c2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 0.75 grams (3.6 mmole) of the tryptamine, 2.0 ml. of pyridine, and 8.0 ml. of benzene was prepared. Acetic anhydride (1.0 ml.) was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvents then were removed in vacuo with moderate heating. The resulting crystalline residue was dissolved in a 1:1 mixture of warm ethyl acetate and chloroform. The solution was washed with water, then with sodium chloride solution, and then dried over sodium sulfate. The solvents were removed in vacuo. The crystalline residue was boiled in benzene for a few minutes. The mixture was allowed to stand at room temperature for several hours, and the resulting product was collected by filtration and dried to obtain 0.81 grams (90 percent) of N-[2-(5-methoxy-6-fluoroindol-3-yl)ethyl]acetamide, m.p. 158°-159° C.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1)#[N:3].[OH-:28].[Na+]>S(=O)(=O)(O)O>[CH2:26]([N:23]1[CH2:22][CH2:21][N:20]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:2](=[O:28])[NH2:3])=[CH:9][CH:8]=3)[N:11]=2)[CH2:25][CH2:24]1)[CH3:27]
Reactant: [OH-]
Reactant: CCN1CCN(c2nc(-c3ccc(C#N)cc3)cc3ccccc23)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCN1CCN(c2nc(-c3ccc(C(N)=O)cc3)cc3ccccc23)CC1
Yield: 23.8 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-cyanophenyl)isoquinoline (1.0 g) obtained in Example 62 was reacted in concentrated sulfuric acid (40 ml) at 60° C. for 5 hr. The reaction solution was cooled and then poured over ice, and was then adjusted to pH 8 to 9 by a 8N aqueous solution of sodium hydroxide. The resulting white precipitates were collected by filtration, washed with water and dried, to give the title compound (0.25 g, yield; 23.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].O.C(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(Cl)c(Cl)c1
Yield: 82.2 %

Procedure:
A solution of 16.3 g (0.1 mole) of 3,4-dichlorophenol in 100 ml of toluene was heated at reflux utilizing a Dean-Stark trap to remove any water that may have been present. The solution was cooled in an ice bath, treated with 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate, and heated at reflux overnight. The solution was cooled in an ice bath, vigorously stirred, and treated dropwise with water until carbon dioxide evolution ceased. The solid which precipitated was collected by filtration, washed with water and benzene, dried, and recrystallized from benzene to yield 19.9 g (82%) of a white solid, mp 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[CH2:39][CH:40]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:40][CH2:39][C:38]([F:43])([F:42])[F:37])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: O=CCC(F)(F)F
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCC(F)(F)F)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3,3,3-trifluoropropanal instead of acetone and was obtained as a light brown oil. MS m/e: 620.3 [M]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[CH2:38][OH:39])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>C(Cl)Cl>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[CH:38]=[O:39])=[CH:33][CH:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCC(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Yield: 86.2 %

Procedure:
Dess-Martin periodinane (5.38 g, 12.7 mmol) was suspended in CH2Cl2 (70 mL). Compound 3 (3.22 g, 10.0 mmol) dissolved in 20 mL CH2Cl2, was added under stirring. The resulting mixture was stirred overnight at room temperature. Diethyl ether (200 mL) was added and the organic phase was washed with NaOH (2×30 mL, 2M), NaHCO3 (50 mL, saturated aqueous solution), and brine (50 mL) and dried over Na2SO4. Filtration and evaporation of the solvent under reduced pressure gave a crude material which was purified by column chromatography (heptane:ethyl acetate 4:1) to yield 2.76 g, 86% of 4 as a white solid. 1H-NMR (CDCl3) δ; 9.94 (dd, 1H, J=2.0 Hz and 1.5 Hz), 7.45-7.26 (m, 6H), 7.16 (d, 2H, J=8.6 Hz), 7.14-7.08 (m, 3H), 7.0 (d, 2H, J=9.0 Hz), 5.11 (ad, 1H, J=1.2 Hz), 5.07 (s, 2H); 13C-NMR (CDCl3) δ 197.6 (d, J=1.5 Hz), 160.7 (d, J=247 Hz), 158.5, 136.8, 130.5 (d, J=2.0 Hz), 130.5 (d, J=2.0 Hz), 129.3 (d, J=8.1 Hz), 128.6, 128.0, 127.4, 127.1, 124.4 (d, J=3.5 Hz), 115.7 (d, J=22.3 Hz), 115.5 (2C), 70.1, 57.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:20]([O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: Oc1ccccc1-n1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1(C)Oc2ccccc2-n2cccc21

Procedure:
A solution of the compound of formula 2, N-(2-hydroxyphenyl)pyrrole (5 g), described in Example 1, ethyl acetoacetate (4.3 g) and p-toluenesulfonic acid (0.5 g) in benzene (1,500 ml) is stirred and heated at reflux with a Dean-Stark water trap for 3 hr. Ethyl acetoacetate (1.0 g) is added and the reaction mixture kept under the refluxing condition overnight. After being cooled, the mixture is washed with a 5% solution of sodium bicarbonate and then water. The benzene solution is dried (MgSO4), filtered and evaporated. The crude product is purified by chromatography on a column of silica gel. Elution with chloroform gives 4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-acetic acid ethyl ester (3; R1 and R2 = H,R3 = CH3, n = 1, X = 0 and A = COOC2H5), νmaxCHCl3 1,725, 1,600, 1,505, 1,345, 1,080, 1,031 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:25]1[NH:26][C:27](=[O:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:26]3[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=[N:25]3)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1cccn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2ncccc2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Yield: 795.3 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (335 mg) in DMF (7.0 mL) were added 3(2H)-pyridazinone (79 mg) and potassium carbonate (143 mg), and the mixture was heated at 60° C. for 4 hr. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.49 g).