Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:15][S:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: C=C(C(=O)OCC)c1ccc(OC)cc1
Product: CCOC(=O)C(CSc1cccc(OC)c1)c1ccc(OC)cc1

Procedure:
A process for preparing a compound of formula (6): ##STR120## characterized in that a compound of formula (1): ##STR121## is reacted with oxalic acid diethyl ester and sodium hydride to produce a compound of formula (2): ##STR122## the resulting compound of formula (2) is reacted with 3-methoxybenzenethiol represented by the formula: ##STR123## to produce a compound of formula (3): ##STR124## the resulting compound of formula (3) is reacted with hydrochloric acid to produce a compound of formula (4): ##STR125## the compound of formula formula (4) is then cyclized to produce a compound of formula (5): ##STR126## and the compound of formula (5) is reacted with methyl iodide in the presence of lithium diisopropylamide to produce the compound of formula (6).
Reaction SMILES: C[Si](C)(C)Cl.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl>C(OC(C)C)(=O)C.[Zn]>[OH:13][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CBr
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: COC(=O)CC(O)c1ccccc1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 5.7 g of zinc powder (87 mmol) in 35 ml of isopropyl acetate. After 1.65 ml of trimethylchlorosilane (13 mmol) had been added, the mixture was heated at 65° C. for 30 min. Following cooling to 60° C., 6.2 g of benzaldehyde (58 mmol) were added and, over the course of 4 min, 10.6 g of methyl bromoacetate (70 mmol) were added dropwise at 55° C., the temperature being maintained at 55° C. by external cooling. The mixture was then stirred at 55° C. for 5 min and, after cooling to 0° C., acidified with 40 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 40 ml of 0.5 N hydrochloric acid and finally washed with 20 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was distilled off under reduced pressure. Methyl 3-hydroxy-3-phenylpropionate was obtained in a yield of 8.9 g (85% of theory) with a boiling point of 76° C. (0.07 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19](Cl)=[O:20]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:19](=[O:20])[O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
1-(4-bromophenyl)methanamine (300 mg, 1.612 mmol) was taken up in dichloromethane (8062 μl) and triethylamine (225 μl, 1.612 mmol) was added. The solution was cooled to 0° C. and methyl chloridocarbonate (118 μl, 1.612 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. It was quenched with aqueous sodium bicarbonate and extracted using ethyl acetate (3×). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (50-100% ethyl acetate in hexanes) to yield the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Si:17]([O:34][CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]=[C:38](Cl)[CH:37]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Si:17]([O:34][CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[N:39]=[C:38]([O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH:37]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)[Si](OCc1cc(Cl)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(F)(F)F)n2)CC1
Reaction time: 0.75 h

Procedure:
To sodium hydride (36 mg, 0.89 mmol, 60% in mineral oil) in tetrahydrofuran (1.0 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (0.18 g, 0.89 mmol, Aldrich). After stirring for 45 minutes, 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-6-(trifluoromethyl)pyridine (0.20 g, 0.44 mmol, from Step B) in tetrahydrofuran (0.60 mL) was added and the mixture was stirred overnight. The reaction was quenched and diluted with water and extracted with ether. The extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-5% EtOAc in hexanes afforded product as an oil (0.19 g, 52%). LCMS (M-tBu+H)+: 559.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>C(Cl)(Cl)Cl>[CH2:30]([O:32][CH2:33][C:34]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:31]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate (9.25 g, 30.7 mmol) in chloroform (100 mL) was cooled to 0° C.; triethylamine (5.13 mL, 36.8 mmol) was added. Ethoxyacetyl chloride (4.51 g, 36.8 mmol) was then added dropwise over a period of five minutes. The reaction was allowed to warm to ambient temperature, heated at reflux overnight, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol) to provide 7.73 g of ethyl 6-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[N:6][CH:7]=1.[CH3:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=[C:28]([O:41][CH2:42][C:43]2([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44]2)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:25][C:26]1[CH:27]=[C:28]([O:41][CH2:42][C:43]2([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44]2)[N:29]=[CH:30][C:31]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)nc3)cn2)CCC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
N,N-dimethylformamide (3 mL) was added to 5-bromo-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (338 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}methyl)-cyclobutanecarboxylate (300 mg) and palladium chloride (dppf) methylene chloride complex (33 mg), and after adding 2N aqueous sodium carbonate solution (1.2 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was filtered by using Celite, and ethyl acetate and water were added to the filtrate to extract the objective compound. The organic layer was separated, washed with a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]-cyclobutanecarboxylate (344 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24]([CH3:26])=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24]([CH3:26])=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nc(C)n4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccc4c(c3)nc(C)n4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate in MeOH (2 mL) and THF (2 mL) was added a sodium hydroxide solution (2 M aqueous, 500 μL). The reaction mixture was stirred at 50° C. for 4 h. The mixture was purified using reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C29H29ClN3O3S: 534.2 (M+H+); Found: 534.2 (M+H+); 1H NMR (400 MHz, CD3OD): δ 8.38 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.69 (m, 1H), 7.60 (m, 3H), 5.26 (s, 1H), 4.00 (s, 3H), 2.87 (s, 3H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH3:6][Si:7]([CH3:10])([CH3:9])Cl.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:6][Si:7]([CH3:10])([CH3:9])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Product: CCCCO[Si](C)(C)C
Yield: 92 %

Procedure:
1 mole of n-butanol and 1.5 moles of trimethylchlorosilane were heated to reflux (54°-91° C.) with the addition of 0.0005 moles of tetra-n-butyl ammonium bromide. Vigorous evolution of HCl was observed. When evolution of gas ceased, the IR spectrum did not show an OH band. When the product was worked up by distillation, pure 1-trimethylsiloxybutane was obtained as distillate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=2)[O:35]1>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:40]=2)[O:35]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1F)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2F)O3)nc1

Procedure:
2-(2-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 315 mg of 2-(2-fluorophenyl)chroman-4,6-diol (Example 19(b)). The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.61 (m, 1H), 7.43 (m, 1H), 7.31-7.24 (m, 3H), 7.23 (d, 1H, J 9.1 Hz), 7.02 (dd, 1H, J 8.7, 3.1 Hz), 6.89 (d, 1H, J 8.7 Hz), 5.69 (d, 1H, J 6.3 Hz), 5.55 (d, 1H, J 11.9 Hz), 5.00 (m, 1H), 2.33 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.S(=O)(=O)(O)O.[CH:18](=O)[CH:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH:19]1([CH:18]([C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2]([CH3:1])([CH3:12])[CH2:3][S:4][C:5]=3[CH:11]=2)[C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2]([CH3:12])([CH3:1])[CH2:3][S:4][C:5]=3[CH:11]=2)[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1
Reactant: CC1(C)CSc2ccccc2N1
Reactant: O=CC1C=CCCC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1(C)CSc2cc(C(c3ccc4c(c3)SCC(C)(C)N4)C3CC=CCC3)ccc2N1

Procedure:
90 g (0.5 mole) of 3,3-dimethyl-2,3-dihydro-4H-1,4-benzothiazine, 500 ml of toluene, 3.2 g of concentrated sulphuric acid and 27.5 g (0.25 mole) of tetrahydrobenzaldehyde are refluxed for 5 hours, washed with water, the organic phase dried and the solvent removed in vacuo. Unreacted 3,3-dimethyl-2,3-dihydro-4H-1,4-benzothiazine is distilled off under a high vacuum, leaving as residue 1-cyclohex-3-enyl-1,1-di-(3,3-dimethyl-2,3-dihydro-4H-1,4-benzothiazin-7-yl)-methane in the form of a dark brown brittle resin.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]>CC(O)=O.C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1C#N
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CN
Yield: 68.9 %

Procedure:
A clear solution of tert-butyl (5-cyano-6-methoxy-4-methylpyridin-2-yl)carbamate (0.60 g, 2.279 mmol) in HOAc (5 mL) and ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr. LCMS showed that the reaction was complete (86% pure). The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 12% (5% NH4OH/MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum to give the product tert-butyl (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.42 g, 1.571 mmol, 68.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.16 (s, 1H), 3.80 (s, 3H), 3.57 (s, 2H), 2.28 (s, 3H), 1.46 (s, 9H). MS(ES)+ m/e 268.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)CNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), isobutylamine (0.240 g, 3.28 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-isobutyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.936 g, 77.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[CH3:20][S@:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[NH:23])=[O:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:23]=[S@@:21]([CH3:20])(=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: C[S@](=N)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of 5-bromonicotinic acid (1.21 g, 6.0 mmol), N,N-diisopropylethylamine (2.1 mL, 12.0 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (931 mg, 6.0 mmol) in DMF (11.0 mL) cooled to 0° C. was treated with 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (3.43 g, 6.6 mmol). The reaction mixture was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na2SO4 and concentrated. The residual brown oil was purified by chromatography (silica gel, hexane/EtOAc). The product containing eluent was concentrated and then triturated with hexane to give the title compound as an off-white solid (1.88 g, 92%).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:18][C:11]=3[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2].[CH2:24](Cl)Cl.CCCCCC>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]([CH3:24])[C:11]=3[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1cc2ccc3c(c4ccccc4n3CC)c2[nH]1
Reactant: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1cc2ccc3c(c4ccccc4n3CC)c2n1C
Yield: 90.5 %

Procedure:
Using the procedure outlined in Example 34A, ethyl 6-ethyl-1,6-dihydropyrrolo[3,2-c]carbazole-2-carboxylate (H.G. Pars Pharmaceutical Laboratories, Inc.) gave a 90.5% yield of ethyl 6-ethyl-1,6-dihydro-1-methylpyrrolo[3,2-c]carbazole-2-carboxylate, mp 115.5°-116°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][O:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].C(O)C>[N:5]1[N:6]2[C:7]([CH2:8][O:9][CH2:10][CH2:11]2)=[CH:12][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc2n(n1)CCOC2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCOC2
Reaction time: 2 h
Yield: 73 %

Procedure:
A 500-mL Parr hydrogenation bottle was purged with nitrogen and charged with 129a (1.01 g, 5.92 mmol), 10% palladium on carbon (50% wet, 125 mg dry weight) and ethanol (50 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 25 psi and shaken for 2 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged to the bottle. The catalyst was removed by filtration through a pad of CELITE® 521 and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography using 400 cc of silica gel and eluting with 3% methanol in methylene chloride. The fractions containing 129b were collected to afford, after concentrating under reduced pressure, a 73% yield (601 mg) of 129b as a yellow solid: mp 74-76° C. 1H NMR (300 MHz, CDCl3δ 5.37 (s, 1H), 4.72 (s, 2H), 4.07 (t, 2H, J=5.1 Hz), 3.98 (t, 2H, J=5.1 Hz), 3.57 (br s, 2H); MS (ESI+) m/z 140.4 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(=O)(OCC)OCC)=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:25]([CH2:27][CH2:28][C:29]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)([CH3:31])[CH3:30])=O.C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[CH:8]=[CH:25]/[CH2:27][CH2:28][C:29]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)([CH3:31])[CH3:30])=[O:5])[CH3:2]
Reactant: CC(C)(CCC=O)n1ccnc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/C=C/CCC(C)(C)n1ccnc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
Under an atmosphere of nitrogen, 2.0 g of diethyl (E)-3-ethoxycarbonyl-2-propenylphosphonate was added dropwise to 25 ml of a 0.32 M solution of lithium diisopropylamide in tetrahydrofuran at -78° C. and the mixture was stirred at -70° C. for 30 minutes. To it was added a solution of 1.0 g of 1-(3-formyl-1,1-dimethylpropyl)imidazole (prepared as described hereafter) in 2 ml of tetrahydrofuran at -70° C., the mixture was stirred at room temperature for 30 minutes. To it was added 0.91 ml of acetic acid. After evaporation under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium bicarbonate, water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of chloroform and ethanol (99:1) as eluent to give 0.85 g of the title compound having the following physical characteristics:
Reaction SMILES: C1O[C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:22]([O-])=O)=[C:10]([S:13][C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[F:21])[CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:22][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:4](=[O:3])[CH2:5][CH2:6]2
Reactant: O=[N+]([O-])c1cc2c(cc1Sc1ccc(F)cc1F)C1(CC2)OCCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc2c(cc1Sc1ccc(F)cc1F)C(=O)CC2
Yield: 88.5 %

Procedure:
A mixture of 5-nitro-6-(2,4-difluorophenylthio)-1-indanone ethylene ketal (580 mg, 1.59 mmol), iron powder (500 mg, 8.9 mmol) and ammonium chloride (50 mg, 0.93 mmol) in 30 mL of ethanol:water (2:1) was refluxed for 1 h. The hot mixture was filtered through celite. The solvente was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous MgSO4 and concentrated to give the title compound (410 mg, 81%) as a light brown solid. 1H NMR (CDCl3) δ7.95 (s, 1H), 7.00 (m, 1H), 6.80 (m, 2H), 6.72 (s, 1H), 4.95 (br s, 2h), 3.05 (t, 2H), 2.65 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 4-chlorobenzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (100 mL) was added pyrrolidine (6.55 g, 92 mol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 h. After cooling to 4° C., the resulting precipitate was collected and dried to give 21 g of E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. MS: 291 (M+H)+.