Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1.[C:24]([NH2:27])(=O)[CH3:25].C1(C)C(C)=CC=CC=1.[NH4+].[Cl-]>C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:18](=[O:23])[CH:19]=[C:20]([CH3:21])[N:27]=[C:24]2[CH3:25])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CC(=O)CC(=O)Nc1ccc(NCCCC2CCCO2)c(F)c1
Reactant: CC(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)n(-c2ccc(NCCCC3CCCO3)c(F)c2)c(C)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A mixture of N-(3-fluoro-4-((3-(tetrahydrofuran-2-yl)propyl)amino)phenyl)-3-oxobutanamide (250 mg, 0.78 mmol), acetamide (92 mg, 1.56 mmol), titanium tetraisopropanolate (1.9 mL) and xylene (10 mL) was stirred at 165° C. for 24 h. The mixture was then cooled to rt. 60 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added and the resulting mixture was stirred further at rt overnight. The mixture was then filtered and the filtrate was extracted with DCM (15 mL×3). The combined organic layers were washed with brine (15 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:2) to give the title compound as a yellow solid (80 mg, 29%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2/[C:14](=[CH:22]/[C:23]2[NH:24][CH:25]=[CH:26][C:27]=2[O:28][CH3:29])/[C:15](=[O:21])[NH:16]3)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccc(O)cc3)c21
Yield: 38.4 %

Procedure:
In accordance with Method S above, 4-hydroxy-phenyl boronic acid (96.6 mg, 0.70 mmol) (see Gilman, supra) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.47 mmol) (Starting Material 7) using (Ph3P)4Pd (27 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.47 mL, 0.94 mmol) and DME (10 mL) at reflux for 2 days to give (Z)-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 60 mg, 73%, based on 70 mg recovered starting oxindole).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].F[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]3[CH2:8]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc([N+](=O)[O-])nc3)CC2C1
Yield: 63.6 %

Procedure:
Following Example 188a, reaction of 404 mg of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2 mmol) and 566 mg 5-fluoro-2-nitropyridine (1.1 mmol) gave 335a as a yellow solid (234 mg, 35%). MS: [M+H]+ 335. 1H NMR (500 MHz, DMSO) δ 8.18 (d, J=9.0, 1H), 7.87 (d, J=3.5, 1H), 7.06 (dd, J=9.0, 1H), 3.66 (s, 2H), 3.55 (s, 2H), 3.36 (s, 2H), 3.18 (s, 2H), 3.05 (s, 2H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]1[S:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C([Li])CCC.[CH3:13][C:14]1[CH:15]=[C:16]([C:20]2[O:21][C:22]([CH3:36])=[C:23]([CH2:25][O:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([CH2:33][CH:34]=[O:35])[CH2:28]3)[N:24]=2)[CH:17]=[CH:18][CH:19]=1.Cl>O1CCCC1.CCCCCC>[OH:35][CH:34]([CH:1]1[S:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH2:33][C@H:29]1[CH2:30][CH2:31][CH2:32][C@@H:27]([O:26][CH2:25][C:23]2[N:24]=[C:20]([C:16]3[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=3)[O:21][C:22]=2[CH3:36])[CH2:28]1
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC=O)C3)c(C)o2)c1
Reactant: O=C1CSC(=O)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC(O)C4SC(=O)NC4=O)C3)c(C)o2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
214 mg of thiazolidinedione are dissolved in 20 ml of tetrahydrofuran and, at −78° C., 1.4 ml of a 2.7 M solution of n-butyllithium in n-hexane are added. The mixture is stirred at −78° C. for 30 minutes, and 500 mg of {cis-3-[2-(3-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehyde, dissolved in 10 ml of tetrahydrofuran, are then added. After 30 minutes of stirring at −78° C., the mixture is allowed to warm to room temperature. 20 ml of 1N hydrochloric acid are added and the mixture is extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 420 mg of 5-{1-hydroxy-2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione as a white solid. C23H28N2O5S (444.45), MS (ESI): 445 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C[O:20][CH2:19]C1.C([Li])CCC.CN(C=O)C>O.CCCCCC>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH:3]=2)[CH:19]=[O:20])=[N:14]1
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1Br
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C2=NC(C)(C)CO2)cc1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
2-(3-Bromo-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (2.1 g, 7.4 mmol) and THF (15 ml) were mixed, and this solution was cooled to -78° C. A hexane solution (1.6M, 4.75 ml) of n-butyllithium (7.6 mmol) was added, and the mixture was stirred for 2 hours. DMF (1.16 ml, 15 mmol) was added and the mixture was stirred for 20 minutes. Water (20 ml) was added to stop the reaction. The aqueous layer was extracted twice with ethyl acetate (20 ml). The organic layers were combined, and washed with saturated brine (30 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=3/1-1/3) to give 5-(4,4-dimethyl-4,5-dihydrooxazole-2-yl)-2-methoxybenzaldehyde (0.71 g, 41%) as colorless transparent crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClS([N:32]=[C:33]=[O:34])(=O)=O.S(=O)(O)[O-].[Na+].[OH-].[Na+]>C1C=CC=CC=1.CCOCC.O>[CH2:12]([C@@:10]1([CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:32][C:33](=[O:34])[CH2:11]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C=C(CCCCCCCCCCCCCCCC)COCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC[C@]1(COCc2ccccc2)CC(=O)N1
Reaction time: 8 h

Procedure:
To a solution of 3.0 g of 2-[(phenylmethoxy)methyl]-1-octadecene in 10 ml of benzene under argon is added 1.05 ml of chlorosulfonyl isocyanate. The mixture is stirred overnight and then poured into a solution of 22 g of sodium bisulfite, 100 ml of water, 5 ml of 10% sodium hydroxide and 100 ml of ether. This mixture is stirred for 2 hours, and the organic layer separated, dried and evaporated. The residue is purified by chromatography, to give 1.1 g of the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2]
Reactant: CCc1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.66 g (4.2 mmol) 2-ethyl-1H-indole in 10 mL acetic acid were mixed with 1.3 g (20 mmol) sodium cyanoborohydride and stirred for one day at RT. The reaction mixture was evaporated down using the rotary evaporator, combined with 20 mL aqueous 4N hydrochloric acid and stirred for 1 h at RT. While cooling with ice 45 mL of an aqueous 4N sodium hydroxide solution were then added and the mixture was extracted with ethyl acetate. The organic phase was dried on sodium sulphate, filtered, evaporated down and the residue was dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)nc2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(Cl)nc2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 252F (1.56 g, 6.4 mmol) in THF (30 mL) at room temperature treated with a solution of LiOH.H2O (0.537 g, 12.8 mmol) in water (5 mL), heated to reflux for 4 hours, cooled to room temperature and concentrated. The mixture was neutralized with 1N HCl and extracted ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (APCI) m/e 234 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28]O>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 56.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (444 mg, 2.27 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (513 mg, 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].COCCOC.[CH:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32]>>[CH:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:37]=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Solvent: COCCOC
Product: CC(C)c1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 30.5 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml) 2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-isopropyl-phenylboronic acid (32 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (17 mg, 31%). LC-MS m/e 429.39 (M+H+)
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[C:14]1([CH2:24][CH2:25][Mg]Cl)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:24][CH2:25][CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]CCc1cccc2ccccc12
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Product: COC(=O)c1cc2c([nH]1)C(CCc1cccc3ccccc13)CC2

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) and (2-(naphthalen-1-yl)ethyl)magnesium chloride (synthesized in situ) were reacted according to General Procedure 3 to give the exo olefin-containing compound (E)-methyl 6-(2-(naphthalen-1-yl)ethylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. (Note: (2-(naphthalen-1-yl)ethyl)magnesium chloride was synthesized as follows: Activated magnesium turnings (0.306 g, 12.6 mmol; washed sequentially with 3N HCl, water, THF and diethyl ether) was placed in a flask and anhydrous THF (50 mL). 1-(2-chloroethyl)naphthalene ((0.168 M in THF, 75.0 mL, 12.6 mmol) was added dropwise followed by a few grains of I2 (catalytic). The solution was stirred gently at ambient temperature for 30 min. Additional anhydrous THF (25 mL) was added and the solution refluxed for 3 h, and then allowed to cool to ambient temperature). (E)-methyl 6-(2-(naphthalen-1-yl)ethylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate was hydrogenated according to General Procedure 6 (with 5% Pd/C), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-25% EtOAc/heptane affording the title compound. 0.051 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.86-2.03 (m, 1H), 2.08-2.29 (m, 2H), 2.55-2.81 (m, 3H), 3.03-3.31 (m, 3H), 3.67-3.86 (m, 3H), 6.54-6.72 (m, 1H), 7.30-7.37 (m, 1H), 7.37-7.45 (m, 1H), 7.45-7.58 (m, 2H), 7.75 (d, J=8.10 Hz, 1H), 7.83-7.93 (m, 1H), 8.01 (d, J=8.25 Hz, 1H), 8.74 (br. s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:31]=[CH:32][CH:33]=3)=[C:20]([C:40]([F:43])([F:42])[F:41])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:45]>C(O)C>[ClH:45].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:32][CH:33]=2)=[C:20]([C:40]([F:41])([F:42])[F:43])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(-c4ccccc4)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(-c3ccccc3)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 79-5 (810 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.
Reaction SMILES: [CH3:1][C@:2]12[CH2:14][CH2:13][CH2:12][N:3]1[CH:4](C(Cl)(Cl)[Cl:9])[O:5][C:6]2=[O:7]>CO.Cl>[ClH:9].[CH3:1][C@:2]1([C:6]([O:5][CH3:4])=[O:7])[CH2:14][CH2:13][CH2:12][NH:3]1
Reactant: C[C@]12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@]1(C)CCCN1
Yield: 0.1 %

Procedure:
To a solution of (7aR)-7a-methyl-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (D2) (0.11 g, 0.42 mol) in dry MeOH (2 ml), HCl 1M sol in MeOH (0.3 ml, 0.85 mol) was added and the mixture refluxed under a constant current of nitrogen for 1 h. Solvent was evaporated to afford the title compound (D3) 60 mg.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([CH:44]([CH3:47])[CH2:45][OH:46])[CH:38]=[CH:37]2.[C:48](O)(=[S:50])[CH3:49]>C1COCC1.C(OCC)(=O)C>[C:48]([O:46][CH2:45][CH:44]([C:39]1[CH:38]=[CH:37][C:36]2[C:41](=[CH:42][CH:43]=[C:34]([O:33][CH3:32])[CH:35]=2)[CH:40]=1)[CH3:47])(=[S:50])[CH3:49]
Reactant: CC(O)=S
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)COC(C)=S)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of diethylazodicarboxylate (4.03 g, 23.14 mmol) and triphenyl phosphine (6.06 g, 23.14 mmol) at 0° C. in THF (50 mL) was added 2-(6-methoxy-2-naphthyl)propan-1-ol (2.5 g, 11.57 mmol) and thioacetic acid (1.76 g, 23.14 mmol). The reaction mixture was stirred for 30 minutes before it was allowed to warm to room temperature and then stirred overnight. The reaction mixture was diluted with ethyl acetate ("EtOAc") (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate-hexane (1:9)) to give 1.5 g of the title compound as an oil. 1H NMR (CDCl3)δ1.38 (d, 3 H, CH3), 2.29 (s, 3 H, SCH3), 3.10 (m, 1 H), 3.18 (m, 2 H), 3.91 (s, 3 H, OCH3), 7.11-7.72 (m, 6 H).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=[CH:2]1.[Br:10]Br>C(O)(=O)C.O>[Br:10][C:2]1[S:1][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: O=C1NCc2ccsc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1NCc2cc(Br)sc21
Temperature: 0 °C
Yield: 82.8 %

Procedure:
A solution of 4H-thieno[2,3-c]pyrrol-6(5H)-one (1.0 g, 7.2 mmol) in acetic acid (9 mL) and water (7 mL) was cooled to 0° C. Bromine (407 μL, 7.92 mmol) was added and the reaction was maintained at 0° C. for 1.5 h. At completion, water (30 mL) was added and the mixture was and extracted with EtOAc (2×50 mL). The combined organics were washed with 5% aq. Na2SO3 (30 mL), sat. aq. NaHCO3 (30 mL) and brine (30 mL), then dried over Na2SO4, filtered, concentrated. The crude material was purified by flash chromatography over silica gel (5% MeOH/DCM) to yield 2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one (1.3 g, 83% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.28 (s, 1H), 4.39 (s, 3H); MS (EI) m/z=140.2 [M+1]+.
Reaction SMILES: [C:1]1([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[C:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][Si](C=[N+]=[N-])(C)C>CCOCC.CO>[C:1]1([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[C:9]([O:11][CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C(=O)C(=O)[O-])c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)C(C)(C)c1ccccc1
Temperature: 0 °C
Yield: 87.7 %

Procedure:
To a 0° C. (ice water bath) solution of 3-phenyl-3-methyl-2-oxobutanoate (9.0 g, 47 mmol, from Reference Example 35) in ether (40 mL) and methanol (60 mL). Trimethylsilyl diazomethane (2.0 M solution in hexanes, 35 mL, 70 mmol, Aldrich) is added dropwise until the evolution of gas ceased and the yellow color of the reagent persisted in solution. The solvents are evaporated under reduced pressure and the residue is taken up in ether/hexanes (1:1) and washed with 2% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The combined extracts are then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a straw-colored liquid (8.5 g, 88%). MS (ES+): (M+H)=206.9
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(O)(=O)C1C=CC=CC=1.[C:24]1([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O.ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=C(O)c1ccccc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(Br)cc1
Yield: 94.4 %

Procedure:
Suspending 3.0 g (15 mmol) of 4-bromobenzoic acid into 30 milliliter of 1,2-dichloroethane, adding 2.7 g (23 mmol) of thionyl chloride and 3 drops of N,N-dimethylformamide, the resultant solution was stirred with heating at the temperature of about 50° C. for 1 hour and 30 minutes until benzoic acid as the material disappeared. After completion of the reaction, removing the solvent and excess thionyl chloride by distillation, dissolving the resultant acid chloride into 30 milliliter of N-methylpyrrolidone, adding 2.8 g (15 mmol) of N-phenyl-1,2-phenylenediamine, the resultant solution was stirred at room temperature for a night. After completion of the reaction, adding water and filtering the precipitated solid, further washing with water and by drying under reduced pressure, 5.2 g of 4-bromo-N-(2-phenylamino-phenyl)-benzamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1.[F:24][C:25]1[C:30]([OH:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([O:31][C:30]4[C:29]([F:32])=[C:28]([F:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=4[F:24])(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (480 mg, 1.30 mmol) in DCM (5 mL) was added pentafluorophenol (240 mg, 1.30 mmol) at 0° C. Triethylamine (0.27 mL, 1.95 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with DCM (3 mL) and concentrated under reduced pressure. The crude mass was purified by combi flash column chromatography (12 g column; elution: 7% ethyl acetate in hexane) to provide perfluorophenyl 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (370 mg, 54.9%) as clear liquid. 1H NMR (400 MHz, DMSO) δ 8.22 (d, J=2.5 Hz, 1H), 7.96 (dd, J=8.7, 2.5 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.31 (dd, J=8.7, 2.3 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 4.41 (s, 2H), 3.86 (s, 2H); LCMS (ESI) m/z; 516.02 (M+H).
Reaction SMILES: C([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16](C(N)=O)[C:15]=2[C:14]2[C:9]1=[C:10](C)[CH:11]=[CH:12][C:13]=2OC)C1C=CC=CC=1>CCOCCOCCO.[Pd]>[CH:10]1[C:9]2[NH:8][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(C)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Agent: [Pd]
Solvent: CCOCCOCCO
Product: c1ccc2c(c1)[nH]c1ccccc12
Yield: 43 %

Procedure:
A solution of 0.805 g of 9-benzyl-5-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxamide in 24 ml of carbitol was treated with 1.1 g of 5% palladium on carbon and was refluxed for 6 hours open to the air. After cooling, the solution was filtered thourough a pad of celite and the pad was washed with ethyl acetate. The filtrates were diluted with ether and washed four times with water and dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using methanol/0-4% in dichloromethane to afford 0.166 g (28%) of debenzylated carbazole. ESIMS m/e 255 (M++1), 253 (M+−1) NMR (300 MHz, CDCl3): δ8.13 (br, 1H); 7.51 (d, J=8.1, 1H); 7.40 (t, J=7.6, 1H); 7.32 (d, J=7.2, 1H); 7.18 (d, J=7.8, 1H); 6.60 (d, J=8.0, 1H); 5.68 (br, 2H); 3.99 (s, 3H); 2.50 (s 3H).