Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:17]>>[Cl:15][C:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([S:2](=[O:4])(=[O:3])[NH2:17])[CH:14]=2)[C:9]([Cl:16])=[CH:10][N:11]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N
Product: NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-chlorosulphonyl-1,4-dichloroisoquinoline (110 mg, 0.37 mmol) was dissolved in a solution of saturated methanolic ammonia (NH3) (10 mL) and the solution stirred at room temperature for 1.5 hours. The solvents were evaporated in vacuo and the residue was azeotroped with CH2Cl2 and then partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo to give 1,4-dichloro-7-sulphamoylisoquinoline (98 mg, 0.35 mmol) as a white solid.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N:18]#CBr.C[C:22](C)=[O:23].C([N:27](CC)CC)C>O>[O-:17][C:14]#[N:18].[O-:23][C:22]#[N:27].[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:3])[CH3:2])=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: N#CBr
Reactant: CC(C)=O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O
Product: N#C[O-]
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
A 456.60 gram portion of 4,4'-isopropylidene diphenol (2.00 moles), 444.91 grams of cyanogen bromide (4.20 moles) and 1,100 milliliters of acetone were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was cooled to -5° C., then 406.82 grams of triethylamine (4.02 moles) was added to the reactor over a 60 minute (3600 s) period and so as to maintain the reaction temperature at -5° to -3° C. After completion of the triethylamine addition, the reactor was maintained at -5° to -3° C. for an additional twenty-five minutes (1500 s) followed by addition of the reactor contents to 1.5 gallons (5.685) of deionized water. After 5 minutes (300 s), the water and product mixture was multiply extracted with three 500 milliliter volumes of methylene chloride. The combined methylene chloride extract was washed with 500 milliliters of 0.05 percent by weight aqueous hydrochloric acid followed by washing with 500 milliliters of deionized water, then drying over anhydrous sodium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum for 60 minutes (3600 s) at 100° C. Bisphenol A dicyanate (545.8 grams) was recovered in 98.1 percent yield as a light tan colored, crystalline solid. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure (disappearance of phenolic hydroxyl absorbance, appearance of cyanate absorbance).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[NH+:19][O:20][CH3:21])[C:16]([OH:18])=O)[N:14]=1)=[O:8].[NH2:22][CH:23]1[C:38](=[O:39])[N:25]2[C:26]([C:35]([OH:37])=[O:36])=[C:27]([CH2:30][S:31][C:32](=[O:34])[CH3:33])[CH2:28][S:29][C@H:24]12>C(Cl)Cl.C(N(CC)CC)C>[C:32]([S:31][CH2:30][C:27]1[CH2:28][S:29][C@@H:24]2[CH:23]([NH:22][C:16](=[O:18])[C:15]([C:13]3[N:14]=[C:10]([NH:9][C:7](=[O:8])[CH2:6][Cl:5])[S:11][CH:12]=3)=[N:19][O:20][CH3:21])[C:38](=[O:39])[N:25]2[C:26]=1[C:35]([OH:37])=[O:36])(=[O:34])[CH3:33]
Reactant: CO[NH+]=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1
Reaction time: 0.25 h

Procedure:
3.8 ml of thionyl chloride and 26 ml of methylene chloride were added at 0° C. under nitrogen to a mixture of 15.3 g of the syn isomer of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminioacetic acid in 80 ml of methylene chloride and after standing at 0° C. for 15 minutes, 7 ml of triethylamine were added thereto. A mixture of 14.4 g of 7-amino-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid in 100 ml of methylene chloride and 14 ml of triethylamine were added to the mixture at 0° C. under nitrogen and the temperature was allowed to return to 20° C. The mixture was stirred for an hour and was then evaporated to dryness at 30°-35° C. under reduced pressure. The residue was taken up in 250 ml of water and the solution was raised through carbon black. 50 ml of 2N hydrochloric acid were added thereto and the mixture was vacuum filtered. The product was washed with water and the raw product was suspended in 80 ml of ethanol. 7 ml of triethylamine were added thereto at 5° C. and 15 ml of 4N sulfuric acid were added thereto all at once with stirring at 5° C. After standing for 15 minutes, the mixture was vacuum filtered and the product was empasted with ethanol, then with ether and was dried under reduced pressure to obtain the syn isomer of 3-acetylthiomethyl-7-[{2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1C=[C:4](C#CC(O)=O)[CH:5]=[CH:6][C:7]=1C1CCCCC1.N1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:20]=1[C:21]#[C:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: c1ccc2ncccc2c1
Reactant: O=C(O)C#Cc1ccc(C2CCCCC2)c(Cl)c1
Solvent: O
Product: Clc1ccccc1C#CC1CCCCC1

Procedure:
3-chloro-4-cyclohexylphenylpropiolic acid (7.3 g.) is heated at 120°-124° for 5 hours in quinoline. The reaction product is diluted with water and washed thoroughly with dilute hydrochloric acid. This is followed by washing with sodium bicarbonate (10%). The material is passed through a short aluminum (H+) column, eluted with N-hexane to give a fraction free of carbonyl absorption (I.R.). Removal of solvent gives 3-chloro-4-cyclohexylethynylbenzene.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]([NH:14][NH2:15])(=O)[CH3:12].CCOC(C)=O>O=P(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:8][C:11]([CH3:12])=[N:14][N:15]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)NN
Reactant: O=C(O)c1ccc(I)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc(I)cc2)o1
Temperature: 80 °C
Yield: 31.9 %

Procedure:
A mixture of 4-iodobenzoic acid (1.0 g) and acethydrazide (329 mg) in POCl3 (4 ml) is stirred over night at 80° C., then another day at 100° C. AcOEt (50 ml) is added and the mixture is washed with H2O (50 ml), sat. aq. Na2CO3 sol. (50 ml) and H2O (50 ml). After drying over Na2SO4 the solvent is evaporated and the product is purified by flash chromatography (silica gel, CH2Cl2/MeOH/25% aq. NH4OH 90:9:1). 368 mg of 2-(4-iodo-phenyl)-5-methyl-[1,3,4]oxadiazole (19) are obtained as a yellowish solid, MS (ESI) 287.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:37]1([CH2:43][CH2:44][S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[OH:51][C:50]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:14][CH:15]=2)[O:21][C:47](=[O:48])[C:46]=1[S:45][CH2:44][CH2:43][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3ccc4ccccc4c3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(2-naphthalenylmethoxy)acetophenone (1.39 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 152-154° C.; 1H NMR (400 MHz, DMSO-d6) δ2.77 (t, 2 H), 2.98 (t, 2 H), 5.38 (s, 2 H), 6.68 (s, 1 H), 7.21 (m, 7 H), 7.54 (m, 2 H), 7.60 (d, 1 H), 7.96 (m, 4 H).
Reaction SMILES: CN1CCCC1=O.O.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:37][C:38](=[N:68]O)[C:39]1[CH:67]=[CH:66][C:42]([O:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH2:55][O:56][C:57]3[CH:65]=[CH:64][C:60]([C:61]([NH2:63])=[O:62])=[CH:59][CH:58]=3)[CH2:49][CH2:48]2)=[CH:41][CH:40]=1>O.C(OCC)(=O)C>[NH2:68][C:38](=[N:37][O:23][C:22](=[O:24])[C@@H:17]([NH:16][C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:39]1[CH:67]=[CH:66][C:42]([O:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH2:55][O:56][C:57]3[CH:58]=[CH:59][C:60]([C:61]([NH2:63])=[O:62])=[CH:64][CH:65]=3)[CH2:49][CH2:48]2)=[CH:41][CH:40]=1
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To an N-methyl-2-pyrrolidone (5 mL) solution of 0.23 g of N-(tert-butoxycarbonyl)-L-leucine monohydrate was added 0.34 g of 1,1′-carbonyldiimidazole at room temperature, which was then stirred at the same temperature for 1 hour and 30 minutes. An N-methyl-2-pyrrolidone (5 mL) solution of 0.20 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added to the mixture at room temperature, which was then stirred at the same temperature for 5 hours. The reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=10:1) to provide 0.14 g of 4-(3-{4-[3-(4-{amino[(2S)-2-(tert-butoxycarbonyl)amino-4-methylpentanoyloxyimino]methyl}phenoxy)propyl]-1-piperidinyl}propoxy)benzamide=O-[(2S)-2 (tert-butoxycarbonyl)amino-4-methylpentanoyl]oxime as white solid form.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].C1C(=O)N([Br:25])C(=O)C1.O>CN(C=O)C>[Br:25][C:5]1[O:4][C:3]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[C:2]([CH3:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccoc1C=C1C(=O)Nc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)oc1C=C1C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of 3-((3-methylfuran-2-yl)methylene)indolin-2-one (330 mg, 1.47 mmol) in DMF (7.0 mL) was added NBS (265 mg, 1.49 mmol) in DMF (1.0 mL) at 0° C. The reaction was stirred at 0° C. for 1 h and added H2O (13 mL). The resulting precipitate was collected by filtration to yield desired 3-((5-bromo-3-methylfuran-2-yl)methylene)indolin-2-one (320 mg). LCMS (ES): m/z 304 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[C:13](F)=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C>[CH2:3]([O:10][C:13]1[C:12]([Br:11])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1cccc(Br)c1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Br)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a flask containing sodium hydride (1.44 g, 60.0 mmol) suspended in DMF (60 mL, 800 mmol) at 0° C. was added benzyl alcohol (6.21 mL, 60.0 mmol) over 5 min. The reaction mixture was stirred at 0° C. for 30 min and then 3-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in DMF (20 mL) was added. The reaction mixture was warmed to room temperature and stirred at 80° C. for 2 h, cooled to room temperature, and extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was suspended with ethyl acetate:hexanes (1:3; 50 mL). The resulting suspension was stirred vigorously for 1 h, filtered, and dried. The mother liquor was concentrated and recrystallized. The crystals were combined and dried under vacuum to give the title compound (10.3 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[C:18]=[CH:17][CH2:16][NH2:19])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: C=CCN
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CCO
Product: COc1cc(C=C=CCN)c([N+](=O)[O-])cc1OC
Yield: 99.9 %

Procedure:
A suspension of 6-nitroveratraldehyde (84 g, 0.4 mole) and ethanol (1200 ml) was refluxed with a solution of allylamine (21 g, 0.44 mole) and ethanol (100 ml) for 1.5 hrs. The resulting dark solution was concentrated to dryness in vacuo leaving 100 g of a dark oil which solidified.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([NH2:37])=O)=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:40]N.COC(OC)[N:45]([CH3:47])C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]5[NH:37][CH:47]=[N:45][N:40]=5)=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=3)(=[O:15])=[O:16])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(-c4nnc[nH]4)ccc23)cc1

Procedure:
Dimethylformamide dimethylacetal (10 ml) was added to 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxamide (the compound of Example 28, 180 mg, 0.36 mmol) and the slurry was heated at reflux for 48 h. The solvent was removed in vacuo and the residue redissolved in glacial acetic acid (8 ml). Hydrazine hydrate (12 mg, 4.68 mmol) was added and the solution heated at reflux for 24 h. After cooling the crude product was extracted from brine (50 ml) with ethyl acetate (2×50 ml). The organic layers were dried (MgSO4) and concentrated. Flash column chromatography (elution with 96% dichloromethane/4% methanol) gave the desired product as a pale yellow solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([S:8]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9])[CH3:7].[S:16](=[O:18])=[O:17].C([O-])(=O)C.[Na+].[NH2:24]OS(O)(=O)=O>CCCCCC.O1CCCC1.O>[N:11]1([S:8]([CH:6]([S:16]([NH2:24])(=[O:18])=[O:17])[CH3:7])(=[O:10])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCS(=O)(=O)N1CCCC1
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(S(N)(=O)=O)S(=O)(=O)N1CCCC1
Reaction time: 6 h

Procedure:
Under an N2 atmosphere, 68.8 ml (0.11 mol) of a 1.6N solution of n-butyllithium in hexane are added dropwise at -78° C. to 16.3 (0.1 mol) of 1-ethylsulfonylpyrrolidine in 150 ml of absolute tetrahydrofuran. After 6 hours at -78° C., 26.0 g (0.4 mol) of sulfur dioxide are passed in at the same temperature, the mixture is subsequently allowed to come to room temperature, and stirring is continued for 14 hours. Evaporation of the reaction solution gives a crude sulfinate which is dissolved in 300 ml of water without purification. 18.0 g (0.22 mol) of sodium acetate in 20 ml of water and 12.4 g (0.11 mol) of hydroxylamine-O-sulfonic acid in 10 ml of water are added in succession, and the mixture is stirred for 7 hours at room temperature. The water phase is extracted using ethyl acetate, and the organic phase is dried and evaporated. For purification, the crude product obtained in this manner is taken up in 200 ml of 2N sodium hydroxide solution, the water phase is washed 3 times using 100 ml portions of diethyl ether, and the water phase is acidified with hydrochloric acid to pH 2 and extracted using ethyl acetate. After the organic phase has been dried and evaporated, 12.8 g (53% of theory) of 1-pyrrolidinosulfonylethanesulfonamide of melting point 78°-80° C. remain.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:25][C:26]([CH3:40])([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH2:27][OH:28]>C(OCC)C>[CH3:25][C:26]([CH3:40])([CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[CH:27]=[O:28]
Reactant: COc1ccc(COCC(C)(C)CO)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(COCC(C)(C)C=O)cc1

Procedure:
In a dry three-neck flask equipped with a mechanical stirrer and an addition funnel was placed 110 g of pyridinium dichromate and 200 ml of dry CH2Cl2. The mixture was stirred vigorously and then 42 g of 2,2-dimethyl-3-(4-methoxyphenylmethoxy)propanol, the product of Example 5a, was added in one portion. The resulting reaction mixture was stirred for 4 hours. The black brown mixture was poured into 400 ml ethyl ether and the mixture was filtered through a dry silica gel column to obtain a colorless solution. Removal of the solvent gave a residue which was distilled through a vigreux column to obtain the title compound, bp 83°-100°/0.25 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([C@@H:19]([NH2:21])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(NC(=O)OC(C)(C)C)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 106.4 %

Procedure:
To a solution of the above tert-butyl 1-((2S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)ethylcarbamate 50a (40 mg, 0.096 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h before being concentrated. The residue was subjected reverse phase column chromatography (CH3CN/H2O/0.1% Formic acid=5% to 100%) to give 52 (32.7 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8.0 Hz, 1 H), 7.27 (d, J=2.0 Hz, 1 H), 7.15 (m, 2 H), 7.02 (m, 2 H), 6.72 (d, J=7.6 Hz, 1 H), 4.04 (dd, J=5.2, 12.0 Hz, 1 H), 2.95 (m, 2 H), 2.78 (dd, J=12.0, 15.6 Hz, 1 H), 2.13 (m, 1 H), 1.80 (m, 1 H), 1.51 (q, J=12.4 Hz, 1 H), 1.35 (broad, 1 H), 1.14 (d, J=6.4 Hz, 3 H); 13CNMR (100 MHz, CDCl3) δ 147.67, 138.79, 137.29, 132.64, 130.88, 130.68, 130.41, 129.57, 129.43, 128.43, 126.58, 126.15, 51.16, 46.91, 42.31, 37.48, 32.60, 21.20; ESI MS m/z 320.1.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12]C)[CH:8]=[CH:7][CH:6]=2)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
3.1 g (11.7 mmol) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole was O-demethylated by treating it with 48.6 mL of 1M BBr3 in methylene chloride with stirring at room temperature for 5 hours, followed by concentration at reduced pressure. The residue was dissolved in ethyl acetate, washed with brine and dried (MgSO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.58 g (54% yield) of 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole, mp, 86-90° C.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCn1c2ccccc2c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21

Procedure:
To a mixture of 8.17 g (0.05 mole) of N-ethylcarbazole and 3.7 g (0.025 mole) of phthalic anhydride in 112 g of chlorobenzene, 6.65 g (0.05 mole) of aluminum chloride was added in small increments at ambient temperature after which the mixture was warmed in the range of 50°-70° C. for two hours. The reaction mixture was poured onto ice and rendered acidic by the addition of 10 percent hydrochloric acid. The chlorobenzene layer was separated and steam-distilled to remove the chlorobenzene. The residue was extracted with 10 percent aqueous sodium hydroxide, filtered to remove the insolubles and then acidified with dilute hydrochloric acid. The solid which separated was collected by filtration, washed with water and dried to obtain 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid (Formula VII: Ro =R1 =R2 =R3 =H; R8 =CH2CH3) melting over the range 120°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:10])[CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NC(=O)C(C)(C)C)c(C)c1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 4-methoxy-2-methylphenylamine (15.0 g, 109 mmol) and triethylamine (13.3 g, 131 mmol) in anhydrous THF (350 mL) at 0° C. was added pivaloyl chloride (14.1 mL, 13.8 g, 114 mmol). A white precipitate formed and the suspension was stirred for additional 30 min before water (10 mL) was added. The mixture was stirred for 30 min, THF evaporated and the residue was mixed with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and evaporated to an oil (23.5 g, 97%): LC/MS (+APCI) m/z 222 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([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])[C:5]=1[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:30])=O.CN(C)C=O>CCCCCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([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])[C:5]=1[C:6]([Cl:30])=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl

Procedure:
To a stirred solution of 2-Ethoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Ethoxy-6-pentadecylbenzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.