Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>O=[Mn]=O.C(Cl)(Cl)Cl>[C:1]1([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH:12]=[O:13])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OCc1cccc(C2=CCCC2)c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(C2=CCCC2)c1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
1.35 g (8 mmol) of (3-cyclopenten-1-ylphenyl)methanol (5a) and 80 ml of chloroform are introduced into a round-bottomed flask. 6.8 g of MnO2 are then added and the suspension is heated at 60° C. for 2 hours. The mixture is filtered in the hot state, the precipitate washed with chloroform and then the filtrate concentrated under reduced pressure. The title product (1.05 g) is obtained in the form of a yellow oil which is used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[S:15][C:14]2[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:13]=2[CH:12]=1)C1C=CC=CC=1.O1CCOCC1.[OH-].[Na+].O>C=C>[CH3:21][O:20][C:19]1[C:13]2[CH:12]=[C:11]([NH2:10])[S:15][C:14]=2[C:16]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Agent: C=C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(N)cc12
Yield: 60 %

Procedure:
A stirred solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester (1.7 g, 4.36 mmol) in ethylene gylcol and dioxane was heated under reflux with 2N NaOH (20 ml, 9.1 eq) for 4 h. After cooling and addition of water (20 ml) the mixture was extracted with EtOAc (3×25 ml), the combined extracts were washed with brine, dried with Na2SO4 filtered and evaporated. The crude residue was then chromatographed over silica gel eluting with dichloromethane/2N NH3 in MeOH (99:1). This afforded the title compound (668 mg, 60% yield) as a red gum. MS m/e=256.2 (M+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:4][N:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22].[OH-].[NH4+].ClC1N=CC=CN=1>CO.C(Cl)(Cl)Cl.O.C(O)C>[CH2:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH2:23][CH2:21][OH:22])[N:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCCO
Reactant: CCCCCCCCCCCCNc1ccnc(Cl)n1
Agent: Clc1ncccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCNc1ccnc(NCCO)n1
Yield: 97 %

Procedure:
A mixture of 2-chloro-4-(n-dodecylamino)pyrimidine (6.0 g, 0.02 m), ethanolamine (12.2 g, 0.2 m), ethanol (70 ml) and water (20 ml) is stirred and refluxed until thin-layer chromatography (silica gel; 10 parts chloroform, 0.2 parts methanol, 0.5 parts concentrated ammonium hydroxide) indicates the absence of the 2-chloropyrimidine compound. The ethanol is removed in vacuo, the residue is distributed between water and methylene chloride, the aqueous layer is extracted again with methylene chloride, the combined organic layer is washed well with water, dried (Na2SO4) and concentrated to leave a residue of 6.3 g (98%) of 4-(n-dodecylamino)-2-(2-hydroxyethylamino)pyrimidine as an oil which crystallizes readily on standing.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([C:17]3[C:18]([F:28])=[C:19]4[C:24](=[CH:25][C:26]=3[F:27])[N:23]=[CH:22][CH:21]=[CH:20]4)[CH3:16])=[N:13][N:14]=2)[N:11]=1)=[CH2:5])C.Cl>CC(O)=O>[F:28][C:18]1[C:17]([CH:15]([C:12]2[N:10]3[N:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]3=[N:14][N:13]=2)[CH3:16])=[C:26]([F:27])[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2
Reactant: C=C(OCC)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 6-{1-[6-(1-ethoxy-vinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-ethyl}-5,7-difluoro-quinoline obtained from the previous step was dissolved in HOAc (50 mL), 3N HCl aqueous solution (5 mL) was added. The reaction mixture was stirred at rt overnight. LC/MS showed the reaction was complete. Solvent was removed under reduced pressure. EtOAc was added, and cold 1N NaOH aqueous solution was added slowly until pH 8-9. The mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to afford 1.0 g (65% for two steps) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.92 (dd, 1H), 8.32 (d, 1H), 8.14 (d, 1H), 7.68 (d, 1H), 7.61 (d, 1H), 7.42 (dd, 1H), 5.32 (q, 1H), 2.43 (s, 3H), 2.21 (d, 3H). LCMS (method A): [MH]+=354, tR=4.42 min.
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9](=[O:37])/[CH:10]=[CH:11]/[C:12]1[C:13]([NH:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])=[N:14][C:15]([S:26][CH3:27])=[N:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25])C.Cl.CCOC(C)=O>CO.O>[CH3:6][O:8][C:9](=[O:37])[CH2:10][CH2:11][C:12]1[C:13]([NH:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])=[N:14][C:15]([S:26][CH3:27])=[N:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25]
Reactant: CCOC(=O)/C=C/c1c(Nc2c(F)cccc2F)nc(SC)nc1-c1ccc(F)cc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)CCc1c(Nc2c(F)cccc2F)nc(SC)nc1-c1ccc(F)cc1C
Reaction time: 0.5 h

Procedure:
To a solution of SmI2 in THF (0.1M) (Aldrich) (15 mL, 1.5 mmol) and MeOH (3 mL) was added the product of Example 30 (100 mg, 0.22 mmol) and the reaction mixture maintained its blue color. The presence of new product and the disappearance of starting material was indicated by hplc. After 30 min, the reaction was diluted with H2O (10 mL), then 1 M HCl (3 mL), followed by EtOAc (20 mL), the layers were shaken together and separated. The aq phase was washed with EtOAc (20 mL) and the combined EtOAc was dried (MgSO4) and the solvent was evaporated in vacuo and the residue was crystalized from i-PrOH/H2O (1:1) to afford 3-[4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-propionic acid methyl ester. LC MS (m/e)=448.2 (MH+), Rt=2.17 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:14][CH:13]=3)=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:33][CH:32]=3)[S:8][C:7]=2[CH:45]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:14][CH:13]=3)=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:35][CH:36]=3)[S:8][C:7]=2[CH:45]=1
Reactant: COc1ccc2c(Cc3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: CC(Cl)Cl
Product: Oc1ccc2c(Cc3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of 1.150 g (1.84 mmol) (±)-6-methoxy-3-[4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part A) in 20.0 mL of anhydrous dichloroethane at 0° C. was added 1.10 mL (14.7 mmol) of ethanethiol, followed by the addition of aluminum chloride (982 mg, 7.36 mmol). The yellow biphasic reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched at 0° C. with 20 mL of saturated aqueous NaHCO3. The aqueous layer was separated and extracted with EtOAc (3×200 mL). The combined organic layers were washed with 150 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by using flash chromatography (silica gel, 60:37:3 THF-hexanes-TEA) to afford 1.067 g (1.75 mmol, 95%) of a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[NH2:7][C@H:8]([C:13]([NH2:15])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11].C(=O)([O-])[O-].[K+].[K+].N[C@H](C(N)=O)CC(=O)N>O.C(OCC)C>[C:1]([NH:15][C:13](=[O:14])[C@H:8]([CH2:9][C:10](=[O:12])[NH2:11])[NH2:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)C[C@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C=CC(=O)NC(=O)[C@@H](N)CC(N)=O
Reaction time: 0.17 h

Procedure:
A 5 ml portion of acrylic acid chloride and 200 ml of diethyl ether were put into a 500 ml capacity eggplant type flask and stirred on an ice bath. Next, 1.84 g of asparagineamide hydrochloride (mfd. by Kokusan Kagaku) was dissolved in 40 ml of deionized water, and 3 g of potassium carbonate was dissolved in 20 ml of deionized water. The asparagineamide aqueous solution was mixed with the potassium carbonate aqueous solution. The mixed liquid was added dropwise into the eggplant type flask spending 10 minutes while stirring constantly, and the mixture after completion of the dropwise addition was stirred for 24 hours. Diethyl ether layer in the thus obtained reaction liquid was discarded, and the water layer was concentrated at 25° C. under a reduced pressure. One liter of acetone was added to the thus obtained residue and stirred for 1 hour. The insoluble solids were removed by suction filtration. By recrystallizing from the acetone layer, 0.5 g of colorless crystals were obtained.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][O:14][C:15]1[CH:43]=[CH:42][C:18]2[NH:19][C:20]([C:25]3[C:26](=[O:41])[N:27]([NH:36][CH2:37][CH:38]4[CH2:40][CH2:39]4)[C:28]4[C:33]([C:34]=3[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:21][S:22](=[O:24])(=[O:23])[C:17]=2[CH:16]=1)C1C=CC=CC=1>CN(C)C=O.[Pd]>[CH:38]1([CH2:37][NH:36][N:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]([OH:35])=[C:25]([C:20]3[NH:19][C:18]4[CH:42]=[CH:43][C:15]([O:14][CH2:13][C:9]5[NH:10][CH:11]=[CH:12][N:8]=5)=[CH:16][C:17]=4[S:22](=[O:23])(=[O:24])[N:21]=3)[C:26]2=[O:41])[CH2:40][CH2:39]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4nccn4Cc4ccccc4)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ncc[nH]4)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 70 °C
Yield: 43.9 %

Procedure:
Product of Example 390A (16 mg, 0.027 mmol) in N,N-dimethylformamide (1 mL) was added 1,4-cyclodiene (25.5μl, 0.27 mmol) and palladium black (16 mg). The mixture was heated at 70° C. for 1 day. The mixture was filtered with Celite® and washed with N,N-dimethylformamide. The solution was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with dichloromethane:methanol (98:2) to give the title compound (6 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 0.16 (d, J=4.41 Hz, 2 H) 0.43 (d, J=7.35 Hz, 2 H) 0.99 (m, 1 H) 2.78 (s, br, 2 H) 5.25 (s, 2 H) 6.27 (s, br, 1 H) 7.22 (s, 2 H) 7.31 (m, 1 H) 7.39 (dd, J=9.01, 2.76 Hz, 1 H) 7.49 (d, J=2.57 Hz, 1 H) 7.54 (d, J=8.82 Hz, 1 H) 7.77 (m, 1 H) 7.95 (d, J=8.09 Hz, 1 H) 8.13 (dd, J=8.09 Hz, 1.47 Hz, 1 H) 14.83 (s, br, 1 H). MS (ESI−) m/z 505 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.Cl.[C:26]([NH:29][CH2:30][C:31](=N)OCC)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:26]([NH:29][CH2:30][C:31]1[N:17]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:13]2[CH:12]=[CH:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=4[N:7]=3)=[CH:16][C:14]=2[N:15]=1)(=[O:28])[CH3:27]
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Reactant: CCOC(=N)CNC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)NCc1nc2cc(-c3nc4cc(Cl)ccc4o3)ccc2n1C1CCOCC1
Yield: 21.1 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in ethanol (5 mL) was added ethyl 2-acetylaminoacetimidate hydrochloride (263 mg, 1.45 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (65.2 mg, 21% yield) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][C:22]2[CH:23]=[C:24]3[C:16]([C:13]4[CH:14]=[CH:15][O:11][CH:12]=4)=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cnc2[nH]cc(-c3ccoc3)c2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cnc2[nH]cc(-c3ccoc3)c2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
4-Fluorobenzoyl chloride (29.7 mg, 0.19 mmol) was added to a solution of amine 48 (25 mg, 0.125 mmol), DMAP (1.53 mg, 12.5 μmol) and Et3N (12.6 mg, 0.125 mmol) in DMF (0.6 mL). The mixture was stirred at r.t. overnight, concentrated and separated by means of LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 49 (2.13 mg, 5%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 6.45 (dd, J=1.9, 0.9 Hz, 1H), 6.91 (t, J=1.8 Hz, 2H), 7.22 (s, 1H), 7.23 (t, J=1.7 Hz, 1H), 7.56 (m, 1H), 7.73-7.76 (m, 2H), 8.15 (d, J=2.1 Hz, 1H), 8.25 (d, J=2.3 Hz, 1H); MS (ES) m/z 363 (MH++MeCN).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8].COC1C=CC(O)=CC=1>>[CH2:8]=[CH:7][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCc1ccccc1
Agent: C=C(C)C(=O)O
Agent: COc1ccc(O)cc1
Product: C=Cc1ccccc1

Procedure:
Example 1 was repeated except that a mixture of methacrylic acid, ethylbenzene and 100 ppm, based on methacrylic acid, of p-methoxyphenol was used instead of the methacrylic acid/ethylbenzene mixture fed to the second and third polymerization vessels. Styrene/methacrylic acid copolymer was obtained at a rate of 3.2 kg per hour.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[CH:18]=[CH:19][CH:20]=[C:9]2[CH2:8]1)=[O:6].NN>C(O)C.[Pd]>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]3[CH:18]=[CH:19][CH:20]=[C:9]3[CH2:8]2)=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Yield: 85.2 %

Procedure:
A mixture of 1.22 g 10,11-dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.2 g of 10% Pd/C and 0.35 g of anhydrous hydrazine in 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour. The reaction mixture is filtered hot through diatomaceous earth and evaporated in vacuo to a residue. The residue is crystallized from methylene chloride-hexane to give 0.95 g of the desired product as crystals, m.p. 232°-234° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[C:5]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:28][CH:29]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(C2CCCCC2)cc1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-cyclohexylphenoxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxyphenyl)-2-(4-cyclohexylphenoxy)-2-methylpropionic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)(=[O:3])[CH3:2].Cl.[CH3:17][O:18][C:19]([C:21]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.O>CN(C=O)C>[CH3:17][O:18][C:19]([C:21]1([NH:28][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:20]
Reactant: COC(=O)C1(N)CCCCCC1
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OC(C)=O)c2)CCCCCC1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
3-Acetoxy-4-methoxy-benzoic acid (7.10 g, 33.8 mmol) was dissolved in DMF (70 ml). The solution was cooled in an ice bath and 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (7.72 g, 37.2 mmol), EDIA (24.4 ml, 135 mmol) and TOTU (16.6 g, 50.7 mmol) were added sequentially. Stirring was continued at room temperature for 1 h. Water was added and stirring was continued for 1 h. The solid material which formed was collected by filtration, washed with water and dried in vacuo. The obtained material was stirred with a diethyl ether/HEP mixture, filtered and dried in vacuo to yield the title compound (9.03 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:19]=[CH:18][C:17]2[N:16]([CH3:20])[C:15]3[CH2:21][CH:22]4[NH:26][CH:25]([C:14]=3[C:13]=2[C:12]=1C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)(=[O:10])=[O:9].[ClH:34]>C(OCC)C>[ClH:34].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]1[CH2:21][CH:22]3[NH:26][CH:25]([C:14]2=1)[CH2:24][CH2:23]3)(=[O:10])=[O:9]
Reactant: Cc1ccccc1S(=O)(=O)c1ccc2c(c1C(=O)OC(C)(C)C)c1c(n2C)CC2CCC1N2
Agent: Cl
Solvent: CCOCC
Product: Cc1ccccc1S(=O)(=O)c1ccc2c(c1)c1c(n2C)CC2CCC1N2

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide) followed by semi-preparative HPLC. The free base was treated with 1.25 M HCl in methanol (0.5 mL) and lyophilized to give 2-(2-methylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (6 mg, 17%, AUC HPLC 96.3%) as a white solid: mp 186-188° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.18 (br s, 2H), 8.30 (d, J=1.5 Hz, 1H), 8.06 (dd, J=7.8, 1.5 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.45-7.60 (m, 3H), 7.33 (d, J=7.2 Hz, 1H), 5.36 (d, J=3.9 Hz, 1H), 4.47 (br s, 1H), 3.69 (s, 3H), 3.01 (d, J=17.1 Hz, 1H), 2.39 (s, 3H), 2.20-2.33 (m, 2H), 2.07-2.14 (m, 2H), 1.73-1.90 (m, 1H); ESI MS m/z 367 [M+H]+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:10]=[C:11]([CH2:14][N:15]([CH3:17])[CH3:16])[S:12][CH:13]=1>[Cu]=O.[I-].[Na+].Cl>[CH3:16][N:15]([CH2:14][C:11]1[S:12][CH:13]=[C:9]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH:10]=1)[CH3:17]
Reactant: OCCCO
Reactant: CN(C)Cc1cc(Br)cs1
Agent: O=[Cu]
Agent: Cl
Agent: [H-]
Product: CN(C)Cc1cc(OCCCO)cs1
Reaction time: 1 h

Procedure:
A mixture of 1,3-propanediol (20 ml) and sodium hydride (1 g) was stirred at 80° for 1 h. Copper (II) oxide (1.3 g), sodium iodide (0.05 g) and 4-bromo-N,N-dimethyl-2-thiophenemethanamine (5 g) were added and heating was continued for 2 days. Dilute hydrochloric acid (60 ml) was added and the aqueous solution was washed with diethyl ether (50 ml), basified with aqueous sodium hydroxide and extracted with chloroform (200 ml). The organic extract was distilled to give the title compound (1.7 g) as an off-white wax. m.p. 32°-4°
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:7]1[CH:6]=[CH:5][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCCc2ccccc21
Product: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under nitrogen, to fuming nitric acid (60 ml) was added 6,7,8,9-tetrahydrobenzocyclohepten-5-one (20 g) on ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was poured into ice water (200 ml). The precipitates were collected by filtration and dissolved into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (14.87 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][CH2:8][C:9]([O:11]CC)=O.C(N(CC)CC)C>C(O)C>[NH:1]1[C:9](=[O:11])[CH2:8][NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@H:2]12
Reactant: CCOC(=O)CN[C@H]1CCC[C@@H]1N
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CN[C@H]2CCC[C@@H]2N1
Temperature: 85 °C

Procedure:
Ethyl N-[(1S,2S)-2-aminocyclopentyl]glycinate (HCl salt) (708 mg, 3.18 mmol) was dissolved in ethanol (16 mL), and triethylamine (4.43 mL, 31.8 mmol) was added. The resulting mixture was stirred and heated at 85° C. for 24 hours. The mixture was then cooled and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting slurry was filtered. The filtrate was concentrated under reduced pressure to afford (4aS,7aS)-octahydro-2H-cyclopenta[b]pyrazin-2-one, which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 6.31 (s, 1H), 3.68-3.67 (m, 2H), 3.23-3.17 (m, 1H), 2.86-2.81 (m, 1H), 1.97-1.82 (m, 5H), 1.49-1.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:13]2[O:12][C:11](=[O:14])[C:10](=[O:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:11](=[O:14])[C:10](=[O:15])[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:13]=3[OH:12])=[CH:32][CH:33]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: CC(C)(C)c1cccc2c1OC(=O)C2=O
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Solvent: ClCCl
Product: COc1ccc(CCc2ccc(NC(=O)C(=O)c3cccc(C(C)(C)C)c3O)cc2)cc1OC

Procedure:
A solution of 7-(1,1-dimethylethyl)-2,3-benzofurandione (1.0 g, 5 mmol) and 4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (1.0 g, 4 mmol) in 10 ml of dichloromethane is stirred at room temperature for 48 hours. The solvent is evaporated and the residue crystallized from ether/hexane. Recrystallization from acetonitrile gave the pure product, (1.0 g) mp 143°-144° C.