Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]([C:22](=[O:37])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]([CH:22]([OH:37])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:29][CH:30]=1)[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(=O)CCc1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 0.67 h
Yield: 79.7 %

Procedure:
To a solution of the compound (100 mg) obtained from step 1 above in methanol (2 ml) at −10° C. to −2° C. was added sodium borohydride (9 mg) and stirred the mixture for 40 minutes at the same temperature. The solvent was evaporated under reduced pressure and the residue thus obtained was quenched with saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 5% methanol in dichloromethane as eluant to furnish the title compound (80 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2].CI.N1(C2CCCCCCCCCC2)CCCCCCCC[CH2:35]N1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([O:24][CH3:35])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2]
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Reactant: Cc1c(F)c(Oc2cccc(C#N)c2)nc(Oc2cccc(CCC(=O)O)c2)c1F
Solvent: CI
Solvent: ClCCl
Product: COC(=O)CCc1cccc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-propionic acid (0.50 g, 1.2 mmol) in methylene chloride (20 mL) was added methyl iodide (0.26 g, 1.8 mmol) and diazabicycloundecane (2.8 g, 1.8 mmol). After stirring for 15 hours, the solution was concentrated in vacuo and chromatographed on silica gel with ethyl acetate/hexane (1/4) to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionic acid, methyl ester; NMR (CDCl3) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 3.68 (s,3), 2.9 (t,2), 2.55 (t,2), 2.4 (s,3) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:28][CH2:29]Cl)[CH3:27]>C(OCC)C.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][O:28][CH2:26][CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCOCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a mixture of diisopropylamine (2.1 ml, 15 mmol) and tetrahydrofuran (30 ml) was added dropwise n-butyllithium (2.4M n-hexane solution, 5.0 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred for 30 minutes. To the mixture was added dropwise tributyltin hydride (3.3 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred at 0° C. (external temperature) for 40 minutes. The reaction mixture was cooled to −78° C. (external temperature), and ethoxymethyl chloride (1.1 ml, 12 mmol) was added dropwise to the reaction mixture. After the reaction mixture was raised to room temperature, to the reaction mixture were added diethyl ether and an aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:diethyl ether=30:1) to obtain the title compound (2.8 g, 7.9 mmol, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:23]([CH3:38])=[N:24][N:25]([C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].CO.[OH-].[Li+].O>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:23]([CH3:38])=[N:24][N:25]([C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2cc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c(C)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn([C@H]4CC[C@H](C(=O)O)CC4)nc3C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl trans-4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-3-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylate (20.0 mg, 0.0371 mmol) in MeOH (3 mL, 70 mmol) was added lithium hydroxide (4.44 mg, 0.186 mmol) and H2O (1 mL, 60 mmol). The mixture was stirred at rt for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water (pH=2). The organic layer was concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=511.20/513.20 (100/50) [MH+]. HPLC: tR=1.45 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[NH:31])OCC)=[CH:22][CH:21]=1>C(O)C>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccc(OC)cc1
Reactant: Cc1ccccc1COc1cccnc1N
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC(=N)Nc2ncccc2OCc2ccccc2C)cc1
Yield: 3 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl 4-methoxyphenylacetimidate hydrochloride (6.1 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours, then the solvent evaporated. The residue was taken up in chloroform, filtered to remove an insoluble solid, and the filtrate purified by flash chromatography (chloroform/methanol) to obtain the product (0.29 g), m.p. 58°-67° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42](COS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:42]2[C:43](=[O:44])[N:38]([CH2:37][CH:34]3[CH2:36][CH2:35]3)[N:39]=[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)[CH:41]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 98.9 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a pale brown oil (yield: 98.9%).
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[C:31](OCC)(=[O:34])[NH:32][NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].[Na+]>C(O)CCC>[CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]3[C:31](=[O:34])[NH:32][N:33]=[C:7]3[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)C=C(c1ccc(-n3c(C)nc4cnccc43)cc1)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,3-dihydro-7,8-dimethyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (411 mg, 1.0 mmol), ethyl carbazate (210 mg, 2 mmol) and p-toluenesulphonic acid (10 mg) in n-butanol (5 ml) was stirred overnight at reflux. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (etuting with dichloromethane/methanol=9:1). The intermediate carbazate was then dissolved in dry tetrahydrofuran (5 ml) and cyclised by the addition of sodium hydride (60% dispersion in oil, 40 mg, 1 mmol) and stirring for 3 hours at room temperature. The mixture was partitioned between 2N hydrochloric acid (5 ml) and ethyl acetate (20 ml). The aqueous phase was neutralised with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate:tetrahydrofuran=1:1 (2×30 ml). The extracts were combined, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane:methanol=10:1). The product was further purified by recrystallisation from methanol/dichloromethane to give a white solid, (85 mg, 20%), m.p.>325° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])(O)=O.[Na+]>CCO>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH3:17])[CH3:16]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Yield: 83 %

Procedure:
A mixture of 3,4-dichloroaniline (20.0 g, 120 mmol), ethyl 2-bromopropionate (26.0 g, 144 mmoL), and NaHCO3 (15.1 g, 180 mmol) in EtOH (200 mL) was heated at reflux. After 16 h another portion of ethyl 2-bromopropionate (13.9 g, 96.7 mmol) and NaHCO3 (8.00 g, 95 mmol) was added, and the mixture heated at reflux for an additional 24 h, then evaporated under vacuum. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 1:1) afforded the title compound (26.1 g, 83%). Yellow oil, MS: 262.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH:27](/B(O)O)=[CH:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:27]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:9]=2)=[CH:6][CH:7]=1)=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(C=Cc3ccccc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.46 g, 3.2 mmol), trans-beta-Styreneboronic acid (0.7 g, 4.9 mmol), Na2CO3 (2M, 7 mL), and Pd(PPh3)2Cl2 (300 mg, 0.26 mmol) in toluene/ethanol (1:1, 20 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 6-(4-Styryl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as yellow solid in 68% yield.
Reaction SMILES: C1C[C@@H](C(N[C@H](C([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=O)CCCN=C(N)N)=O)N(C([C@H](N)CC2C=CC=CC=2)=O)CC1>C(O)C(N)(CO)CO.Cl>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: NC(N)=NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](N)Cc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: NC(CO)(CO)CO
Product: Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h

Procedure:
An inhibitor sample is dissolved in a 0.05 M Tris-hydrochloric acid buffer solution (pH=8.3) to make a total volume of 400 μl. To this solution, 50 μl of a 0.2 mM S-2238 solution is added and the mixture is incubated at a temperature of 37° C. for 5 minutes in a constant temperature bath. Then, 50 μl of a 0.2 unit/ml bovine thrombin solution is added thereto and the absorbance, at 405 nm, of the p-nitroaniline formed per minute is determined at a temperature of 37° C. by using the so-called initial velocity method. Thus, the concentration I50 (μmol) of the inhibitor sample at which the absorbance is one half (i.e., 1/2) of that obtained in the absence of the inhibitor sample, is determined.
Reaction SMILES: [I:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C:6](=O)[NH:7][CH:8]([C:10]([F:13])([F:12])[F:11])[CH2:9][N:4]2[N:3]=1>C1COCC1>[I:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[CH2:6][NH:7][CH:8]([C:10]([F:12])([F:11])[F:13])[CH2:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(I)nn2c1C(=O)NC(C(F)(F)F)C2
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn2c1CNC(C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.9 %

Procedure:
To a stirred solution of Intermediate 346B (0.1 g, 0.248 mmol) in THF (1 mL) was added BH3.DMS complex (0.236 mL, 2.481 mmol) under nitrogen and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then cooled to 0° C., quenched with methanol (1 mL) and stirred for 15 min at RT. The volatiles were removed under reduced pressure and the crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 25% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 346C as a white solid (0.025 g, 25%). MS(ES): −m/z=390.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.37-4.27 (m, 2H), 4.22 (q, J=7.4 Hz, 3H), 4.12-4.00 (m, 3H), 1.33-1.26 (m, 3H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C(#N)C>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CC#N
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture containing cis,trans muconic acid (1.00 g), a catalytic amount of iodine (53 mg, 3.0 mole percent), and acetonitrile (35 ml) is heated to reflux for 11 hours. The reaction is performed in the presence of ambient light in the laboratory. After cooling to room temperature, the precipitated solid is filtered off and washed with acetonitrile. After drying under high vacuum, 0.80 g (80 percent yield) of pure trans,trans muconic acid are present as a tan-colored powder. The material obtained by this procedure from cis,trans muconic acid is identical to the material obtained from cis,cis muconic acid by the previous procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](=[O:19])[CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1.BrBr.[Br:23]N1C(=O)CCC1=O.P(Br)(Br)Br>>[Br:23][C:10]1[C:9]([CH3:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([CH3:13])[C:11]=1[C:14](=[O:19])[CH2:15][CH:16]1[CH2:17][CH2:18]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Agent: BrBr
Agent: BrP(Br)Br
Product: Cc1c(Br)c(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1

Procedure:
Bromination of (3) usinga brominating reagent such as bromine, N-bromosuccinimide, or phosphorous tribromide (as described in Elena Dvornikova et al., Synlett, 2002, No. 7, 1152-1154) yields 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)-2-cyclopropylethanone (4). Preferably, the bromination reaction is carried out in the presence of N-bromosuccinimide in THF.
Reaction SMILES: O[CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].P(CCCC)(CCCC)CCCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:51]1(=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:60])[NH:52]1>C1COCC1.CCOCC>[O:61]=[C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:60])[N:52]1[CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred solution of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (4.61 g, 17.5 mmol) and n-Bu3P (10.6 g, 52.4 mmol) in anhydrous THF (150 mL) was added 1,1′-(azodicarbonyl)dipiperidine (ADDP; 8.83 g, 35.0 mmol) at rt under nitrogen. The reaction mixture was stirred at rt for 30 min. To the reaction mixture was then added isoindoline-1,3-dione (3.09 g, 21.0 mmol), followed by heating at reflux for 20 h. After this time, the reaction mixture was cooled to rt, diluted with Et2O (100 mL), and further cooled with an ice/water bath. The resulting mixture was filtered and the filter cake was washed with Et2O (40 mL). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with hexanes/CH2Cl2/EtOAc (50:48:2) to hexanes/CH2Cl2/EtOAc (50:42:8). The material obtained from the chromatography was triturated with hexanes/CH2Cl2 (5:1) and solids removed by filtration. Concentration of the filtrate afforded the title compound as a colorless oil (6.12 g, 89%). ESI MS (M+H) 393.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@@H:17]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Br:39])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[Br:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@H:17]1[CH2:16][C@H:15]2[C@H:14]3[C@H:23]([CH2:22][CH2:21][C@:19]2([CH3:20])[C@H:18]1[OH:27])[C:24]1[CH:25]=[CH:26][C:9]([OH:8])=[CH:10][C:11]=1[CH2:12][CH2:13]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C[C@H](CCCCCCCCCCCBr)[C@@H]2O
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@H](CCCCCCCCCCCBr)[C@@H]2O
Yield: 89 %

Procedure:
A stirred suspension of 3-benzyloxy-16β-(11′-bromoundecanyl)-1,3,5(10)-estratrien-17β-ol (step C, 300 mg, 0,50 mmol) and 10% Pd/C (150 mg) in dry THF (4 mL) was stirred under hydrogen atmospheric pressure for 3–6 h. The reaction was followed by TLC until completion. The insoluble material was filtered off with diethyl ether (70 mL) and the filtrate was concentrated to give the crude product. It was purified by flash chromatography (hexanes:acetone (4:1)) to give 225 mg (90%) of a white solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Dissolve 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (400 mg, 1.34 mmol) in anhydrous pyridine (10 mL) and add methanesulfonyl chloride (616 mg, 416□L, 5.38 mmol). Stir overnight at room temperature, then concentrate. Take residue up in ethyl acetate and 1N HCl and separate the layers. Extract aqueous layer with ethyl acetate, combine organics, and dry (MgSO4). Concentrate to a brown oil. Purify via silica gel chromatography (2:3 ethyl acetate:hexanes) to yield 350 mg (70%) of yellow foam, mp 66.3° C. 1H NMR (CDCl3) δ 2.71 (s, 3H), 2.75-3.56 (br m, 4H), 6.09 (s, 1H), 6.64-7.43 (m, 13H); MS (ES) 398 (M+23), 374 (M−H). HPLC shows 96% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:15])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][C:28]1=[O:36].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:15])[CH:9]2[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[NH:29][C:28]3=[O:36])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccccc2n1CCCBr
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
2.1 g (0.007 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl]piperidine, 1.8 g (0.007 mole) of 1-(1-bromo-3-propyl)-1,3-dihydro-2(2H)-benzimidazolone, 0.85 g (0.008 mole) of Na2CO3 and a few crystals of NaI are heated for 5 h at reflux temperature in 60 ml of methyl isobutyl ketone. The solvent is evaporated off, the residue is taken up with a mixture of water and CH2Cl2, and the organic phase is dried and evaporated down. A solid residue is obtained which is chromatographed on a column of silica (eluent: CH2Cl2/MeOH 97/3, 96/4 and then 94/6). The pure fractions are evaporated down, the evaporation residue is taken up with ether and a white product is filtered off and crystallized from 90 ml of ethyl acetate. M.p.=141°-143° C.