Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccc1F
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccccc1F

Procedure:
A mixture of 25.0 g. of o-fluoroacetophenone and 35 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. Evaporation gives a thick oil which is dissolved in methylene chloride and passed through a short column of hydrous magnesium silicate. Evaporation of the solvent gives 34.2 g. of the desired compound as an oil.
Reaction SMILES: BrC1C=CC(O[C:7]2[C:20]3[C:19](=[O:21])[C:18]4[C:13](=[C:14](OC5C=CC(Br)=CC=5)[CH:15]=[CH:16][CH:17]=4)[C:12](=[O:30])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=CC=1.[OH-].[K+].[C:35]1([CH3:42])[CH:40]=[CH:39][C:38]([SH:41])=[CH:37][CH:36]=1>CN(C=O)C>[CH3:42][C:35]1[CH:40]=[CH:39][C:38]([S:41][C:7]2[C:20]3[C:19](=[O:21])[C:18]4[C:13](=[C:14]([S:41][C:38]5[CH:39]=[CH:40][C:35]([CH3:42])=[CH:36][CH:37]=5)[CH:15]=[CH:16][CH:17]=4)[C:12](=[O:30])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:37][CH:36]=1
Reactant: O=C1c2cccc(Oc3ccc(Br)cc3)c2C(=O)c2cccc(Oc3ccc(Br)cc3)c21
Reactant: Cc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cccc3c2C(=O)c2cccc(Sc4ccc(C)cc4)c2C3=O)cc1
Temperature: 110 °C

Procedure:
10 parts of 1,5-bis(4-bromophenoxy)anthraquinone, 8 parts of potassium hydroxide, and 9 parts of 4-toluenethiol were added to 100 parts of DMF, and the mixture was stirred under heat at 110° C. for 3 hours. The precipitated solid after cooling was filtered, washed, and dried, to give 6.5 parts of an intermediate (1,5-bis(4-methylphenylthio)anthraquinone).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:37](C(OC(C)(C)C)=O)[CH:38]=[CH:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 25.1, 100 mg, 0.216 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (127 mg, 0.433 mmol) Pd(PPH3)2Cl2 (15.18 mg, 0.022 mmol), Na2CO3 (92 mg, 0.865 mmol), DME (918 μL), water (262 μL) and EtOH (131 μL) were added to a MW vial, which sealed, evacuated/purged with argon and the RM was stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 91 mg, 0.130 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 40% to 100% EtOAc) followed by preparative SFC (Column DEAP, from 24% to 29% in 10 min) to afford the title compound as a grey solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=449.2 [M+H]+, m/z=447.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (dd, J=6.48, 2.57 Hz, 1H) 1.83 (dd, J=8.68, 4.28 Hz, 1H) 2.98 (d, J=11.98 Hz, 1H) 3.22-3.29 (m, 2H) 3.37-3.50 (m, 1H) 4.19 (d, J=2.45 Hz, 1H) 4.81 (d, J=3.42 Hz, 1H) 5.94-6.17 (m, 2H) 6.67-6.87 (m, 1H) 7.67 (d, J=8.80 Hz, 2H) 7.83-7.99 (m, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.25 (s, 1H) 11.11 (br. s, 1H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[C:19]([NH:22][C:23]1[C:35]([Cl:36])=[C:34]2[C:26]([C:27]3[C:32]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33]2)[CH2:31][CH2:30][C:29](=[O:41])[C:28]=3Br)=[CH:25][C:24]=1[F:43])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.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>[C:19]([NH:22][C:23]1[C:35]([Cl:36])=[C:34]2[C:26]([C:27]3[C:32]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33]2)[CH2:31][CH2:30][C:29](=[O:41])[C:28]=3[C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[CH:25][C:24]=1[F:43])(=[O:21])[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)c(Cl)c1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C(c3ccco3)=C1c1cc(F)c(NC(C)=O)c(Cl)c1C2
Temperature: 100 °C
Yield: 101.2 %

Procedure:
Tributyl(2-furyl)stannane (0.47 mL, 1.7 mmol) was added to a mixture of 7-(acetylamino)-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.367 g, 0.86 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.121 g, 0.17 mmol) in anhydrous toluene (8.6 mL). The mixture was purged with N2, then stirred and heated in an oil bath at 100° C. for 2 hours. After cooling to room temperature, the mixture was added to a pad of silica gel and the product eluted with EtOAc (20 mL). The solvent was evaporated and the residue (0.93 g) was purified by Biotage flash chromatography on a 40S silica gel column (4×7 cm) using 2:1 hexane-EtOAc as eluting solvent. The product containing fractions were concentrated under vacuum to provide crude 7-(acetylamino)-9a-butyl-8-chloro-6-fluoro4-(2-furyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.362 g) as an orange foam.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2([C:39]([O:41]CC)=[O:40])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.[Li+].[OH-]>O>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:24]=2)([C:39]([OH:41])=[O:40])[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CCOC(=O)C1(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)(C(=O)O)CC1
Yield: 86.8 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-((1-trityl-1H-imidazol-4-yl)methyl)piperidine-1,4-dicarboxylate from step A (330 mg, 0.57 mmol) in 1:1:2 THF:MeOH:H2O (10 mL) was added LiOH (136 mg, 5.7 mmol). The mixture was refluxed until LCMS showed complete conversion to product, then concentrated under vacuum, dissolved in water (3 mL), neutralized to pH 5-6 with aq. NaHSO4, and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum to give the title compound (273 mg, 86%). MS (ES+) [M+H]+=552.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18].[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]
Reactant: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2N1c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
600 mg 1-(2,6-dichloro-phenyl)-1,3-dihydro-indol-2-one are dissolved in 5 ml concentrated sulphuric acid and cooled to 0° C. To this is added dropwise a solution of 160 μl concentrated nitric acid in 1 ml concentrated sulphuric acid. The mixture is stirred for 30 minutes and then added to 50 g ice. Then the mixture is stirred for 1 hour and the solid is suction filtered. After drying in vacuo the solid is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 20:80).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
A solution of triphenylphosphine (48 mg, 0.183 mmol) in methylene chloride (700 μL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (33 mg, 0.183 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (prepared as in Example 135, 50 mg, 0.159 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (33 mg, 0.35 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide (23.7 mg, 38%) as a pink solid: mp 76–79° C.; EI-HRMS m/e calcd for C20H23FN2O3S (M+) 390.1413, found 390.1420.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4cccnc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3cccnc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.13 g) synthesized in the above-mentioned (1) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (3.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (3.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.08 g, 95%) as a pale-yellow solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1[nH]c2ccccc2c1CCSC(C)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(CCSC(C)=O)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.8 %

Procedure:
To a solution of methyl 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.364 g, 1.31 mmol), phenylboronic acid (0.239 g, 1.97 mmol), and copper(II)acetate (0.237 g, 1.31 mmol) in dichloromethane (10 mL) was added pyridine (0.91 mL, 6.55 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was passed through a column of silica gel (EtOAc/hexanes, 1:9) to afford 3-(2-acetylthioethyl)-1-phenyl-1H-indole-2-carboxylic acid, methyl ester (0.153 g, 0.43 mmol, 33%) as a clear oil: 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.20–3.24 (m, 2H), 3.39–3.43 (m, 2H), 3.75 (s, 3H), 7.07 (d, J=8.2 Hz, 1H), 7.20–7.32 (m, 4H), 7.42–7.53 (m, 3H), 7.87 (d, J=7.9 Hz, 1H).
Reaction SMILES: [Li][CH2:2]CCC.[S:6]([N:16]1[CH2:21][C:20](=O)[C:19]2[S:23][CH:24]=[CH:25][C:18]=2[CH2:17]1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:2]=[C:20]1[CH2:21][N:16]([S:6]([C:9]2[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:17][C:18]2[CH:25]=[CH:24][S:23][C:19]1=2
Reactant: [Li]CCCC
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3sccc3C2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CN(S(=O)(=O)c2ccc(C)cc2)Cc2ccsc21
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.05 g, 5.73 mmol, 2.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (3.58 mL, 1.6 M solution, 2.0 equiv) and stirred for 30 min followed by addition of 5,6-dihydro-5-tosylthieno[3,2-c]pyridin-7(4H)-one (880 mg, 2.86 mmol, 1.0 equiv) in THF (5.00 mL). The reaction mixture was stirred at rt for 1 h, then quenched by the addition of a saturated aqueous solution of ammonium chloride. Purification by column chromatography using 5% ethyl acetate in hexanes elution gave 175 mg of the yellow solid, 20%.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].P(Br)(Br)[Br:12]>N1C=CC=CC=1>[Br-:12].[Br-:12].[CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9]
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: OCCOCCOCCO
Product: [Br-]
Reaction time: 8 h

Procedure:
66 g. of triethylene glycol and 13.3 g. of anhydrous pyridine are slowly added to 100 g. of phosphorous tribromide while agitating and cooling the mixture. After standing overnight at room temperature, the mixture is poured on to ice and the organic phase is decanted, washed with water and dilute hydrochloric acid and dried over sodium sulphate. After distillation under vacuum (95°C and 0.5 mm. Hg) the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC([NH:26][CH:27]1[CH2:32][CH2:31][N:30](N)[CH2:29][CH2:28]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:30]3[CH2:31][CH2:32][CH:27]([NH2:26])[CH2:28][CH2:29]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1CCN(N)CC1
Product: NC1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC1
Yield: 18.1 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (50 mg, 0.11 mmol) and 4-(tert-butoxycarbonylamino)-aminopiperidine (39 mg, 0.2 mmol) were reacted according to GP8 to give 6.5 mg of the title compound (166JO55). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>>[OH:20][CH2:19][C@H:9]1[C@@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of rac-(cis)-1-(tert-butoxycarbonyl)-3-phenylpyrrolidine-2-carboxylic acid (0.77 g, 2.6 mmol) (prepared as described by Damour et al. Synlett 1999, 2, 189-192) in THF (10.00 mL, 122 mmol) was added BH3●THF (9.3 mL, 1.0 M in THF, 9.3 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was then cooled to 0° C., and the resulting mixture was quenched with MeOH, concentrated, and the remaining residue was diluted with 1.0 N aqueous NaOH (10 mL), and extracted with EtOAc (10 mL×3). The organic layers were washed with brine, dried over Na2SO4, and concentrated to give a residue which was purified with flash column chromatography (pure hexane →30% EtOAc in hexanes) to obtain the desired product as a colorless sticky syrup, which solidified upon standing. LCMS (API-ES) m/z (%): 278.4 (100%, M+H); 1H NMR (400 MHz, CDCl3) δ ppm (mixture of rotatomers) 1.50 (s, 9H) 2.10-2.17 (m, 2H), 3.33 (d, J=4.70 Hz, 2H), 3.42-3.51 (m, 1H), 3.60-3.67 (m, 2H), 4.26-4.33 (m, 1H) 7.23 (d, J=11.74 Hz, 2H), 7.30-7.39 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[S:15][CH:14]=[N:13][C:12]=3[CH:11]=[C:10]([CH3:17])[C:9]=2[C@H:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.ClCCl.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1.C(OCC)(=O)C>[C:27]([O:20][CH2:19][C@H:18]([C:9]1[C:10]([CH3:17])=[CH:11][C:12]2[N:13]=[CH:14][S:15][C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[OH:21])(=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25]
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethane-1,2-diol (5H) (0.018 g, 0.056 mmol) in pyridine (0.5 mL)/dichloromethane (1 mL) was added trimethylacetyl chloride (0.010 mL, 0.081 mmol). Reaction mixture was stirred for 1 h at room temperature and additional trimethylacetyl chloride (0.020 ml 0.081 mmol) was added and left it overnight at room temperature. More trimethylacetyl chloride (0.030 ml, 0.242 mmol) was added to the mixture and stirred at room temperature for 30 min. Reaction mixture was diluted with ethyl acetate. Organic layer was washed with saturated sodium bicarbonate solution, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C21H22ClNO3S: 404.1 (M+H+). Found: 404.1 (M+H+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH:9]=[O:10].C(O)C>O>[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]
Reactant: Cc1csc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1csc(C)c1CO
Reaction time: 0.25 h

Procedure:
0.68 G. (18 mmol) of sodium borohydride was added in three portions to a solution of 10.08 g. (72 mmol) of 2,4-dimethylthiophene-3-carboxaldehyde in 120 ml. of ethanol. After 15 min., the reaction mixture was poured into water, extracted with ether, dried and the solvent evaporated. The resulting residue was recrystallized from hexane to yield 2,4-dimethyl-3-hydroxymethylthiophene, m.p. 80°-81° C.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[C:24]([C:23]1[CH:27]=[C:19]([N:18]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=[C:6]2[C:5]2[CH:16]=[CH:17][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][C:22]=1[OH:28])([OH:26])=[O:25]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(O)cc3)cc3c2CCCC3)ccc1O

Procedure:
A mixture of 11.5 g. (0.05 mole) of 2-(p-hydroxyphenacyl)cyclohexanone, 7.6 g. (0.05 mole) of 5-aminosalicylic acid, and 40 ml. of glacial acetic acid was heated under reflux under nitrogen for 1.5 hours, cooled and filtered to provide 10.6 g. (61%) of solid, m.p. 214°-217°. Recrystallization from acetonitrile gave crystals, m.p. 217°-219°.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([C:11]2[C:12]([CH3:51])([CH3:50])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:49])([C@@:17]4([CH3:48])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+]>O1CCOCC1>[O:47]=[S:43]1(=[O:46])[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][CH2:37][NH:36][C@:20]23[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]2[C@@H:22]2[C@@:17]([CH3:48])([CH2:18][CH2:19]3)[C@@:16]3([CH3:49])[C@@H:25]([C@:26]4([CH3:29])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:51])([CH3:50])[C:11]([C:9]3[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[CH:2][CH:10]=3)=[CH:28][CH2:27]4)[CH2:24][CH2:23]2)[CH2:41][CH2:42]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(C)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 60.8 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-dioxido-4-thiomorpholinyl)propyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (15 mg, 0.021 mmol) and 1N sodium hydroxide (0.104 mL, 0.104 mmol) in dioxane (1 mL) was heated at 78° C. for 3 hours. The reaction mixture was purified by prep HPLC to provide the title compound as a white solid (9 mg, 58%). LCMS: m/e 705.49 (M+H)+, 2.60 min (method 10). 1H NMR (400 MHz, Acetic acid d4) δ ppm 7.99 (d, J=8.28 Hz, 2H), 7.25 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.77 Hz, 1H), 4.82 (s, 1H), 4.71 (s, 1H), 3.87 (br. s., 4H), 3.56 (d, J=4.27 Hz, 4H), 3.51-3.40 (m, 2H), 3.39-3.22 (m, 2H), 2.86-2.69 (m, 1H), 2.57-2.34 (m, 2H), 2.27-1.18 (m, 22H), 1.72 (s, 3H), 1.16 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].O=[C:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:41][CH:40]([CH2:42][O:43][CH3:44])[O:39][C:38]3=[O:45])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.O>O1CCCC1>[CH3:44][O:43][CH2:42][CH:40]1[O:39][C:38](=[O:45])[N:37]([C:34]2[CH:35]=[CH:36][C:31]([CH:28]3[CH2:29][CH2:30][C:25](=[CH2:2])[CH2:26][CH2:27]3)=[CH:32][CH:33]=2)[CH2:41]1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(c2ccc(N3CC(COC)OC3=O)cc2)CC1
Yield: 83.4 %

Procedure:
5.76 g (13.8mmol) of methyltriphenylphosphonium bromide/sodium amide mixture were stirred at room temperature under argon in 170 ml of tetrahydrofuran for 1 hour. Then, a solution of 4.20 g (13.8 mmol) of (RS)-3-[4-(4-oxo-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one was added dropwise within 5 minutes. After boiling under reflux overnight the mixture was poured into water and extracted with methylene chloride. After drying with sodium sulfate and concentrating the residue was chromatographed over silica gel with ethyl acetate/n-hexane (1:2). 3.47 g (83%) of a solid were obtained. A small sample was recrystallized from hexane. M.p.: 63°-65°.