Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][C:3]1[N:8]=[C:7]([Zn+])[CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15](=[O:31])[N:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]>O1CCCC1.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:10]([O:14][C:15](=[O:31])[N:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[N:8]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cccc([Zn+])n1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cncc(N(C(=O)OC(C)(C)C)c3ccc(Cl)cc3)n2)n1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (54 mg, 0.076 mmol) was dissolved in degassed tetrahydrofuran (5 mL) Diisobutylaluminum hydride (1M in hexanes, 0.15 mL, 0.15 mmol) was added and the mixture was stirred for 15 minutes. 6-Methyl-2-pyridylzinc bromide (0.5 M in tetrahydrofuran, 2.29 mL, 1.15 mmol) and a solution of (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester (260 mg, 0.76 mmol) in tetrahydrofuran (3 mL) was added and the mixture was stirred at room temperature over night. The reaction was quenched with aqueous sodium hydrogen carbonate. The aqueous phase was extracted with ethyl acetate (4×15 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtrated and evaporated. The crude product was purified by column chromatography (ethyl acetate/heptane as eluent) to give (4-chloro-phenyl)-[6-(6-methyl-pyridin-2-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (113 mg, 23%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])=[O:13].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])=[O:13]
Reactant: O=C(Nc1ccccc1Br)Nc1cccc([N+](=O)[O-])c1O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of N-(2-hydroxy-3-nitrophenyl)-N'-(2-bromophenyl)urea (300 mg, 0.85 mmol) in ethanol (20 mL), Tin chloride (958 mg, 4.25 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH8 with aq. NaHCO3 then extracted with ethyl acetate (3×). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give product (274 mg, 99%). EI-MS m/z 323 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[C:25]([O:27]C)=[O:26].O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:19]([O:18][CH3:17])[CH:20]=2)=[CH:3][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (300 mg, 1.06 mmol) and (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid (245 mg, 1.16 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (1.0 g, 3.18 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (61 mg, 0.05 mmol) was added and allowed to stir at 120° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The aqueous layer was neutralized with 1N HCl, extracted with DCM (2×50 mL), washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The crude compound was washed with diethyl ether to afford 260 mg (yield: 69.33%) of the title compound as pale yellow solid.
Reaction SMILES: [C:1]([C@@:3]1([OH:25])[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)#[CH:2].[Br:26]Br>CO.Br.C(Cl)Cl>[Br:26][CH2:14][C:13](=[O:15])[C@@H:12]1[C@:16]2([CH3:24])[C@H:9]([C@H:8]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C@@H:5]([CH2:4][C@:3]([C:1]#[CH:2])([OH:25])[CH2:22][CH2:21]2)[CH2:6][CH2:7]3)[CH2:10][CH2:11]1
Reactant: BrBr
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: Br
Solvent: ClCCl
Solvent: CO
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A solution of 3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (3 g, 8.77 mmol) in MeOH (110 mL) was treated with two drops of HBr (48%), followed by bromine (0.5 mL, 10.8 mmol). The mixture was stirred at room temperature for 1 hr and was poured into ice-water. The separated solid was collected by filtration, washed with water, and dried (3.2 g). This semi-dried solid was then dissolved in EtOAc and dried over anhyd. MgSO4. Filtration and removal of the solvent gave the crude bromo derivative. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:EtOAc mixture (4:1) gave 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (3.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:31])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Yield: 75.4 %

Procedure:
A solution of 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (327 mg, 0.87 mmol) and m-CPBA (226 mg, 1.31 mmol) in DCM (6 mL) was stirred at 0° C. for 3.5 h. The mixture was washed with aq Na2S2O3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (256 mg, 75.52%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.97 (s, 1H), 7.87-7.89 (m, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H), 7.36 (d, J=6.6 Hz, 1H), 5.68 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 391 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C@@H:7]([CH3:15])[CH2:6]1)=[O:4].C(N(CC)C(C)C)(C)C.[C:25](Cl)(=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:7]([CH3:15])[CH2:6]1)=[O:4]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@H](C)Nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.6 %

Procedure:
A round bottom flask with magnetic stirrer was charged with cis-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (5.42 g, 26 mmol) in dichloromethane (100 mL) under an argon atmosphere at room temperature. To the reaction was added N,N-diisopropylethylamine (11.8 mL, 68 mmol), followed by p-anisoyl chloride (6.31 g, 37 mmol). The reaction was stirred at room temperature for 18-20 hours and poured into saturated sodium bicarbonate (1000 mL), diluted with dichloromethane (50 mL), and shaken vigorously. The resulting organic layer was separated, washed with brine (1×100 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford an oily residue. Diethyl ether (50 mL) was added to the residue and the resulting white solid was collected via suction filtration to afford cis-1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (6.94 g, 78%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].C(OCC)(OCC)OCC>C([O-])(O)=O.[Na+]>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: COC(=O)c1ccc(C2OCCO2)cc1
Reaction time: 0.08 h

Procedure:
Methyl 4-formylbenzoate (3.28 g, 20.0 mmol) was suspended in ethylene glycol (4.46 mL, 80.0 mmol), then successively treated with triethyl orthoformate (3.66 mL, 22.0 mmol) and Me3NPhBr3 (376 mg, 1.00 mmol) at 22° C.; within 5 min, all solids dissolved. The resulting orange solution was stirred 0.5 h, then diluted with saturated aqueous NaHCO3 (50 mL), transferred to separatory funnel and washed with EtOAc (3×50 mL). The combined EtOAc washes were dried over MgSO4, filtered and concentrated in vacuo to a colorless oil (Rf 0.4 in 4:1 pentane/EtOAc, KMnO4). This material was used without further purification in the subsequent reduction step.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2>CN1CCCC1=O.O.Cl.[Fe](Cl)(Cl)Cl>[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)#[N:3]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2cc(O)ccc2c1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
Copper (I) cyanide (2.73 g, 0.03 mol) was added to a solution containing 5 g (0.022 mol) 6-bromo-2-hydroxynaphthalene in 25 ml of dry N-methyl-2-pyrrolidinone and refluxed at 200° C. under nitrogen for 1.5 h. The reaction mixture was cooled to 100° C., poured into a solution of iron(III) chloride (5.9 g) in water (91 ml) and concentrated hydrochloric acid (3.18 ml), and stirred at 60° C. for 30 min. The obtained mixture was extracted with ethyl ether. The ether layer was treated with charcoal, dried over anhydrous sodium sulfate, and then evaporated to dryness. The obtained solid was recrystallized from water to yield 2.04 g (54%) white solid. 1H-NMR (CDCl3, TMS, δ in ppm): 5.60 (s, 1H, --OH), 7.10-8.07 (m, 6, aromatic protons).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C1(N)CCCC1.[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5[N:45](CC)[C:44]6[CH:48]=[CH:49][C:50](C(O)=O)=C[C:43]=6N=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5[N:45]([CH:44]6[CH2:43][CH2:50][CH2:49][CH2:48]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:57][CH:58]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: NC1CCCC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCC4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and cyclopentylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:65][CH2:66][CH2:67][C:68]1[CH:69]=[CH:70][C:71]2[C:75]([CH3:77])([CH3:76])[O:74][B:73]([OH:78])[C:72]=2[CH:79]=1>CN(C=O)C.O>[OH:78][B:73]1[C:72]2[CH:79]=[C:68]([CH2:67][CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:27]([F:30])([F:28])[F:29])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:69]=[CH:70][C:71]=2[C:75]([CH3:77])([CH3:76])[O:74]1
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(O)c2cc(CCNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.37 mmol) and HATU (207 mg, 0.6 mmol) in DMF (5 mL), DIPEA (142 mg, 1.1 mmol) can be added. The reaction mixture can be stirred at rt for 10 min and crude compound 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (0.5 mmol) can be added. The reaction mixture can be stirred overnight. Water can be added and the mixture can be extracted three times with ethyl acetate. The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.
Reaction SMILES: C[S:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].N.[Na].[NH4+].[Cl-]>CCCCCC.C(OCC)(=O)C.C1COCC1>[SH:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]
Reactant: CSc1ccccc1Cc1ccccc1O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccccc1Cc1ccccc1S
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of 0.68 g 2-(2-(methylthio)benzyl)phenol (1) (2.96 mmol) in 4 ml freshly distilled THF at −78° C. was added 8 mL condensed ammonia followed by 0.15 g sodium. The blue solution was stirred for 2 hours at −78° C. before the mixture was warmed to ambient temperature. The reaction was allowed to stir overnight before NH4Cl was added until neutral. The mixture was extracted with ethyl acetate and the combined organic extracts washed with brine, dried over magnesium sulfate and concentrated. Flash silica chromatography (hexane:ethyl acetate 80:20) afforded 0.457 g product (2.12 mmol, 71% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:13][CH2:12][CH2:11][C:9]3[O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=CCCc1cc(-c2cccs2)no1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)N2CCN(CCCc3cc(-c4cccs4)no3)CC2)cc1
Yield: 71.2 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(diphenylmethyl)piperazine (12 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.2 hr and followed the same processes as in Example 1 to obtain 15.8 mg (74.2%) of the target compound.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:48])[NH:31][C@H:32]4[CH2:35][C@@H:34]([C:36]([N:38]5[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:47])[CH3:46])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH2:44]([N:41]1[CH2:42][CH2:43][N:38]([C:36]([C@@H:34]2[CH2:35][C@H:32]([NH:31][C:30]([C@:14]34[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:49])([CH2:12][CH2:13]4)[C@@:10]4([CH3:50])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:51])([CH3:52])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:48])[C:33]2([CH3:46])[CH3:47])=[O:37])[CH2:39][CH2:40]1)[CH3:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
A solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1S,3R)-3-(4-ethylpiperazine-1-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 66, 0.760 g) in MeOH:THF (2:1) (45 ml) at 0° C., 2N NaOH (15 ml) were added and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated, the aqueous layer extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as a white solid. Wt: 0.500 g: Yield: 69.9%; 1H NMR (300 MHz, CDCl3): δ 5.90 (d, J=8.1 Hz, 1H), 4.728 (s, 1H), 4.57 (s, 1H), 4.10 (m, 1H), 3.80-3.41 (m, 4H), 3.20-3.10 (m, 2H), 2.9 (m, 1H), 2.60-2.295 (m, 9H), 2.1 (m, 2H), 1.90 (m, 1H), 1.80-1.02 (m, 22H), 0.95, 0.92 (s, 6H), 0.83 (s, 3H), 0.80 (s, 3H). Mass: [M+H+]+ 679 (100%); IR (KBr, cm−1): 3445, 2946, 2867, 1634, 1459, 1463, 1376, 1270, 1242, 1126, 1043, 983, 883, 768, 656; M.R: 122.0° C.-155.1° C.; HPLC: 94.8%.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(C)cc2)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCC(C(=O)O)CC2S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.6 g (61%); off white solid, mp 204° C.; MS: 514.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>CCN(CC)CC.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:17][O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C=CC(=O)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cnc2ccccc2c1
Temperature: 100 °C
Yield: 100 %

Procedure:
A Fisher-Porter pressure bottle was charged with 3-bromoquinoline (2.77 mL, 20 mmol), methyl acrylate (2.25 mL, 25 mmol), palladium diacetate (44 mg, 0.2 mmol), and tri-o-tolylphosphine (244 mg, 0.802 mmol) in Et3N (10 mL). The atmosphere was replaced with argon, the bottle sealed and the mixture was stirred and heated at 100° C. for 6 h. The cooled mixture was partitioned between CH2Cl2 (200 mL) and H2O (100 mL) and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with H2O (100 mL) dried (Na2SO4) and concentrated to give 5.56 g of crude product which was purified by silica gel chromatography, eluting with a mixture of EtOAc and hexane in (1:1) to give (E)-3-(3-quinolinyl)-2-propenoic acid methyl ester (4.26 g, 20 mmol) in quantitative yield, mp 118° -120° C.
Reaction SMILES: C[O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=[O:6])[O:4]C.Br[Si](C)(C)C>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH2:7][P:3](=[O:2])([OH:6])[OH:4])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COP(=O)(CNS(=O)(=O)c1ccc(F)cc1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
A solution of diester 35 (0.58 g, 1.95 mmol) in dry CH2Cl2 (10 mL) and bromotrimethylsilane (1.5 mL, 11.7 mmol) was stirred at room temperature for 5 hours and then concentrated. The resulting residue was dissolved in anhydrous CH3OH (10 mL) and stirred at room temperature for 20 minutes. Insolubles were filtered, and the filtrate was concentrated. Purification by trituration with CH2Cl2 gave the phosphonic acid (iv) (0.51 g, 97%) as a white solid: 1H NMR (300 MHz, CD3OD) δH 3.17 (d, J=13.5 Hz, 2H), 7.35 (m, 2H), 7.97 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.I.[C:31](SC)(=[NH:33])[CH3:32]>CO>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1)(=[NH:33])[CH3:32]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: CSC(C)=N
Agent: I
Solvent: CO
Product: CC(=N)Nc1ccc(CCc2nc(NC(C)=O)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
N-{4-[2-(4-Aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (200 mg), methyl ethanimidothioate hydroiodide (202 mg) and MeOH (4 ml) were combined under N2 atmosphere. The reaction mixture was refluxed for 3 hours. After cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative NH silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The amorphous substance was solidified with ethyl ether to give N-{4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (102.4 mg) as a pale yellow amorphous solid.