Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CC3CCOCC3)nc12

Procedure:
From tetrahydropyran-4-yl-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.1° (c=1.07, CHCl3), ES-MS m/e (%): 393 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:16])[CH3:15])[C:5]([O:12][CH3:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.[C:17](=O)([O-])O.[Na+].O>CO.Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:11][CH3:17])([CH3:9])[CH3:10])[C:5]([O:12][CH3:13])=[C:4]([N:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: COc1c(N(C)C)cc(Br)cc1C(C)(C)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(N(C)C)cc(Br)cc1C(C)(C)OC
Temperature: 25 °C

Procedure:
After dissolving 2-[5-bromo-3-(dimethylamino)-2-methoxyphenyl]-2-propanol (410 mg) in 100 mL of methanol-hydrochloric acid, the solution was heated to reflux for 14 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added for neutralization, water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (370 mg) as an oil. 1H-NMR (CDCl3) δ: 1.57(3H, s), 1.60(3H, s), 2.77(6H, s), 3.40(3H, s), 3.77(3H, s), 6.95(1H, d, J=2 Hz), 7.16(1H, d, J=2 Hz).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH2:21][CH3:22])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1)#[N:2]>N.C(O)C.[Co]>[NH2:2][CH2:1][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH2:21][CH3:22])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1c(CC)nn2ccc3c(c12)C(CC#N)CC3
Agent: [Co]
Agent: N
Solvent: CCO
Product: CCOC(=O)c1c(CC)nn2ccc3c(c12)C(CCN)CC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Ethyl 9-(cyanomethyl)-2-ethyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (80.0 mg, 0.269 mmol) and Raney cobalt (800 mg) were suspended in 2M ammonia/ethanol solution (13 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (81.0 mg, yield 100%).
Reaction SMILES: O[C:2]([C:14]1[C:15]([NH:20][C:21](=[O:26])[C:22](C)(C)C)=[N:16][CH:17]=[CH:18][CH:19]=1)([CH:11]([CH3:13])[CH3:12])CC(OC(C)(C)C)=O>Cl>[CH:11]([C:2]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[NH:20][C:21](=[O:26])[CH:22]=1)([CH3:12])[CH3:13]
Reactant: CC(C)C(O)(CC(=O)OC(C)(C)C)c1cccnc1NC(=O)C(C)(C)C
Agent: Cl
Product: CC(C)c1cc(=O)[nH]c2ncccc12
Yield: 40.9 %

Procedure:
A solution of tert-butyl 3-hydroxy-4-methyl-3-(2-pivalamidopyridin-3-yl)pentanoate (3.78 g, 10.4 mmol) in 12.0 mL 3N HCl were reacted as outlined in Scheme 1 to give the desired 4-isopropyl-1,8-naphthyridin-2(1 H)-one (800 mg, 41%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.34 (d, J=7.03 Hz, 6 H) 3.34 (quin, J=6.81 Hz, 1 H) 6.66 (s, 1 H) 7.23 (dd, J=12.31, 4.10 Hz, 2 H) 8.09 (dd, J=8.06, 1.61 Hz, 1 H) 8.71 (dd, J=4.69, 1.47 Hz, 1 H) 11.98 (br. s., 1 H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([CH3:21])([CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:9](OC)=[O:10].O.[OH-].[Na+]>C1COCC1>[CH3:7][C:8]([CH3:21])([CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH2:9][OH:10]
Reactant: COC(=O)C(C)(C)COC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of LiAlH4 (397 mL, 397 mmol) in THF (250 mL) cooled in an ice bath to 0° C. was added methyl 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propanoate (82 g, 378 mmol) in THF (250 mL) via addition funnel keeping the internal temperature below 6° C. When addition was complete the reaction was allowed to warm to room temperature and stir overnight. The mixture was cooled in an ice bath and quenched with H2O (16 mL, 888 mmol), then after 5 minutes, 10 N NaOH (16 mL, 160 mmol), and after another 15 minutes, H2O (48 mL, 2664 mmol). The mixture was allowed to stir for 30 minutes, then filtered with a THF rinse. The filtrate was concentrated and azeotropically dried with toluene. Further drying under vacuum gave 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 4.58 (m, 1H), 3.85 (m, 1H), 3.6 (d, 1H), 3.5 (m, 2H), 3.4 (m, 1H), 3.2 (d, 1H), 2.8 (t, 1H), 1.8 (m, 2H), 1.6 (m, 4H), 0.85 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[C:19](=[O:26])[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[O:22][C:17]=3[CH:16]=2)=[CH:6][C:5]=1[OH:31])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:36]>O>[Na+:36].[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[C:19](=[O:26])[CH:20]=[C:21]([C:23]([O-:25])=[O:24])[O:22][C:17]=3[CH:16]=2)=[CH:6][C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCCCCCOc2ccc3c(=O)cc(C(=O)O)oc3c2)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(OCCCCCOc2ccc3c(=O)cc(C(=O)[O-])oc3c2)cc1O

Procedure:
A mixture of 3.35 parts of 7-[5-(4-acetyl-3-hydroxyphenoxy) pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid and 0.66 parts of sodium bicarbonate in 200 parts of water, was heated to effect solution. The solution was filtered while hot and on cooling a white solid crystallised. This was filtered, washed with ice-cold water and dried under vacuum over phosphorus pentoxide to yield 3.0 parts of 7-[5-(4-acetyl-3-hydroxyphenoxy) pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt, melting point 210° C (indefinite).
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:6]2[N:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]=1.[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:19][O:18][C:16]([C:12]1[CH:11]=[C:10]([N:7]2[C:8](=[O:9])[C:3]([CH2:2][N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[CH3:24])=[N:4][C:5]3[CH:23]=[CH:22][CH:21]=[N:20][C:6]2=3)[CH:15]=[CH:14][CH:13]=1)=[O:17]
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2c(=O)c(Cn3ccnc3C)nc3cccnc32)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.3 %

Procedure:
A mixture of 2-bromomethyl-4-(3-methoxycarbonylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.22 g) and 2-methylimidazole (1.35 g) in N,N-dimethylformamide (10 ml) was stirred at 80° C. for 1 hour. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (5% methanol in chloroform) to give 4-(3-methoxycarbonylphenyl)-2-[(2-methylimidazol-1-yl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (15 4 mg).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:15][C:14]4[N:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][CH:44]=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35].CO>ClCCl>[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]4[C:8]=3[S:15][C:14]3[N:16]=[CH:17][CH:18]=[CH:19][C:13]4=3)[CH2:6][CH2:5]2)=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Reactant: c1cnc2sc3c(N4CCNCC4)ncnc3c2c1
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ncccn1)c1ccc(NC(=S)N2CCN(c3ncnc4c3sc3ncccc34)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinopyrido[3′,2′;4,5]thieno[3,2-d]pyrimidine (200 mg, 0.74 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 60 mg (15%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([NH:13][C:14](=[O:25])[O:15][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH3:17])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].O>CN(C)C=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:16]([O:15][C:14]([NH:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:7][CH:6]=2)=[N:9][O:10][CH:11]=1)=[O:25])[CH3:17]
Reactant: CC(OC(=O)Nc1conc1-c1ccc(O)cc1)c1ccccc1Cl
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution (2 ml) of 1-(2-chlorophenyl)ethyl 3-(4-hydroxyphenyl)-4-isoxazolylcarbamate (80 mg, 0.223 mmol) in N,N-dimethylformamide were added potassium carbonate (60 mg, 0.435 mmol) and ethyl 5-bromovalerate (60 mg, 0.287 mmol), and the mixture was stirred at 100° C. for 1 hour. Water was added, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (59 mg, 55%).
Reaction SMILES: C(ON=O)(C)(C)C.C(#N)C.N[C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][C:13]=1[N+:29]([O-:31])=[O:30].[ClH:32]>C(OCC)(=O)C.[Cu](Cl)Cl>[Cl:32][C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][C:13]=1[N+:29]([O-:31])=[O:30]
Reactant: Cl
Reactant: CCOC(=O)c1cccc(-c2cnc(N)c([N+](=O)[O-])c2)c1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2cnc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 70 °C
Yield: 61 %

Procedure:
A solution of tert-butylnitrite (3.23 mL, 27.17 mmol), anhydrous copper(II) chloride (2.9 g, 21.74 mmol) and anhydrous acetonitrile (90 mL) was warmed to 70° C. Ethyl 3-(6-amino-5-nitropyridin-3-yl)benzoate (5.2 g, 18.11 mmol) was then added portionwise over a period 10 minutes to the reaction solution. The reaction mixture was maintained at 70° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was then poured into 110 mL of 20% aqueous HCl solution, followed by extraction with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography using a 95:5 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(6-chloro-5-nitropyridin-3-yl)benzoate (3.4 g, 61% yield) as a tan solid.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[CH2:21]([N:20]([CH3:19])[C@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:13][CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 160 ml of a methylene chloride solution containing 16.93 g of 4-(tert-butoxycarbonylamino)cyclohexanone and 10.55 ml of N-methylbenzylamine was added 19.08 g of sodium triacetoxyborohydride under ice-cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was suspended in hexane and collected by filtration. This mother liquor was concentrated and the residue was purified by NH-silica gel chromatography (solvent: hexane-ethyl acetate (97:3 to 83:17)). The residue was further suspended in hexane and collected by filtration and combined with the filtered product to-obtain 13.55 g of N′-benzyl-N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([C@H:33]2[CH2:37][C:36]([F:39])([F:38])[CH2:35][N:34]2C(OC(C)(C)C)=O)=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([C@H:33]2[CH2:37][C:36]([F:38])([F:39])[CH2:35][NH:34]2)=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)[C@H]1CC(F)(F)CN1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
(R)-tert-butyl 2-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate (33.9 mg, 0.05 mmol) was dissolved in a solution of TFA/CH2Cl2 (2 mL/2 mL) and the reaction mixture was stirred overnight. The solvent was removed and the residue dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 100A, C18; mobile phase: MeCN/H2O/TFA) to yield (R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4-difluoropyrrolidine-2-carboxamide as a white solid (22.4 mg, 78% yield). LC/MS RT=3.876 min; [M+H]=576.2 (LCMS Method 3). NMR: 500 MHz 1H (CDCl3); 8.35 ppm, 1H, d, J=5 Hz;, 7.79 ppm, 1H, m; 7.38 ppm, 1H, d, J=10 Hz; 7.17 ppm, 1H, m; 7.04 ppm, 4H, m; 6.89 ppm, 1H, m; 6.51 ppm, 1H, d, J=5 Hz; 6.21 ppm, 1H; m; 4.56 ppm, 1H′ t, J=9 Hz; 4.19 ppm, 1H, d, J=13 Hz; 3.84 ppm, 1H, d, J=13 Hz; 3.60 ppm, 2H′ t, J=12 Hz; 2.68 ppm, 1H, m; 2.22 ppm, 1H, m.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH2:34])[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:22]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH:34][C:2]2[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=2[CH3:15])[CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Br)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(C)c1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
To a solution of ethyl (2E)-3-(6-bromo-5-methyl-3-pyridyl)acrylate (500 mg) in dioxane (5 mL) was added palladium(II) acetate (41.6 mg) and 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-diphenylamine (109 mg) and cesium carbonate (843 mg), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (359 mg). The mixture was heated at 100° C. for 18 hours. The resulting mixture was poured into sat.NH4Cl aqueous solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by preparative thin layer chromatography (chloroform:methanol 90:10) to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate (366 mg) as pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([F:13])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:14][C:9]1[CH:8]=[C:7]([F:6])[CH:12]=[C:11]([F:13])[CH:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cc(F)cc(F)c1

Procedure:
A solution of 1-bromobutane (11.0 g, 0.08 mol) in acetone (30 ml) was added dropwise to a stirred, refluxing mixture of 3,5-difluorophenol (9.1 g, 0.07 mol) and potassium carbonate (30 g, 0.2 mol) in acetone (200 ml). The stirred mixture was heated under reflux for 24 h (glc analysis revealed absence of starting material). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water, 5% sodium hydroxide, water and dried (MgSO4). Most of the solvent was removed in vacuo, and after the removal of the final amount of solvent and the excess of 1-bromobutane at atmospheric pressure, the residue was distilled to yield a colourless liquid.
Reaction SMILES: [O:1]=[S:2]1(=[O:52])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:45])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20](/[CH:33]=[CH:34]/[C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1.CO>[O:52]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:45])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20](/[CH:33]=[CH:34]/[C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a solution of methyl 4-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-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)vinyl)benzoate (35 mg, 0.048 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 50° C. for 2 h. The crude product was purified by prep HPLC (method 4) to give 4-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-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)vinyl)benzoic acid as a white solid (12 mg, 35.0%). MS: m/e 717.5 (M+H)+, 2.798 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.08-7.95 (m, 2H), 7.47 (br. s., 2H), 6.98-6.83 (m, 1H), 6.77-6.64 (m, 1H), 5.87 (d, J=4.8 Hz, 1H), 4.72 (br. s., 1H), 4.61 (br. s., 1H), 3.27-3.06 (m, 8H), 2.95 (d, J=7.3 Hz, 2H), 2.86-2.62 (m, 3H), 2.23-2.00 (m, 3H), 1.98-1.79 (m, 4H), 1.73 (br. s., 3H), 1.66-1.50 (m, 5H), 1.48-1.18 (m, 10H), 1.11 (s, 3H), 1.09-1.05 (m, 3H), 1.03-0.96 (m, 6H), 0.76 (s, 3H).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@@H:23]([O:35][C:36]2[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[C:37]=2[NH2:43])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@@H:23]([O:35][C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[NH:42][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[N:43][C:37]=23)[CH2:22]1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cccc2ccccc12
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 68 %

Procedure:
A mixture of 1-naphthalenecarboxaldehyde (115 mg, 0.000738 mol), 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclo pentyl]oxy}pyridine-2,3-diamine (115.1 mg, 0.0002460 mol) and sodium metabisulfite (0.140 g, 0.000738 mol) in acetonitrile (2.00 mL) was subject to microwave irradiation at 180° C. for 25 mins. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative plate chromatography (25% EtOAc/hexanes) to afford the title compound (0.101 g, 68%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([N:11]([CH3:45])[C:12](=[O:44])[CH2:13][N:14]([C:31]1[CH:36]=[CH:35][C:34]([C:37]3[N:41]=[C:40]([CH3:42])[O:39][N:38]=3)=[CH:33][C:32]=1[CH3:43])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH3:23])=[O:17])[CH2:6]2.FC(F)(F)C(O)=O.N.[ClH:54].C(OCC)(=O)C>ClCCl.C(OCC)(=O)C.C(OCC)C>[ClH:54].[ClH:54].[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([N:11]([CH3:45])[C:12](=[O:44])[CH2:13][N:14]([C:31]1[CH:36]=[CH:35][C:34]([C:37]3[N:41]=[C:40]([CH3:42])[O:39][N:38]=3)=[CH:33][C:32]=1[CH3:43])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21][CH2:22][CH3:23])=[O:17])[CH2:6]2
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2cccc(F)c2C1)c1ccc(-c2noc(C)n2)cc1C)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCNCCNC(=O)CN(CC(=O)N(C)N1Cc2cccc(F)c2C1)c1ccc(-c2noc(C)n2)cc1C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
The compound (753 mg, 1.21 mmol) obtained in step A was dissolved in dichloromethane (2 ml), trifluoroacetic acid (2 ml) was added at room temperature, and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added aqueous ammonia, and the organic layer was extracted 55 twice with dichloromethane. The organic layer was dried over sodium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a pale-yellow oil. This oil was dissolved in ethyl acetate (2 ml), and 4N hydrochloric acid-ethyl acetate solution (0.75 ml, 3.0 mmol) was added at room temperature. Then, diethyl ether (20 ml) was added to allow precipitation of a solid. This was filtered, washed with diethyl ether, and dried under reduced pressure to give the title compound (655 mg, yield 91%) as a pale-yellow solid.