Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[C:41]([C@H:42](O)[CH3:43])=[CH:40][C:39]2[C:34](=[C:35]([F:45])[CH:36]=[CH:37][CH:38]=2)[N:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:31][C:32]1[C:41]([C@@H:42]([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH3:43])=[CH:40][C:39]2[C:34](=[C:35]([F:45])[CH:36]=[CH:37][CH:38]=2)[N:33]=1
Reactant: C[C@@H](O)c1cc2cccc(F)c2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1cc2cccc(F)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 81.8 %

Procedure:
In a round bottomed flask was combined phthalimide (6.38 g, 43.3 mmol), triphenylphosphine (1.14 g, 43.3 mmol), and (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (8.15 g, 36.2 mmol) in THF (240 mL). The solution was cooled to 0° C. and diisopropylazodicarboxylate (DIAD, 8.5 mL, 43.3 mmol) was added dropwise. The reaction was allowed to warm to rt overnight. The reaction was concentrated to a volume of ˜100 mL and diluted with 1 L of Et2O and 200 mL of water. The layers were separated and the aqueous layer was back extracted with 200 mL of Et2O. The combined organic layers were washed with 160 mL of brine, dried over MgSO4, filtered, and concentrated. Column chromatography using 100% DCM afforded (S)-2-(1-(2-chloro-8-fluoroquinolin-3-yl)ethyl)-isoindoline-1,3-dione (10.5 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (br s, 1H), 7.74 (m, 2H), 7.64 (m, 3H), 7.45 (td, J=7.8, 4.9 Hz, 1H), 7.35 (ddd, J=10.2, 7.8, 1.2 Hz, 1H), 5.89 (q, J=7.2 Hz, 1H), 1.90 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][CH:34]=1)[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24]C(OC(C)(C)C)=O)=[CH:19][CH:18]=1)=[O:14])=[O:8])(=[O:3])[CH3:2].C(OCC)C.[ClH:47].C(O)(=O)C>>[ClH:47].[C:1]([S:4][CH2:5][CH:6]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][CH:34]=1)[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccc(CN)cc2)c1

Procedure:
4-(t-Butyloxycarbonylaminomethyl)benzyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)amino]benzoate (compound of Example 121) (0.73 g) is dissolved in 1M hydrochloric acid-acetic acid solution (20 ml), and the mixture is reacted at room temperature for 45 minutes. The reaction mixture is added slowly to diethyl ether (100 ml) with stirring under ice cooling. The precipitates are separated by filtration and washed with diethyl ether to give the title compound (0.61 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:32]([NH:34][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:27][CH:26]=1)([CH3:33])[CH3:31]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.1 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87.0 mg, 0.214 mmol) and propan-2-amine (18.93 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (39.6 mg, 0.088 mmol, 41.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6 H) 1.85-2.00 (m, 3 H) 2.11-2.24 (m, 1 H) 2.41-2.48 (m, 4 H) 3.17-3.27 (m, 4 H) 3.34-3.44 (m, 3 H) 3.53-3.65 (m, 1 H) 3.93-4.13 (m, 2 H) 6.91 (d, J=9.09 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.62 (d, J=2.02 Hz, 1 H) 7.72 (d, J=9.09 Hz, 2 H) 7.89 (d, J=7.83 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [OH:1]O.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5](=[O:15])C1=O.Cl>[OH-].[Na+]>[NH2:3][C:11]1[CH:10]=[C:9]2[C:8]([CH2:14][CH2:13][CH2:12]2)=[CH:7][C:6]=1[C:5]([OH:15])=[O:1]
Reactant: OO
Reactant: O=C1Nc2cc3c(cc2C1=O)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30% Aqueous hydrogen peroxide solution (5.4 mL) was added to a solution of a mixture of 1,5,6,7-tetrahydrocyclopenta[f]indole-2,3-dione and 1,5,6,7-tetrahydrocyclopenta[e]indole-2,3-dione (3.9 g, 20.8 mmol) in 2 N sodium hydroxide (41 mL) over a period of 5 min. The mixture was then stirred at room temperature for 3 h. 1N HCl was added to adjust the pH to 5. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 6-aminoindane-5-carboxylic acid. The solid was dissolved in EtOAc (4 mL) and ethanol (4 mL). To the solution above was added (trimethylsily)diazomethane (2 M in hexane) (18 mL, 36 mmol) at room temperature and The mixture was stirred for 16 h. The solvent was removed in vacuo. Flash chromatography of the residue (Si, hexanes/EtOAc) afforded methyl 6-aminoindane-5-carboxylate which contained about 10% methyl 5-aminoindane-4-carboxylate. LCMS calc.=192.1; found=192.2 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.71 (s, 1H); 6.60 (s, 1H); 3.87 (s, 3H); 2.85-2.79 (m, 4H); 2.08-2.02 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: c1ccc(COc2ccc(C3CN(Cc4ccccc4)CCO3)cc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(C2CNCCO2)cc1
Yield: 96.2 %

Procedure:
To a solution of 4-benzyl-2-(4-benzyloxy-phenyl)-morpholine (8.35 g; 23.2 mmol) in MeOH (100 mL) was added a catalytic amount of palladium hydroxide (0.65 g; ˜20 wt % on carbon, wet). The resulting mixture was treated with hydrogen (1 atm.) at RT, overnight. Subsequently, the mixture was filtered over kieselguhr, rinsed with MeOH, and concentrated in vacuo to afford 4-morpholin-2-yl-phenol (4.00 g), which was used as such.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:32][C@H:33]2[CH2:35][O:34]2)(=O)=O)=CC=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:32][C@H:33]2[CH2:35][O:34]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a stirred solution of 1-(4-(benzyloxy)-2-hydroxyphenyl)ethanone (3.36 g, 13.9 mmol) in anhydrous DMF (15 ml) was added NaH (0.62 g, 15.5 mmol). The mixture was allowed to stir at RT for 30 min, and a solution of (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (3.17 g, 13.9 mmol) in DMF was added dropwise at RT. The mixture was slowly heated to 60° C. and stirred for 3 h. The reaction was quenched by addition of water (80 ml) and extracted three times with EtOAc. The combined organic layers were extracted twice with aq 1 M NaOH and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated. The crude product obtained was purified by column chromatography with EtOAc/heptane (1:1) as eluent to afford the title compound (2.64 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl>[CH3:7][O:6][C:4]([C:3]1[C:2]([CH2:1][Cl:12])=[N:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COC(=O)c1cccnc1C
Solvent: ClCCl
Product: COC(=O)c1cccnc1CCl
Yield: 45.7 %

Procedure:
A solution of methyl 2-methylnicotinate (20.0 g, 0.132 mol) and trichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100 mL) was stirred at room temperature overnight. The reaction mixture was then washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated in vacuo to provide the title compound as a yellow liquid (11.2 g), which is used as such in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]=[O:13])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (1.5 g, 10 mmol) in anhydrous dichloromethane was treated with titanium tetrachloride (1.86 mL, 17 mmol) followed by α,α-dichloromethyl ether (0.9 mL, 20 mmol). The reaction was allowed to warm to ambient temperature over 1 h, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography using 2–2.5% ethyl acetate in hexane as the eluent to afford the title compound (1.37 g, 77%). 1H NMR (300 MHz, CDCl3): δ 11.02 (s, 1H), 9.81 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (dd, J=8.2, 1.7 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:30])[C:13](=[O:29])[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:18])([CH3:4])([CH3:3])C.CCN(C(C)C)C(C)C.[CH3:41][C:42](OC(C)=O)=[O:43]>C(Cl)(Cl)Cl>[CH:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:30][C:42](=[O:43])[CH3:41])[C:13](=[O:29])[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[CH3:18])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCNC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@@H](CCCCNC(=O)OC(C)C)C(=O)NCCN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of compound H (1.4 g, 3.21 mmol) in CHCl3 (10 mL) at room temperature was added DIEA (2.6 mL, 15 mmol) followed by Ac2O (0.85 mL, 9.0 mmol). The reaction mixture was stirred at room temperature for 2 h. Solvents were removed in vacuo and then the residue was dissolved in dichloromethane (100 mL). The organic layer was washed with 10% citric acid (75 mL), saturated NaHCO3 (75 mL) and brine (75 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to afford compound I (1.45 g, 99%). LC-MS [M+H] 479.5 (C24H38N4O6+H, calc: 479.5).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([N:12]2[C:16]([CH2:17][NH2:18])=[CH:15][C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]2)[CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH3:3].[F:23][C:24]1[CH:25]=[C:26]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:27]=[CH:28][C:29]=1[CH2:30][O:31][CH2:32][CH2:33][OH:34]>C(#N)C>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([N:12]2[C:16]([CH2:17][NH:18][C:36]([NH:35][C:26]3[CH:27]=[CH:28][C:29]([CH2:30][O:31][CH2:32][CH2:33][OH:34])=[C:24]([F:23])[CH:25]=3)=[O:37])=[CH:15][C:14]([C:19]([F:20])([F:21])[F:22])=[N:13]2)[CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH3:3]
Reactant: CCOc1cc(C)cc(-n2nc(C(F)(F)F)cc2CN)c1
Reactant: O=C(Nc1ccc(COCCO)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CCOc1cc(C)cc(-n2nc(C(F)(F)F)cc2CNC(=O)Nc2ccc(COCCO)c(F)c2)c1
Yield: 39.2 %

Procedure:
To a stirred solution of (1-(3-ethoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (100 mg, 0.300 mmol, 1.0 eq) in acetonitrile (7 mL) was added TEA (0.166 mL, 1.20 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-((2-hydroxyethoxy)methyl)-phenylcarbamate (93 mg, 0.306 mmol, 1.02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:1)) to get 1-((1-(3-ethoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)urea (60 mg, 39%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 98b (1.1 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 90%).
Reaction SMILES: Cl.[C:2]1([C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C[O:21][C:22]1C=CC=C[C:23]=1N1CCN(CCO)CC1>>[C:2]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:23][CH2:22][OH:21])[CH2:16][CH2:15]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccc2ccccc12)N1CCNCC1
Reactant: COc1ccccc1N1CCN(CCO)CC1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(CCO)CC1
Yield: 30 %

Procedure:
2-(4-Naphthoyl-piperazin-1-yl)-ethanol (39B) is prepared from 39A as described for 28A.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:28])[CH:26]=[CH2:27])=[CH:10][N:9]=1.[CH3:29][OH:30]>S(=O)(=O)(O)O>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25]([CH2:26][CH2:27][O:30][CH3:29])=[O:28])=[CH:10][N:9]=1
Reactant: CO
Reactant: C=CC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COCCC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1

Procedure:
A mixture of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(acryloyl)pyrimidine (31 mg), methanol (1 ml) and conc. sulfuric acid (one drop) is heated under reflux for 2 days. After the reaction is complete, the solvent is evaporated under reduced pressure, and the residue is separated by silica gel thin layer chromatography (solvent; chloroform:methanol=30:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine (27 mg) as colorless oil, MS (m/z): 435 (MH+).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[N:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][NH2:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]1([CH2:1][NH:57][CH2:56][CH2:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][N:49]=1)[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccccn3)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: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-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)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and 2-(2-pyridyl)ethylamine (0.024 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h then an additional 0.1 g of sodium triacetoxyborohydride was added to the mixture and it was stirred for 23 h. To the mixture was added additional acetic acid (1M in DCM) (0.167 ml, 0.167 mmol), 2-(2-pyridyl)ethylamine (0.024 ml, 0.200 mmol), and sodium triacetoxyborohydride (0.071 g, 0.334 mmol). The mixture was stirred at rt for an additional 19 h, was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound. LCMS: m/e 705.4 (M+H)+, 2.90 min (method 6).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[B:27](OCC)([O:31]CC)[O:28]CC.Cl>C1COCC1.CCCCCC>[C:16]1([C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([B:27]([OH:31])[OH:28])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
An amount of 14 g (42 mmol) of 9-bromo-10-phenylanthracene was dissolved in dehydrated THF and cooled to −80° C. Then, 31.2 ml (49 mmol) of a solution of n-butyllithium in n-hexane was added dropwise. Forty minutes later, 13 g (89 mmol) of triethyl borate was added. After two-hour reaction, a diluted hydrochloric acid solution was added and allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 10 g (33.6 mmol) of 10-phenylanthracene-9-boronic acid. The yield was 75.2%.