Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19].[O:21]1[CH2:26][CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:24]2[CH2:25][CH2:26][O:21][CH2:22][CH:23]=2)=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19]
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
To a stirred solution of 4.36 g (15.6 mmol) 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 3.30 g (14.2 mmol) trifluoromethanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester in 33 ml ethanol and 82 ml toluene was added 580 mg (0.71 mmol) dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct. The mixture was heated at 80° C. and 16.5 ml (33.0 mmol) 2 M aqueous sodium carbonate solution was added dropwise. The reaction mixture was stirred for 20 minutes at 80° C. and then cooled to room temperature, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4 ethyl acetate/hexane) afforded 2.00 g (60%) 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran as a light yellow solid. ES-MS m/e (%): 253 (M+NH4+, 100), 236 (M+H+, 24).
Reaction SMILES: [C:1]1([C:11]2[N:12]=[N:13][S:14][C:15]=2[S:16][CH2:17][C:18]([O:20]C)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:11]2[N:12]=[N:13][S:14][C:15]=2[S:16][CH2:17][C:18]([OH:20])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CSc1snnc1-c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSc1snnc1-c1cccc2ccccc12

Procedure:
A mixture of methyl 2-(4-(naphthalen-1-yl)-1,2,3-thiadiazol-5-ylthio)acetate (60 mg, 0.19 mmol), sodium hydroxide (10% aq. 5 mL) and methanol (5 mL) was stirred at reflux for 2 hours. The reaction was then cooled to room and the methanol removed. Water was added, neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% DCM/5% MeOH) afforded 2-(4-(Naphthalen-1-yl)-1,2,3-thiadiazol-5-ylthio)acetic acid as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:15]1[CH2:18][CH2:17][CH2:16]1>COCCOC>[N:15]1([C:2]2[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: Clc1ncncc1I
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Ic1cncnc1N1CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
To a 16×100 mm reaction tube under N2 was added 4-chloro-5-iodopyrimidine (200 mg, 0.832 mmol), cesium carbonate (817 mg, 2.508 mmol) and 1,2-dimethoxyethane (5 mL). The reaction mixture was flushed with nitrogen and then treated with azetidine (112 μL, 1.662 mmol). The reaction mixture was securely capped, stirred at room temperature for 5 min, and then heated at 90° C. for 18 h. The reaction mixture was filtered through a small Celite plug by gravity, washed with dichloromethane (70 mL) and the solvent was evaporated off in vacuo to give 200 mg (92%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]5([C:33]([O:35]C(C)C)=[O:34])[CH2:32][CH2:31]5)[N:29]=4)[N:26]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[C:39]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]5([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]5)[N:29]=4)[N:26]=3)[CH2:15][CH2:16]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)OC(=O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CC1
Yield: 70.6 %

Procedure:
554 mg of isopropyl 1-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxylate dihydrochloride was dissolved in 3 ml of ethanol; 1.73 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water, washed with ethyl acetate and ajusted to pH 5.5 by the addition of 1 N hydrochloric acid. The mixture was crystallized by the addition of acetone, washed with acetone and dried to yield 321 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([Cl:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.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>[N:20]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[Cl:19])[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1Cl
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1Cl)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(Benzyloxy)-2-chlorophenyl]acetic acid (0.52 g, 1.88 mmol) was dissolved in DMF (1 ml) and azetidine (0.161 g, 2.82 mmol), DIEA (0.99 ml, 5.64 mmol), and HATU (1.43 g, 3.76 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 316 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:15][CH3:16])[CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1OCC(=O)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Br)ccc1OCC(O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanone Part B (1.7 g, 5.96 mmol) in THF (12 mL) and MeOH (12 mL) was slowly added sodium borohydride (0.226 g, 5.96 mmol). After stirring at RT for 30 min, the mixture was concentrated, diluted with EtOAc, washed with sat NaHCO3, 1N HCl, brine, dried (Na2SO4) and concentrated. The crude product was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 50:50 gradient) to afford the desired product 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanol 16C (1.53 g, 5.33 mmol, 89% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ 6.97-7.07 (2H, m), 6.81 (1H, d, J=8.53 Hz), 4.14 (1H, dd, J=9.79, 2.76 Hz), 3.90-3.98 (1H, m), 3.85 (3H, s), 3.31 (1H, t, J=2.51 Hz), 2.78 (1H, s), 0.88-1.01 (1H, m), 0.49-0.67 (2H, m), 0.44 (1H, dd, J=9.41, 4.64 Hz), 0.25-0.33 (1H, m).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:17])=O)C1C=CC=CC=1>CO>[NH2:11][CH2:12][CH2:13][CH2:14][CH:15]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(CCCNC(=O)OCc1ccccc1)C(=O)N1CCCC1Cc1c(CCC(=O)O)oc2ccccc12
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCCN)C(=O)N1CCCC1Cc1c(CCC(=O)O)oc2ccccc12

Procedure:
A solution of the crude 54 (˜3 g, 4.8 mmol) in MeOH (30 mL) was charged with 10% Pd-on-carbon (˜1 g) and placed under an atmosphere of hydrogen gas (45 PSI). The reaction mixture was shaken using a Parr apparatus for 2 h. After removal of the catalyst by filtration over celite, the clarified filtrate was concentrated in vacuo. The crude residue was taken up in DCM and dried using anhydrous Na2SO4, filtered and concentrated to afford 2.3 g (quant.) of 55 as a foamy residue which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.51 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.15 (m, 2H), 6.19 (m, 1H), 4.36 (m, 2H), 3.62-3.48 (m, 2H), 3.10-2.99 (m, 2H), 2.85-1.81 (m, 2H), 2.66-2.60 (m, 2H), 1.99-1.71 (m, 6H), 1.41 (s, 911) ppm. Mass spectrum, m/z 488 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[N:6][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[N:8][CH:9]=1)=[O:3].Cl.[OH-].[Na+]>C(O)(C)C.C(O)C>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:6]=[C:5]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:4]([C:2]([NH2:1])=[O:3])=[CH:9][N:8]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)ncc2C(N)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)ncc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
1,1-Dimethylethyl [(3R,4R)-4-({5-(aminocarbonyl)-4-[(4-methylphenyl)amino]-2-pyrimidinyl}amino)tetrahydro-2H-pyran-3-yl]carbamate (52.2 g) was added to a mixture of hydrogen chloride in isopropanol (5M, 300 ml) and ethanol (400 ml). The mixture was heated to reflux while stirring and heating continued for 24 h with vigorous stirring. The mixture was allowed to cool to room temperature, filtered, the solid washed with ethanol (100 ml) and dried in vacuo. The crude product was suspended in water (900 ml) and heated to reflux, giving a clear solution. The solution was basified with sodium hydroxide solution (2M, 300 ml) and cooled in ice. The precipitated product was collected by filtration, washed with water (2×100 ml) and the beige solid dried in the vacuum oven at 40° C. for 2 h to give 2-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-4-[(4-methylphenyl)amino]-5-pyrimidinecarboxamide as beige solid (37.8 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH:29]([CH3:31])[CH3:30])[NH:9]1)=[O:7])(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH:29]([CH3:31])[CH3:30])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 49b (0.64 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.7 g, 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[SH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C1CCN2C(=NCCC2)CC1.C(=O)(OCC)OCC.C(O)C.[O-]CC.[Na+].Cl.BrC1C=CC(F)=C(C=1)C=O>CN(C=O)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:2]3[S:20][CH2:21][CH2:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][C:3]=3[CH:6]=2)=[CH:11][CH:12]=1)[CH2:18][CH3:19]
Reactant: CCOC(=O)CCCS
Reactant: CCCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Agent: CC[O-]
Agent: Cl
Agent: O=Cc1cc(Br)ccc1F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(=O)OCC
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Under an argon flow, 30.5 g of crude 2-fluoro-5-(4-propoxyphenyl)benzaldehyde was dissolved in 59 ml of DMF and then cooled to 5° C. After the addition of ethyl 4-mercaptobutyrate (32.6 ml, 229.88 mmol), 1,8-diazabicyclo[5.4.0]-7-undecene (34.4 ml, 229.88 mmol) was dropped slowly, while keeping at 0-10° C. The mixture was heated to 20° C. and stirred at 20-30° C. for 3 hours. At 20-30° C., 590 ml of diethyl carbonate was dropped and subsequently an ethanol solution (156 g, 459.76 mmol) of 20% sodium ethoxide was dropped. After stirring at 20-30° C. for 3 hours, the mixture was cooled to 5° C. After adding 338 ml of a 2N hydrochloric acid while keeping 10° C. or lower, phase separation was conducted. The water layer was extracted with 290 ml of ethyl acetate. The organic layers were combined and washed with 300 ml of water, 300 ml of a 5% aqueous sodium hydrogencarbonate solution and 300 ml of a 5% brine. After the addition of activated carbon, Shirasagi A (3.5 g), followed by the addition of tri-n-butylphosphine (4 ml), the mixture was stirred at room temperature for 20 minutes. After filtration, the residue was washed with 60 ml of ethyl acetate and the filtrate was concentrated under reduced pressure. After addition of 60 ml of isopropyl alcohol, the mixture was concentrated under reduced pressure. Subsequently, 60 ml of isopropyl ether was added and stirred at room temperature. The crystals formed were dissolved on heating under reflux. The solution was cooled for 1.5 hours while being stirred and subsequently stirred for 2 hours while being cooled in ice. After filtration, the residue was washed with 60 ml of ice-cooled isopropyl ether and then dried under vacuum (40° C.), yielding 20.34 g of ethyl 7-(4-propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate as pale yellow crystals (Yield from 5-bromo-2-fluorobenzaldehyde 48%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Br:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Br)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
20 g (93.8 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6 -one in 100 ml of dimethylformamide are treated with 17.5 g (98 mmol) of N-bromosuccinimide and stirred at room temperature for 35 minutes. The solution is poured into water and extracted twice with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. After recrystallization from ethyl acetate, the residue yields 3-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 196°-198°.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15]C)=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:20][O:19][C:17]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([OH:15])=[O:14])[CH2:12][CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccccc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccccc1
Yield: 94.1 %

Procedure:
Dimethyl 2-phenylpiperidine-1,4-dicarboxylate (5.88 g, 21.20 mmol) was dissolved in acetonitrile (60 mL) and water (1.2 mL), then lithium bromide (4.25 mL, 169.63 mmol) was added. Triethylamine (11.76 mL, 84.81 mmol) was added and the resulting yellow suspension was heated at reflux for 1 h. Water (60 mL) and MTBE were added. The organic phase was extracted with water (×2). To the pooled aqueous layer was added MTBE and the solution was acidified to pH 1 with 3.8 M aq HCl and then extracted with MTBE (×2). The combined organic layer was washed with water and evaporated. Traces of water were azeotropically removed by MeCN. 1-(Methoxycarbonyl)-2-phenylpiperidine-4-carboxylic acid (5.25 g, 94%) was isolated as a slightly yellow semisolid. MS m/z 264 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:25]=[C:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[O:16]=[C:15]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:17]([O:19][C:26]([CH3:28])([CH3:27])[CH3:25])=[O:18])[CH2:13][CH2:14]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: C=C(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
(S)-1-(Benzyloxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (100 g) was dissolved in dehydrated methylene chloride (2 L), and under ice cooling, concentrated sulfuric acid (10 mL) and isobutene (213 g) were added, followed by stirring overnight at +20° C. or less. The reaction mixture was added to cold aqueous sodium carbonate solution while paying attention to effervescence, followed by liquid separation of the organic phase, washing with saturated brine and drying over anhydrous magnesium sulfate, then the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=7/3), and crystallized with hexane/ethyl acetate to afford 80 g of the title compound as a colorless crystalline powder (yield 67%). Enantiomeric excess 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=2/1, flow rate 1 mL/min., retention time 4.2 min.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:23]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][N:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:21][C@H:22]3[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=4)[CH2:23]3)[N:11]=2)[CH2:13][CH2:14]1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CN1CCCN(c2nc(Cl)nc3ccccc23)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CN1CCCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccc(OC(F)(F)F)cc4)C3)nc3ccccc23)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a mixture of 2-chloro-4-(4-methyl-[1,4]-diazepan-1-yl)quinazoline (0.10 g), Pd2(dba)3 (0.017 g), (±)-BINAP (0.034 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.13 g), and 1,4-dioxane (2 mL) was added sodium t-butoxide (0.10 g) under nitrogen atmosphere, and the mixture was stirred at 80° C. for 3 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=10:1) to obtain colorless amorphous 1-((S)-3-(4-(4-methyl-[1,4]-diazepan-1-yl)quinazolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.12 g).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1)=[O:7])(=O)[CH3:2].[Cl-]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]1[CH:20]=[C:15]([CH:14]=[C:13]([O:12][C:11]2[CH:31]=[CH:32][C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:9][CH:10]=2)[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)NNC(C)=O)cc2)c1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1

Procedure:
To a stirring mixture of Methyl 3-(4-(2-acetylhydrazinecarbonyl)phenoxy)-5-(benzyloxy)benzoate (Intermediate 10) (32 g, 73.7 mmol, 1 equiv.) in toluene in a single necked round bottomed flask fitted with reflux condenser and anhydrous CaCl2 guard tube, thonyl chloride (10.5 g, 88.4 mmol, 1.2 equiv.) was added carefully. The reaction mixture was refluxed until the reaction was complete. After completion, the reaction mixture was poured onto ice and extracted twice with ethyl acetate. The combined organic extracts was washed with brine and dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to give the title compound as yellow solid product (30 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30]Cl)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30][N:38]3[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CCl)ccc2n1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CN3CCC(O)CC3)ccc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of [2-amino-6-(2-chloromethyl-5-fluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 5 ml of acetonitrile. 301 mg of caesium carbonate and 57 μl of piperidin-4-ol are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).