Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:29][CH2:28]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:38][N:36]([CH2:35][CH:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[O:8][CH3:9])=[CH:40][CH:39]=3)[CH:26]=2)[CH2:31]1)[CH3:37]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)Nc1ccc(COc2ccc3c(c2)CCC(CN(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
o-Anisoyl chloride (0.15 ml) was added dropwise to pyridine solution (4 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (200 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; THF), and recrystallized (ethyl acetate-hexane) to give the titled compound (200 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>CC(C)=O>[F:13][C:7]([F:12])([C:8]([F:9])([F:10])[F:11])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([NH:1][C:27]([NH:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)=[O:28])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Solvent: CC(C)=O
Product: O=C(Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1)Nc1ccc(Cl)c(Cl)c1

Procedure:
Five and one-tenth grams of m-amino pentafluoropropionanilide is dissolved in 50 ml of acetone and 3.8 g. of 3,4-dichlorophenyl isocyanate is added. The mixture is heated to reflux, cooled and the acetone stripped off under vacuum. Yield is 8.8 g., m.p. 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:42])[CH:31]=[CH:32][CH2:33][CH2:34][O:35]C5CCCCO5)[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:42])[CH:31]=[CH:32][CH2:33][CH2:34][OH:35])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(C=CCCOC1CCCCO1)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=C(C=CCCO)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Yield: 88.3 %

Procedure:
In a 250 ml rb flask were placed 1-[4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl]-5-(tetrahydro-pyran-2-yloxy)-pent-2-en-1-one (2.26 g, 3.73 mmol) and pyridinium p-toluenesulfonate (0.18 g, 0.74 mmol) in ethanol alcohol (100 ml). The reaction mixture was heated at 80 C for 12 hours. Ethyl alcohol was evaporated and to the residue was added methyl alcohol, sonicated and off-white solid was filtered and washed with methyl alcohol, dried to provide 1.72 g of off-white solid. (88.40%). 1H-NMR (DMSO-d6) δ 8.587-8.578 (m, 1H), 8.396 (s, 1H), 8.182 (s, 1H), 7.887-7.849 (t, 1H), 7.769 (s, 1H), 7.570-7.501 (m, 2H), 7.368-7.356 (t, 1H), 7.231-7.209 (d, 1H), 6.779-6.607 (m, 2H), 5.271 (s, 2H), 4.944 (s, 1H), 4.834 (s, 1H), 4.661 (s, 1H), 3.925-3.848 (d, 2H), 3.519 (m, 2H), 3.245-3.206 (m, 2H), 2.360 (m, 2H). MS m/e 522.0 (M+H), RT=2.54 min
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[CH:12][C:11]2[C:14](I)=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]=2[CH:9]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[Cl-].[Zn+2].[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:7][C:8]1[N:13]=[CH:12][C:11]2[C:14]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[N:15][N:16]([C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]=2[CH:9]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cl[Mg]C1CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: Clc1cc2c(cn1)c(C1CCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Reference: PCT Int. Appl., 2010056631, 2010. To a solution of zinc chloride (1.5 ml, 3.591 mmol, 1.9M in 2-methyl THF) at 0° C. was added a solution of cyclobutyl magnesium chloride in (9.20 ml, 4.60 mmol, 0.5 M in 2-methyl-THF). The reaction solution was stirred at 0° C. to r.t for 1 hr, and then transferred into a mixture of 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3a, 1 g, 1.917 mmol), Pd(OAc)2 (0.043 g, 0.192 mmol) and S-Phos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 0.118 g, 0.287 mmol) at r.t. The result dark suspension was stirred at r.t for 3 hr and then was quenched with water and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography on silica gel (50 g, eluting with 20% ethyl acetate/hexanes) to give 6-chloro-3-cyclobutyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (483 mg, 56%) as a light yellow solid. MS ESI calc'd. for C29H24Cl1N3[M+1]+ 450, found 450.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23][CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:21])([F:20])[F:22])[C:3]=1[S:23]([CH3:24])=[O:33]
Reactant: CSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 6 h

Procedure:
A stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-3-trifluoromethylpyrazole (1.0 g) in chloroform (40 ml) was treated with m-chloroper-benzoic acid (0.42 g), portionwise at room temperature. After stirring for 6 hours, the solution was diluted with dichloromethane and washed in turn with sodium sulphite solution, sodium hydroxide solution, and water. The solution was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a yellow oil. Purification by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm−2) eluting with dichloromethane-ethylacetate (4:1) gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulphinyl-3-trifluoromethylpyrazole in the form of a white solid, m.p. 142-145° C. with decomposition.
Reaction SMILES: [CH3:1][N:2]([N:6]1[CH:10]=[N:9][N:8]=[C:7]1[N:11](C(=O)C)[N:12]=[CH:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])C(=O)C>C(O)(=O)C.Cl.O>[ClH:20].[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:13]=[N:12][NH:11][C:7]1[N:6]([NH:2][CH3:1])[CH:10]=[N:9][N:8]=1
Reactant: CC(=O)N(N=Cc1c(Cl)cccc1Cl)c1nncn1N(C)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CNn1cnnc1NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 6.2 g of 4-(N-Methylacetamido)-3-[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazole in 50 ml of acetic acid, 50 ml of concentrated hydrochloric acid and 50 ml of water is heated at reflux overnight. The solution is evaporated and the residue is recrystallized from ethanolisopropyl ether.
Reaction SMILES: O.Cl[C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=1[CH3:18].[C:19](=O)([O-:21])[O-:20].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(C)(C)C>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:5]1[C:4]([CH3:18])=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([CH3:12])(=[O:11])=[O:10])[C:19]([OH:21])=[O:20]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(Cl)c1C
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(C)(C)O
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Temperature: 160 °C
Yield: 96.9 %

Procedure:
12.5 mL of water was added to 237.5 mL of tert-butanol, then nitrogen gas was blown thereinto for 5 minutes to remove dissolved oxygen thereby to prepare a reaction solvent. Into a 500 mL autoclave, 50.0 g of 1-chloro-3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzene, 28.5 g of sodium carbonate, 1.5 g of 1,4-bis(diphenylphosphino)butane, the above reaction solvent, and 1.5 g of 5% Pd/C were introduced, and the autoclave was closed. With stirring, nitrogen flushing (5.0 MPa) was carried out twice, followed by flushing with carbon monoxide (5.0 MPa) twice. Finally, carbon monoxide was filled (2.5 MPa). By an electric furnace, the autoclave was heated to 160° C., followed by stirring for 7 hours (300 rps). After cooling to room temperature, carbon monoxide gas remaining in the autoclave was removed. The content was poured into water and ethyl acetate, and insolubles were filtered off by celite. Then, the filtrate was subjected to liquid separation, and the aqueous layer was washed twice with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (pH=1) and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (50.1 g). Further, the obtained solid was washed with 150 mL of hexane and then collected by filtration and dried under reduced pressure to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (48.1 g) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]([Mg]Cl)([CH3:13])[CH3:12].[NH4+].[Cl-].Cl>CCOCC.C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([OH:8])[CH:11]([CH3:13])[CH3:12])[CH:9]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)C(O)c1cc(Br)ccc1O
Reaction time: 0.25 h
Yield: 122.2 %

Procedure:
The 5-bromo-2-hydroxybenzaldehyde (4.00 g, 19.9 mmol) in Et2O (40.0 mL) and THF (10.0 mL) was added dropwise to the isopropylmagnesium chloride (2 M in Et2O, 29.8 mL, 59.7 mmol) at ambient temperature. The reaction was stirred for about 15 min then MeOH (5 mL) was added followed by saturated aqueous NH4Cl and 1 N HCl. The reaction was extracted with EtOAc and then the combined organic layers were extracted with brine, dried over MgSO4, filtered, and evaporated to give the title compound as an oil (5.96 g, >100% yield). NMR showed some EtOAc but it was used as is the next step: 1H NMR (DMSO-d6, δ) 0.87 (3H, d), 1.03 (3H, d), 2.06 (1H, m), 2.77 (1H, s), 4.49 (1H, d), 6.78 (1H, d), 7.02 (1H, s), 7.25 (1H, dd), 8.11 (1H, s)
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].O.NN.Cl>C(O)C>[NH2:3][CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14]
Reactant: CC(C)CC(C(O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)CC(N)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
(1RS,2SR)2-(1,3-Dioxo-2-azaindan-2-yl)-4-methyl-1-phenylpentan-1-ol (80.0 g, 247 mmol) was dissolved with heating (50° C.) in ethanol (800 ml), followed by addition of a mixture of 85% hydrazine hydrate (19.0 ml) in ethanol (200 ml). The resulting mixture was heated under reflux for 3 hours. After ice-cooling, 4N-HCl (700 ml) was added. The mixture was stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration through celite and then washed with 4N-hydrochloric acid (140 ml). The washing was added to the filtrate and the solution was condensed under reduced pressure to remove the ethanol. A 6N-NaOH solution (570 ml) was added with ice-cooling and the mixture was extracted three times with chloroform. After being dried over sodium sulfate, the organic layer was evaporated to obtain 43.2 g of the title compound as white crystals (yield: 91%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][NH+:6]=[C:5]([CH2:9]Cl)[C:4]=1[O:11][CH3:12].[F:13][CH:14]([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]2[NH:20][C:21]([SH:23])=[N:22][C:18]=2[CH:17]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>O>[OH2:11].[F:26][CH:14]([F:13])[O:15][C:16]1[CH:25]=[CH:24][C:19]2[NH:20][C:21]([S:23][CH2:9][C:5]3[C:4]([O:11][CH3:12])=[C:3]([Cl:2])[CH:8]=[CH:7][N:6]=3)=[N:22][C:18]=2[CH:17]=1
Reactant: FC(F)Oc1ccc2[nH]c(S)nc2c1
Reactant: COc1c(Cl)cc[nH+]c1CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(Cl)ccnc1CSc1nc2cc(OC(F)F)ccc2[nH]1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 4.6 %

Procedure:
At 55-65° C., a solution of 4-chloro-2-chloromethyl-3-methoxypyridinium chloride (10.0 kg, 43.8 mol) in water (20 L) was added over 2-3 h to a mixture of 5-difluoromethoxy-1H-benzimidazole-2-thiol (8.84 kg, 40.9 mol), toluene (43 L), water (21 L) and 40% aqueous NaOH (10.3 kg, 103 mol). Stirring at 60° C. was continued for 2-3 h before the reaction mixture was cooled to 10-15° C. The precipitate was centrifuged off, washed with toluene (16 L) and re-pulped in water (122 L). Centrifugation followed by an aqueous rinse (32 L) and drying at 35° C. in vacuo gave 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole mono hydrate (KF=4.6%) as an off-white solid (m. p. 95-99° C.); yield 14.2 kg (92%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]=[CH:21][C:5]2=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]3=1)[NH:7]2.[H-].[Na+].[CH3:29]OS(OC)(=O)=O>CN(C)C=O>[CH3:29][O:1][C:2]1[CH:3]=[C:4]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]=[CH:21][C:5]2=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]3=1)[NH:7]2
Reactant: CC1(C)C=Cc2c(cc(O)c3c(=O)c4c(ccc5ccccc54)[nH]c23)O1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(c3[nH]c4ccc5ccccc5c4c(=O)c13)C=CC(C)(C)O2
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 300 mg of compound of Example 1 in 15 ml of anhydrous dimethylformamide is added dropwise to a suspension of 125 mg of sodium hydride in 10 ml of anhydrous dimethylformamide previously cooled to 0° C. The reaction mixture is maintained at 0° C. for 15 minutes, at room temperature for 30 minutes and then 0.57 ml of dimethylsulfate are added. After 17 hours, the reaction mixture is poured into 150 ml of ice-cold water and extracted with dichloromethane (3×50 ml). The combined organic phases are dried over anhydrous sodium sulphate and then filtered and evaporated to dryness under reduced pressure. Chromatography over silica gel (cyclohexane and then a gradient of acetone 5 to 20%) allowing the expected product to be obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.[OH-].[K+]>O>[C:1]([O:5][C:6](=[O:9])[C@H:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 1 h
Yield: 26.2 %

Procedure:
The benzaldehyde Schiff base of glycine tert-butyl ester (compound 9) (0.44 g; 2 mmol), benzyl bromide (0.32 g; 1.9 mmol), and N-(9-anthracenylmethyl)cinchonidium chloride (compound 10) (107 mg; 0.2 mmol) were added to toluene (4 mL), and the mixture was stirred vigorously (1400 rpm) with ice-salt cooling. When the internal temperature thereof had dropped to −5° C. or less, 48% KOH aqueous solution (0.46 g; 4 mmol, 2 equivalents) was added thereto. The mixture was stirred for one hour while maintaining the internal temperature between −5° C. and −2° C. Distilled water (10 mL) was added thereto and the toluene layer was collected, and then the alkylated Schiff base (compound 11) was extracted with toluene (10 mL×2). Thus obtained toluene layers were combined with the toluene layer collected previously, 1 N hydrochloric acid (10 mL) was added thereto, and the mixture was stirred at room temperature for one hour. The aqueous layer was collected by separation, and then the aqueous layer was washed with toluene (10 mL), and sodium carbonate was added thereto carefully to avoid too vigorous bubbling until pH of the solution reached not lower than 11 (confirmed by universal pH test paper). The mixture was extracted with ethyl acetate (10 mL×3) to collect the ethyl acetate layer. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to give (S)-phenylalanine tert-butyl ester (compound (S)-12) (0.11 g; yield 25%, optical purity 80% ee). The optical purity of the compound 12 was measured by HPLC under the following conditions:
Reaction SMILES: [C:1]([C:4]1[C:5]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:42][CH:41]=2)=[N:6][N:7]2[C@H:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:39])/[CH:20]=[CH:21]/[CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:25][CH2:24]4)[CH2:15][CH2:14]3)[CH2:11][CH2:10][NH:9][C:8]=12)(=[O:3])[NH2:2].[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C(Cl)Cl>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[NH2:31][CH2:30][CH2:29][N:26]1[CH2:25][CH2:24][N:23]([CH2:22]/[CH:21]=[CH:20]/[C:19]([N:16]2[CH2:15][CH2:14][CH:13]([C@H:12]3[N:7]4[N:6]=[C:5]([C:40]5[CH:45]=[CH:44][C:43]([O:46][C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)=[CH:42][CH:41]=5)[C:4]([C:1]([NH2:2])=[O:3])=[C:8]4[NH:9][CH2:10][CH2:11]3)[CH2:18][CH2:17]2)=[O:39])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C/C=C/C(=O)N2CCC([C@@H]3CCNc4c(C(N)=O)c(-c5ccc(Oc6ccccc6)cc5)nn43)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1CCN(C/C=C/C(=O)N2CCC([C@@H]3CCNc4c(C(N)=O)c(-c5ccc(Oc6ccccc6)cc5)nn43)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S,E)-tert-butyl (2-(4-(4-(4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate (150 mg, 0.21 mmol) in 10 mL of DCM was added 2 mL of TFA. The reaction mixture was stirred at RT for 15 hr and concentrated to remove the solvent. The residue was used in the next step without further purification. MS (ESI) m/e [M+1]+ 613.0.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C@H:6]([CH3:10])[CH2:5]1.[CH3:11][C:12]([O:15][C:16]([N:18]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:19]([C:27]1[C:32]([F:33])=[C:31](Cl)[N:30]=[C:29]([Cl:35])[N:28]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:14][C:12]([O:15][C:16]([N:18]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:19]([C:27]1[C:32]([F:33])=[C:31]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C@H:6]2[CH3:10])[N:30]=[C:29]([Cl:35])[N:28]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])([CH3:11])[CH3:13]
Reactant: C[C@@H]1CN(C)CCN1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To (3R)-1,3-dimethylpiperazine dihydrochloride (102.22 g, 546.3 mmol) was added a solution of tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (271.71 g, 546.3 mmol) in DMF (900 mL). The mixture was cooled to 0° C., and N,N-diisopropylethylamine (295 mL, 1694 mmol) was added. The solution was stirred and warmed to room temperature overnight. The solution was then diluted with Et2O (1000 mL) and washed with water (1000 mL). The aqueous phase was extracted with a fresh portion of Et2O (1000 mL), and the combined organic phase was washed with water (2×500 mL). The organic phase was then diluted with DCM (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was filtered through a silica gel plug (30% EtOAc in hexanes; 1% Et3N). The solution was then concentrated in vacuo, and the residue was azeotroped with MeOH. The residue was diluted with MeOH (1000 mL), and crystallized by addition of water. The resulting solid was collected by vacuum filtration and washed with 10% MeOH in water. The resulting yellow solid was dried at 50° C. under high vacuum to give tris(1,1-dimethylethyl)2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (257.34 g, 82% yield) as a light yellow solid. LCMS: (M+H)+: 575.2.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:19][C@H:18]([C:20]([O:22]C)=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1.O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:19][C@H:18]([C:20]([OH:22])=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (5R)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate (D8, 120 mg, 0.38 mmol) in THF (2.3 ml) was added LiOH monohydrate (26 mg, 0.61 mmol) dissolved in water (1.1 ml) followed by methanol (1.1 ml). The resulting solution was stirred at room temperature for 3 hours (hydrolysis being monitored by HPLC). When hydrolysis was complete, the organic solvent was evaporated under reduced pressure (maintaining the temperature at 38° C.) to give a crude aqueous residue containing the title compound; Rt (HPLC)=3.63 min; MS: (ES/+) m/z: 298 [MH+], C18H19NO3 requires 297).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][OH:27])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCO)ccc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCOS(C)(=O)=O)ccc23)CC1
Reaction time: 4 h

Procedure:
To a mixture of 4-[7-(2-hydroxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.24 mmol) and DIPEA (167.2 μL) in CH2Cl2 (5 mL) was added MsCl (37.2 μL). The reaction mixture was stirred for 4 h and the solvents were evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc as eluent) to afford almost pure product. 1H NMR (CDCl3) δ 9.15 (s, 1H), 8.09 (d, J=9.33 Hz, 1H), 7.33 (d, J=2.44 Hz, 1H), 7.29 (dd, J=9.18 and 2.59 Hz, 1H), 4.66 (t, J=4.29 Hz, 2H), 4.42 (t, J=4.39 Hz, 2H), 4.33 (m, 2H), 3.61 (m, 1H), 3.11 (s, 3H), 2.94 (m, 2H), 1.83-2.10 (4H), 1.48 (s, 9H). Calcd for C21H30N3O6S (MH+) 452.2, found 452.2.