Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]\[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:30](O)(=O)C.C(=O)([O-])O.[Na+]>CO>[OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]\[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([O:25][CH3:30])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)O
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1(CCCCOc2ccccc2)C=C(SC)C(=O)C1=C/C=C\C(O)CCCO
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of 2 mg of 5-[(Z)-4,7-dihydroxy-2-heptenylidene]-2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 85 dissolved in 1 ml of methanol was added 0.5 μl of acetic acid, and the mixture was stirred for 24 hours. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated, followed by silica gel chromatography to give 1.9 mg (yield 95%) of 5-[(Z)-4,7-dihydroxy-2-heptenylidene]-2-methylthio-4-methoxy-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [N:1]1([CH:6]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO.O>[N:1]1([CH:6]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCC(CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(CCCCCCCCCCCCC(=O)O)n1ccnc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
Diethyl 2-(12-(1H-imidazol-1-yl)hexadecyl)malonate (415 mg, 0.9209 mmol) was dissolved in a 3:1 mixture of methanol (9 ml) and water (3 ml), cooled to 0° C. then NaOH (147 mg, 3.684 mmol) was added and the reaction mixture stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH, cooled to 0° C. to 5° C., the pH adjusted to 5, extracted with DCM (3×25 ml), dried on dry MgSO4, and concentrated under reduced pressure. The crude compound was obtained as a light yellow color liquid. This crude compound was heated at 170° C. to remove one carboxyl acid group from the di-carboxylic acid by the evolution of CO2. The crude product was then purified by silica gel column (3 to 5% of MeOH in DCM) to give 14-(1H-imidazol-1-yl)octadecanoic acid (221 mg, 68%) as a pale yellow gummy liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[O:8][CH2:7][CH2:6]2.[CH3:18][O:19]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:18]=[O:19])[C:9]([CH3:17])([C:13]([F:16])([F:14])[F:15])[O:8][CH2:7][CH2:6]2
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)C(C)(C(F)(F)F)OCC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a stirred solution of 6-methoxy-1-methyl-1trifluoromethylisochroman (460 mg) in dry dichloromethane (5 ml) was added titanium(IV) chloride under nitrogen at −78° C. After 15 minutes, to the yellow solution was added a solution of dichloromethyl methyl ether in dry dichloromethane at the same temperature. The reaction mixture was stirred at −78° C. for one hour, poured onto ice water, and stirred at room temperature for 30 minutes. The aqueous layer was extracted with methylene chloride. The extracts were washed with brine, dried over magnesium sulfate, and concentrated to give a crude product. This was purified by silica-gel column chromatography eluted with a gradient of hexane and ethyl acetate (10:1, 8:1, 6:1) to give the title compound (179 mg, 48.3% from 1,1,1-Trifluoro-2-(4-methoxy-2-(2-(tetrahydropyran-2-yloxy)ethyl)phenyl)-propan-2-ol). 1H-NMR(CDCl3): 10.41 (s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 4.19-4.11 (m, 1H), 3.94 (s, 3H), 3.94-3.87 (m, 1H), 2.91 (t, J=4.4 Hz, 2H), 1.67 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4c(ccn4C)c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (400 mg, 1.24 mmol), (prepared as described for the starting material in Example 9), potassium carbonate (500 mg, 3.62 mmol), 5-hydroxy-1-methylindole (231 mg, 1.57 mmol), (prepared as described for the starting material in Example 291), and DMA (5.0 ml) for 5 minutes. The mixture was then stirred at 90° C. for 3 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography, gradient elution, with dichloromethane/methanolic ammonia (7M), (100/0 to 90/10) to give 6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)prop oxy)quinazoline (247 mg, 44%).
Reaction SMILES: [CH2:1]([N:3]([CH3:27])[C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([O:23]CC)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH2:1]([N:3]([CH3:27])[C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)CC)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 5-(2-(ethyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (366 mg, 985 μmol) and lithium hydroxide hydrate (82.7 mg, 1.97 mmol) in methanol (15 ml) and water (5 ml) was stirred for 5 hours at 50° C. The methanol was evaporated, the residue was diluted with water and was then neutralized with hydrochloric acid 1N (1.97 ml, 1.97 mmol). The precipitated white solid was filtered off, washed with water several times and dried affording 5-[2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid (306 mg, 90.4%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][C:19]3[C:18]([CH3:27])([CH3:26])[CH2:17][CH2:16][C:15]([CH3:29])([CH3:28])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>CO.C(OCC)C>[OH:25][CH2:24][CH2:23][CH2:22][C:21]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=2)=[CH:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][CH2:17][C:18]([CH3:26])([CH3:27])[C:19]=2[CH:20]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2CCCO)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(CCCO)c(/C=C/c3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a solution of 27.0 g (0.66 mmol) of Methyl-4-{(E)-2-[3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate in 10 mL of methyl alcohol was added 5 mL of 1 N LiOH. The reaction mixture was heated to reflux. After 4 hours, the reaction mixture was cooled to room temperature, diluted with diethyl ether and acidified with concentrated HCl. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by crystallization (hexane/ethyl acetate) to give 200 mg (76%) of 4-{(E)-2-[3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoic acid (m.p.: 212.8-213.2° C.) 12.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([O:27][CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>B(F)(F)F.CCOCC.C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([C:24]1[CH:25]=[CH:26][C:21]([O:27][CH3:28])=[CH:22][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(OC)cc1

Procedure:
A solution of 290 mg. (1 mmol.) of N-t-butyoxycarbonyl-2-acetoxyglycine n-butyl ester, 0.5 ml. of anisole and 3 drops of boron trifluoride etherate in 5 ml. of methylene chloride was stirred at 25° for 4 hours. The solvent was removed and the residue was chromatographed on silica gel and eluted with 1:1 chloroform-hexane to give the title compound.
Reaction SMILES: CS[C:3](=[N:6][C:7]#[N:8])[S:4][CH3:5].[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1>>[C:7]([NH:6][C:3](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[S:4][CH3:5])#[N:8]
Reactant: NCCSCc1nccs1
Reactant: CSC(=NC#N)SC
Product: CSC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of dimethylcyanodithioimidocarbonate with 2-[(2-aminoethyl)thiomethyl]thiazole by the method described in Example 3(d) gave N-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea. Fusion of this compound (2.15 g) with 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (2.02 g) on the steam bath for 6 hours, followed by chromatographed purification on a column of silica gel with ethyl acetate/isopropyl alcohol (5:1) as eluant afforded the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[ClH:10].[CH3:11][CH2:12]O>>[ClH:10].[CH2:11]([O:8][C:7](=[O:9])[C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1)[CH3:12]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
Trans-4-hydroxy-L-proline was treated with EtOH and HCl gas, and the mixture was evaporated to give trans-4-hydroxy-L-proline ethyl ester hydrochloride. This product was treated with TsCl in pyridine, to give after aqueous workup N-(toluene-4-sulfonyl)-trans-4-(O-(toluene-4-sulfonyl))-L-proline ethyl ester. This product was treated with PhSH and DBU in DMF to give after aqueous workup and flash chromatography on silica gel, N-(Toluene-4-sulfonyl)-cis-4-(phenylthio)-L-proline ethyl ester. This product was treated with NaOH in CH3OH and H2O, to give after acidification, extraction, drying with MgSO4, filtration and evaporation, N-(toluene-4-sulfonyl)-cis-4-(phenylthio)-L-proline. This product was treated with HCl.Phe-OMe, BOP, and NMM in DMF, to give, after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-cis-4-(phenylthio)-Pro-Phe-OMe. This product was treated with NaOH in CH3OH and H2O, to give, after acidification, extraction, drying with MgSO4, filtration and evaporation, the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.CC([O:16][C:17](OC(OC(C)(C)C)=O)=[O:18])(C)C.[Li]CCCC.C(=O)=O>C1COCC1.CN(C)C1C=CN=CC=1>[NH2:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[C:17]([OH:18])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
4-(trifluoromethyl)aniline (25 g, 0.15 mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET3N (19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried and concentrated. The resulting product was recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol) was dissolved in THF (350 mL) and cooled to −78° C. under nitrogen, then treated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0° C. and held for 1.5 h. The mixture was poured onto excess solid CO2 and stirred overnight at RT. After partitioning against 1 M HCl, the THF layer was evaporated and the residue dissolved in EtOAc, washed with 1 M HCl, then dried and concentrated. The solid product was triturated with hexan to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution/drying process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z (obs, M−H)=204.0.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>O1CCOCC1.O>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: NC(C(=O)O)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(CCCCl)NC(C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
2-Amino-2-phenylacetic acid (1.00 g, 6.62 mmol) and TEA (2.77 ml, 19.8 mmol) were dissolved in a mixture of dioxane (13.2 ml) and water (13.2 ml). The mixture was cooled at 0° C. with an ice-bath and 4-chlorobutanoyl chloride (814 μl, 7.28 mmol) was added dropwise. The mixture was stirred at the same temperature for 1 hour and then dioxane was evaporated. The aqueous solution was acidified with 1N HCl and then was extracted three times with EtOAc (20 ml×3). The organic phase was dried (Na2SO4) and evaporated. The crude pale yellow oil was purified by flash chromatography (DCM/MeOH=9/1) and the collected compound was triturated with Et2O (about 15 ml) to obtain the title compound (658 mg, 38.9% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1=c2cnc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of Example 69e (0.02 g, 0.053 mmol), triethylamine (53.6 mg, 0.53 mmol), and acetyl chloride (0.019 mL, 0.265 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 2 hours. Additional acetyl chloride (0.057 mL, 0.795 mmol) and triethylamine (161 mg, 1.59 mmol) were added, and the reaction mixture was stirred for additional 3 hours. The solvent was evaporated, and the residue was treated with dioxane (3 mL) and 2.0 NaOH (1 mL). The reaction mixture was heated at 80° C. for three hours. The solvents were partially removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC(C18, CH3CN/water (0.1% TFA), 0-100%) to afford 0.018 g (67.3%) of the title compound as the TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 10.87 (d, J=5.8, 1H), 10.31 (s, 1H), 8.53 (d, J=2.75 Hz, 1H), 8.42 (d, J=2.44 Hz, 1H), 7.74 (s, 1H), 7.09 (d, J=5.49 Hz, 1H), 7.03-7.07 (m, 2H), 6.57-6.60 (m, 2H), 4.65 (br s, 2H), 4.07 (s, 3H), 2.13 (s, 3H). MS (DCI+) m/z 420.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([F:12])[C:7]=1[O:8]COC.Cl.O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([F:12])[C:7]=1[OH:8]
Reactant: CCOC(=O)CCc1cc(F)c(OCOC)c(F)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 3,5-difluoro-4-(methoxymethoxy)benzenepropanoate (2.3 g, 8.4 mmol) in ethanol (12 mL) was added hydrochloric acid (0.5 mL), and the mixture was stirred at 50° C. for 1 hour. After the reaction solution was returned to room temperature, water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=9:1 to 1:1) to give the title compound (1.7 g, yield 88%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])=[CH:29][CH:28]=2)O1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])=[CH:29][CH:28]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(=O)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butan-2-one according to Method C (Example 178). Yield: 217 mg (71%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[Br:11][C:8]1[CH:9]=[N:10][C:2]2[N:1]=[C:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:7]=1
Reactant: NC(=O)c1cc(Br)cnc1N
Reactant: O=Cc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2cccc(F)c2)nc2ncc(Br)cc12
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
A mixture of 2-amino-5-bromonicotinamide (100 mg, 0.46 mmol), 3-fluorobenzaldehyde (69 mg, 0.56 mmol), NaHSO3 (40 mg, 0.38 mmol), 4-methylbenzene sulfonic acid (15 mg, 0.05 mmol) in DMAc (3 mL) was stirred at 115° C. for 1.5 h, then additional NaHSO3 (40 mg, 0.38 mmol) was added to the mixture. After 1.5 h, the third portion of NaHSO3 (40 mg, 0.38 mmol) was added to the mixture. After being stirred overnight at 115° C., the reaction mixture was concentrated in vacuo, suspended in water and filtered to give the product of 6-bromo-2-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (70 mg, yield: 47%), which was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 13.04 (br s, 1H), 9.07 (d, J=2.8 Hz, 1H), 8.65 (d, J=2.8 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.02 (dd, J=9.6, 1.6 Hz, 1H), 7.60˜7.68 (m, 1H), 7.45˜7.54 (m, 1H). MS (M+H)+: 320/322.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]3[S:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[CH2:5][C@@H:4]([CH2:18][CH2:19][CH2:20][NH:21][C@H:22]2[C:32]3[C:33]4[N:24]([C:25](=[O:34])[CH:26]=[N:27][C:28]=4[CH:29]=[CH:30][CH:31]=3)[CH2:23]2)[O:3]1.[BH4-].[Na+]>CO.ClCCCl>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]3[S:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[CH2:5][C@@H:4]([CH2:18][CH2:19][CH2:20][NH:21][C@H:22]2[C:32]3[C:33]4[N:24]([C:25](=[O:34])[CH2:26][NH:27][C:28]=4[CH:29]=[CH:30][CH:31]=3)[CH2:23]2)[O:3]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CCCN[C@@H]4Cn5c(=O)cnc6cccc4c65)OC3=O)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: O=C1CSc2ccc(N3C[C@@H](CCCN[C@@H]4CN5C(=O)CNc6cccc4c65)OC3=O)cc2N1
Yield: 78 %

Procedure:
A solution of the compound of Example 48 (33 mg) in MeOH/DCE (5 mL; 4:1) was treated with NaBH4 (3 mg) for 30 min then quenched with 1M HCl (1 mL) and partitioned between DCM and an aq. NH4OH solution. The org. layer was washed with water and brine, dried over MgSO4 and purified by CC (EA/MeOH 19:1 to 9:1 containing 1% NH4OH) affording a colourless solid (26 mg; 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.ClC[CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:42][CH2:43][N:38]3[CH2:37][CH2:41][CH2:40][CH2:39]3)=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3c2CCCC3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)c(C)c2)c2cccc3c2CCCC3)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxy-phenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane (330 mg, 0.001 mol), anhydrous. K2CO3 (2.0 gm, 0.14 mol), 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002 mol) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent to give the title compound of formula I. Yield 210 mg. (7.19%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CCO>[F:41][C:38]([F:39])([F:40])[C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(C(F)(F)F)c5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(C(F)(F)F)c5)n4)n[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (4-{3-[2-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (80 mg, 0.14 mmol) in EtOH (4 mL) was added conc. HCl (4 mL). The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford N-{3-[2-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 40 mg, 50.0%).