Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]2[S:41][C:22]3=[N:23][C:24]([N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[CH:25][C:26](=[O:27])[N:21]3[N:20]=2)[CH:16]=[CH:15][N:14]=1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]2[S:41][C:22]3=[N:23][C:24]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:25][C:26](=[O:27])[N:21]3[N:20]=2)[CH:16]=[CH:15][N:14]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(2-(2-(2-((tert-butoxycarbonyl)amino)acetamido)pyridin-4-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (50 mg, 0.085 mmol) in DCM (1 ml) is added TFA (0.25 ml) and the mixture is stirred at room temperature for 2 h. The solvent is removed in vacuo and the residue is directly purified through preparative HPLC to give the desired 2-Amino-N-(4-(5-oxo-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)pyridin-2-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.10-8.60 (br.s., 2H), 8.61 (d, J=5.1 Hz, 1H), 8.58 (s, 1H), 8.35-8.05 (br.s., 3H), 7.66 (dd, J=5.1, 1.6 Hz, 1H), 5.63 (s, 1H), 3.92 (s, 2H), 3.79 (t, J=4.7 Hz, 4H), 3.19 (t, J=4.7 Hz, 4H); LC/MS: tR=2.163 min; HRMS: m/z (M+H+)=387.1346 (Calculated for C16H19N8O2S=387.1352).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:16]4[C:17]([NH2:21])=[N:18][CH:19]=[CH:20][C:15]=4[O:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:16]4[C:17]([NH2:21])=[N:18][CH:19]=[CH:20][C:15]=4[O:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:32]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine 2HCl (688 mg, 2.016 mmol), 2,5-difluorophenylacetic acid (354 mg, 2.057 mmol), HATU (844 mg, 2.220 mmol), and Hunig's base (1.4 mL, 8.02 mmol) in N,N-Dimethylformamide (DMF) (15 mL) was stirred at room temperature for 17 hr. HPLC indicated complete conversion, so the mixture was poured into water (75 mL), the suspension was stirred for about 10 minutes, and the precipitate was collected by vacuum filtration and dried by suction to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (834 mg, 2.057 mmol, 102% yield) as a tan solid. LC/MS (ES) m/z=406 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=8.34 Hz, 2H), 3.96 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.52 (s, 2H), 6.93 (d, J=5.81 Hz, 1H), 7.14-7.34 (m, 4H), 7.41 (s, 1H), 7.87 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.13 (d, J=8.08 Hz, 1H).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.C(=O)([O-])O.[Na+].[NH2:14][C:15]1[C:16](=[O:24])[N:17]([CH3:23])[C:18]([S:21][CH3:22])=[N:19][N:20]=1>CC(O)C.CO.O>[CH3:23][N:17]1[C:16](=[O:24])[C:15]2=[N:14][CH:3]=[CH:4][N:20]2[N:19]=[C:18]1[S:21][CH3:22]
Reactant: COC(CBr)OC
Reactant: CSc1nnc(N)c(=O)n1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CSc1nn2ccnc2c(=O)n1C
Temperature: 25 °C
Yield: 47.4 %

Procedure:
Bromoacetaldehyde dimethyl acetal (2.57 g, 13.1 mmol), 48% hydrobromic acid (1.06 g, 13.1 mmol) and water (1.5 ml) were heated at 95° C. for 1.5 h. The mixture was allowed to cool to ambient temperature, diluted with propan-2-ol (20 ml) then treated with sodium hydrogen-carbonate (1.46 g, 17.4 mmol) added in portions over 5 min. The mixture was filtered and the filtrate was added to 6-amino-4-methyl-3-methylsulfanyl-4H-[1,2,4]triazin-5-one (1.50 g, 8.71 mmol). The resulting suspension was heated at 95° C. for 18 h. The mixture was allowed to cool to ambient temperature, diluted with methanol (100 ml) and evaporated onto silica. The product was purified by flash column chromatography on silica eluting with dichloromethane (+0.1% 0.880 ammonia) on a gradient of methanol (3-6%). Collecting appropriate fractions gave 3-methyl-2-methylsulfanyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one (0.81 g, 47%) as a pale yellow solid: δH (400 MHz, CDCl3) 2.61 (3H, s), 3.58 (3H, s), 7.49 (1H, d, J1), 7.52 (1H, d, J1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:41][C:42]1([CH3:50])[C:44]([CH3:46])([CH3:45])[CH:43]1[C:47](O)=[O:48]>CCOC(C)=O.C1COCC1.CCN(CC)CC>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:47]([CH:43]3[C:44]([CH3:46])([CH3:45])[C:42]3([CH3:50])[CH3:41])=[O:48])[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)Nc2nc3ccc(F)cc3s2)C1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-fluoro-benzothiazol-2-ylamine (1 equiv), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1 equiv), 1-hydroxybenzotriazole, triethylamine (1.1 equiv), and 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.8 equiv) in 3:1 THF/Et3N (1 M) and were stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Puried by silica gel chromatography afforded the title compound. MS (ESI+) m/z 293 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1/C=C\CCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A solution of tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperazine-1-carboxylate (0.0672 g, 0.127 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(Z)-4-(piperazin-1-yl)but-1-enyl]benzofuran-3(2H)-one (0.0412 g, 75%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O.[Si](C#N)(C)(C)C.[N:29]1([C:34](N2C=CN=C2)=[O:35])C=CN=[CH:30]1>[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:16]([C:15]4[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:13]([O:12][CH3:11])[CH:14]=4)[CH2:30][NH:29][C:34]3=[O:35])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2[nH]cnc2c1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: COc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1OC

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.400 g, 3 mmol), 3,4-dimethoxybenzaldehyde (0.5 g, 3 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1.05 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.730 g, 4.5 mmol) as described in method 2 to give 1-(1H-benzo[d]imidazol-5-yl)-5-(3,4-dimethoxyphenyl)imidazolidin-2-one
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37].[OH-].[Na+].CC(O)C>C(Cl)Cl>[OH:37][CH2:36][CH:35]([NH:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)[CH2:38][OH:39]
Reactant: NC(CO)CO
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(CCl)cc2)ncc1C(F)(F)F)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(c1ncccc1CNc1nc(Nc2ccc(CNC(CO)CO)cc2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
A mixture of 7 (100 mg, 0.200 mmol), 2-amino-1,3-propanediol (90.9 mg, 0.998 mmol), sodium hydroxide (7.98 mg, 0.200 mmol) and 2-propanol (0.5 mL) was heated to reflux. After 30 minutes the mixture was cooled, treated with DCM, and washed with water. The organic phase was dried over MgSO4, filtered and concentrated. The resultant residue was then purified by column chromatography (silica gel; eluting with 6% MeOH/DCM with NH4OH), and the eluents containing the product were combined and concentrated to provide 8 as a white solid. Yield: 60.9 mg, 55%. MS+ 556.2. 1H NMR (500 MHz, d6-DMSO) δ: 9.48 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.59 (m, 2H), 7.34 (m, 3H), 6.99 (d, 2H), 4.75 (d, 2H), 4.35 (t, 2H), 3.58 (s, 2H), 3.34 (m, 4H), 3.12 (s, 3H), 3.09 (s, 3H), 2.45 (m, 1H). FAK IC50: <0.000595 μM (Table 1, Example 389)
Reaction SMILES: [K].[CH:2]1([S:5]([N:8]2[C:12]3[C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]([F:21])=[C:19]([F:20])[C:11]=3[N:10]([C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])C2=O)(=[O:7])=[O:6])[CH2:4][CH2:3]1.C(OCC)(=O)C>C1COCC1.CCCCCC>[F:21][C:18]1[C:14]2[N:15]=[CH:16][O:17][C:13]=2[C:12]([NH:8][S:5]([CH:2]2[CH2:4][CH2:3]2)(=[O:7])=[O:6])=[C:11]([NH:10][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:19]=1[F:20]
Reactant: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)c3ncoc3c2n1S(=O)(=O)C1CC1
Agent: [K]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
Potassium trimethylsilonolate (29 mg, 0.182 mmol) was added to a solution of 8-cyclopropanesulfonyl-4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-19a: 65 mg, 0.121 mmol) in THF (5 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was concentrated and the concentrate was dissolved in water, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (25-35% ethyl acetate in hexane) afforded 18 mg of the product (29.5% yield).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:11]N(C)C)[CH2:7][N:8]([CH3:10])[CH3:9])=O)C.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)[O-].[Na+]>C(O)(C)C>[CH3:9][N:8]([CH2:7][CH:6]1[CH2:11][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:22][C:4]1=[O:3])[CH3:10]
Reactant: CCOC(=O)C(CN(C)C)CN(C)C
Reactant: NNc1ccccc1
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)CC1CN(c2ccccc2)NC1=O

Procedure:
Ethyl-1,3-bis (dimethylamino)-propane-2-carboxylate (20.2g) was added in one portion to a boiling mixture of phenyl-hydrazine (10.8g) and sodium isopropoxide (2.3g of sodium) in isopropanol. The solution was boiled under reflux for 30 minutes and the product (13.6g, 62%) was recovered in a manner similar to that described in Example 16. The product was identified as 4-dimethylaminomethyl-1-phenylpyrazolidin-3-one (melting point 117°-8° C) from its infrared spectrum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]#[N:13])=[C:6]([O:14][CH3:15])[CH:5]=1.Cl.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([CH2:12][NH2:13])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(C#N)c(OC)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(OC)c(CN)c(OC)c1
Reaction time: 5 h

Procedure:
30 G. of 4-cyano-3,5-dimethoxy-benzoic acid methyl ester and 1500 ml. of methanol and 150 ml. of 1N hydrochloric acid is hydrogenated in the presence of 10 g. of palladium-on carbon 10% at room temperature and under atmospheric pressure. In about 5 hours, 2 moles of hydrogen are taken up. The solution is freed of the catalyst by filtration, evaporated to dryness and the residue is taken up in a little water. The solution is thereafter filtered, saturated with solid potassium carbonate and shaken with benzene. From the shaken benzene mixture, is obtained 4-(aminomethyl)-3,5-dimethoxy-benzoic acid methyl ester, which after recrystallization from high boiling petroleum ether has a m.p. of 81°-83°.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[O:28][C:29]=1[CH3:30]>>[Cl:37][C:33]1[CH:32]=[C:31]([C:27]2[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:15]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=3)[N:26]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Product: Cc1oc(-c2cccc(Cl)c2)nc1CN(CC(F)(F)F)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
In analogy to example 22.2, from 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol and 4-chloromethyl-5-methyl-2-(3-chloro-phenyl)-oxazole was prepared 2-{4-[[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow solid, MS: 547 (MH+, 1Cl).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=4)=[CH:35][CH:36]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Methyl 3-[4-({4-[(2-phenyl-1H-indol-1-yl)methyl]benzyl}oxy)phenyl]propanoate (0.17 g, 0.36 mmol) was dissolved in a mixed solution of methanol (4 mL) and tetrahydrofuran (8 mL), and 1 N aqueous sodium hydroxide solution (0.71 mL) was added with stirring at room temperature. The mixture was stirred at the same temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture washed successively with 5% aqueous potassium hydrogensulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate=4/1 to give the title compound (0.15 g, yield 88%) as colorless crystals. MS (APCI−): 460 (M−H), 1H NMR (CDCl3) δ: 2.63 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 4.97 (2H, s), 5.36 (2H, s), 6.65 (1H, s), 6.87 (2H, d, J=8.7 Hz), 7.03 (2H, d, J=8.1 Hz), 7.07-7.19 (5H, m), 7.28-7.47 (7H, m), 7.67 (1H, m).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13]C(C)(C)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][CH:9]([CH2:10][OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(OCc2ccccc2)CO1
Solvent: CO
Product: OCC(CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a methanol (50 ml) solution of the 5-(benzyloxy)-2,2-dimethyl-1,3-dioxane (6.5 g, 29.2 mmol) obtained in the step (9b), DOWEX® 50W-X8 (5 g) was added and stirred at room temperature. After 2 hours, the reaction mixture was filtered and concentrated to obtain the title compound (5.0 g, 93.8%) as a colorless oil.
Reaction SMILES: C[Si](C)(C)CCOC[NH:7][C:8]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)=[O:9]>C(#N)C.O>[C:27]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13]3[N:14]=[C:10]([C:8]([NH2:7])=[O:9])[NH:11][N:12]=3)[CH:16]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCOCNC(=O)c1n[nH]c(-c2cccc(-c3ccccc3-c3ccccc3)c2)n1
Solvent: CC#N
Solvent: O
Product: NC(=O)c1nc(-c2cccc(-c3ccccc3-c3ccccc3)c2)n[nH]1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.035 g of 2-Trimethylsilylethoxymethyl-5-[2′-(Phenyl)biphenyl-3-yl]-1,2,4-triazole-3-carboxamide in 3 mL of acetonitrile and 9 mL of a 50% solution of HF in water was stirred at rt for 6 hours. The reaction mixture was then concentrated and the residue was purified by chromatography (silica, CH3OH: CH2Cl2 0-5% gradient) to give the title compound.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B.C1COCC1.[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][C:37]([CH3:46])([C:42]([F:45])([F:44])[F:43])[CH2:36][C:35]2=[O:47].Cl>C1(C)C=CC=CC=1>[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][C:37]([CH3:46])([C:42]([F:43])([F:45])[F:44])[CH2:36][C@H:35]2[OH:47]
Reactant: CC1(C(F)(F)F)CC(=O)c2cc(Br)ccc2O1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C(F)(F)F)C[C@@H](O)c2cc(Br)ccc2O1
Reaction time: 0.25 h

Procedure:
To a cooled (ice bath) solution of (s)-2-methyl-cbs-oxazaborolidine 1.0 M in toluene (100 μl, 100 μmol) was added borane-dimethyl sulfide 2.0 M in THF (500 μl, 1000 μmol). After stirred 15 min, a solution of 6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-one (309 mg, 1000 μmol) in toluene was added drop wise. The reaction was completed after stirring 9 h at 0° C. 2N HCl was added slowly to quench the reaction. The resulted mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[NH2:12][CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(O)(C)C.C(N(CC)CC)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:12][CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:7][C:6]=12
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Clc1ccn2ncc(Br)c2n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(CCNc1ccn2ncc(Br)c2n1)C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 82 %

Procedure:
To 465 mg (2.00 mmol) of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine was added tert-butyl (2-aminoethyl)(methyl)carbamate (522 mg, 3.00 mmol), 4 mL of isopropanol, and triethylamine (0.56 mL, 4.00 mmol). The resulting mixture is heated at 140° C. for 0.5 hr in the microwave. It was diluted with EtOAc, and washed with water and brine. The organic layer was dried over MgSO4, concentrated and purified on the silica gel column eluting with 20-100% EtOAc/Hex to obtain 607 mg (82%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[OH:15])[C:6]([F:14])([F:13])[O:7][C:8]2([F:11])[F:12])=[O:20]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1F
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 1.5 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.95 g of 3-fluoroisonicotinic acid, 1.68 g of WSC and 13 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.46 g of 3-fluoro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[N:7]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[O-:34][C:35]#[N:36].[K+]>O>[C:23]1([C:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:7]3[C:6](=[O:29])[C:5]4[C:10](=[CH:11][C:2]([NH:1][C:35]([NH2:36])=[O:34])=[CH:3][CH:4]=4)[NH:9][C:8]3=[O:12])[CH2:18][CH:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Reaction time: 3 h
Yield: 27.7 %

Procedure:
To a mixture of 7-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.39 g), acetic acid (5 ml) and water (10 ml) was added a solution of potassium cyanate 0.16 g) in water (2 ml) and the resulting mixture was stirred for additional 3 hours. The reaction mixture was poured into water and precipitated solid was filtered, washed in turn with water and ethanol and dried to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-ureido-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.12 g).