Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=1)C1C=CC=CC=1.Cl>[C].[Pd].CO>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=1
Reactant: CC(C)(C)Nc1nc(NCc2ccccc2)c(F)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)Nc1nc(N)c(F)cc1F
Reaction time: 24 h
Yield: 44.7 %

Procedure:
To 60 ml of methanol were added 10.7 g of the crude 2-benzylamino-6-(t-butylamino)-3,5-difluoropyridine as described above together with 1.10 g of 10% palladium carbon and 3.8 g of concentrated hydrochloric acid, and the mixture was hydrogenated for one day. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 150 ml of chloroform, and the mixture was washed with 80 ml of 10% aqueous solution of sodium carbonate, and the washings were extracted again with 50 ml of chloroform. The chloroform layers were combined, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 100 g; eluent: chloroform:n-hexane, 2:1, and then, chloroform) to obtain 3.3 g of the title compound as a pale brown oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH2:23][C:24]([O:26]CC)=[O:25])=[CH:18][CH2:17][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH2:17][CH2:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1=CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)CC1=CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
To a solution of ethyl {6-[(3-phenoxybenzyl)oxy]-3,4-dihydronaphthalen-1-yl}acetate (0.622 g, 1.50 mmol) in a mixed solvent of ethanol (3 mL) and tetrahydrofuran (3 mL) was added 2 M aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr and further at 70° C. for 5 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) and recrystallized from ethyl acetate-hexane to give the title compound (0.198 g, yield 34%) as colorless needle crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:31]([NH2:36])[CH2:32][CH2:33][CH2:34][NH2:35]>C(O)CCC>[NH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:36][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCCN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)c2nc(NCCCCN)nc3ccccc23)cc1
Temperature: 105 °C
Yield: 39.3 %

Procedure:
To a suspension of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (300 mg, 1.0 mmol) in n-butanol (3 mL) and diisopropylethylamine (323 mg, 2.5 mmol) was added 1,4-butanediamine (132 mg, 1.5 mmol). The reaction was heated to 105° C. for 18 h, cooled to room temperature and concentrated. The crude product was purified by chromatography (amine column, i-PrOH/CHCl3, 0-100%) to give 138 mg (39%) of the title compound. 1H NMR (CDCl3) δ 7.5 (d, 1H), 7.4 (t, 1H), 7.15 (d, 2H), 6.95 (d, 2H), 6.7 (m, 2H), 3.8 (s, 3H), 3.6 (s, 3H), 3.55 (t, 2H), 2.8 (t, 2H), 2.1 (s, 3H), 1.75 (pentet, 2H), 1.63 (pentet, 2H); LC-MS (ESI+; 352 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12]2>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]2
Reactant: CCOC(=O)C1=NNc2ccc(-c3ccccc3OC)cc2C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccccc3OC)ccc2nn1

Procedure:
A solution of ethyl 6-(methoxyphenyl)-1,4-dihydrocinnolin-3-yl carboxylate in ethyl acetate (obtained as described below) was heated to boiling point and manganese dioxide (15 g.) was added. The mixture was heated under reflux for 30 minutes and then filtered. The filtrate was evaporated to approx. 1 ml. in vacuo and the residue was applied to a silica column (30 g. Kieselgel 60). The column was eluted with a 50% v/v mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.). The appropriate fractions were combined and evaporated in vacuo, and the crystalline residue was recrystallised from aqueous ethanol to give ethyl 6-(methoxyphenyl)cinnolin-3-yl carboxylate m.p. 143°-145° C. (believed to be a mixture of isomers varying in the position of the methoxy radical on the phenyl substituent).
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([NH:14][NH:15][C:16]([NH2:18])=[S:17])=O)=[CH:7][CH:6]=2.[OH-].[NH4+]>S(=O)(=O)(O)O>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[S:17][C:16]([NH2:18])=[N:15][N:14]=1)=[CH:7][CH:6]=2
Reactant: NC(=S)NNC(=O)c1ccc2cnc(F)cc2c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1nnc(-c2ccc3cnc(F)cc3c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A mixture of 1-(3-fluoroisoquinoline-6-carbonyl)thiosemicarbazide (0.98 g, 3.71 mmol) in sulfuric acid (10 mL) was stirred at room temperature for 3 hours. The mixture was poured into ice-ammonium hydroxide (33%). The pH was adjusted to >9 with additional ammonium hydroxide. The precipitate was recovered by filtration and washed with water (4×) to provide the product as an off-white solid (0.84 g, 92%). LCMS (API-ES) m/z: 247 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]=[O:7].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
3-Methoxy-4-phenylbenzaldehyde (23.0 g) was dissolved in dichloromethane (150 mL). To the stirred mixture was added dropwise boron tribromide (15.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the stirred reaction mixture was added dropwise water (20 mL) under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was suspended in methanol (100 mL) and 2 mol/L hydrochloric acid (50 mL), and the mixture was stirred at 50° C. for 2 hours. To the reaction mixture was added brine, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (13.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:21])[C:4](=[O:20])[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]([NH:10][CH3:11])=[O:9])[N:7]=1.CN(C=O)C.CC(C)([O-])C.[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][S:41](Cl)(=[O:43])=[O:42])=[CH:36][CH:35]=1>C1COCC1.CCOC(C)=O>[CH3:11][NH:10][C:8]([C:6]1[N:7]=[C:2]([NH:1][S:41]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)(=[O:42])=[O:43])[N:3]([CH3:21])[C:4](=[O:20])[C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: CNC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2ccc(Cl)cc2)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
In a round-bottomed flask, 2-amino-5-(benzyloxy)-N,1-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (250 mg, 867 μmol, Eq: 1.00) was combined with THF (20 ml) to give a white suspension. DMF (4 ml) was added followed by potassium tert-butoxide (117 mg, 1.04 mmol, Eq: 1.2). The resulting mixture was stirred at room temperature for 10 min, then cooled with an ice bath. To this was slowly added a solution of (4-chlorophenyl)methanesulfonyl chloride (240 mg, 1.07 mmol, Eq: 1.23) in THF (1 ml). After stirring at room temperature for 14 h, further t-BuOK (234 mgs) was added. The mixture was stirred for 5 min, cooled in the ice bath and then further (4-chlorophenyl)methanesulfonyl chloride (240 mg, 1.07 mmol) was added. The reaction mixture was stirred for 72 hours at RT and then diluted with EtOAc, washed with saturated aqueous NaHCO3 solution and brine. Some solid precipitated in the EtOAc solution and was collected by filtration. The remaining filtrate was evaporated to dryness, purified by flash chromatography (silica gel, 2% to 6% MeOH in DCM) and then triturated by EtOAc/Hex. The solids were combined to give the desired product as a white solid (0.210 g; 51%). LCMS m/z=477 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[CH2:5][NH:6]CCO.[C:15]([O:22][CH2:23][CH3:24])(=[O:21])[C:16]([O:18]CC)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[CH2:5][N:6]1[CH2:24][CH2:23][O:22][C:15](=[O:21])[C:16]1=[O:18]
Reactant: OCCNCc1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(=O)OCC
Product: O=C1OCCN(Cc2cc(F)c(F)c(F)c2)C1=O
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(3,4,5-trifluorobenzyl)amino]ethanol (6.91 g) and diethyl oxalate (20 mL) was stirred at 170° C. for one hour. The reaction solution was concentrated under reduced pressure, and then a diethyl ether was added to the residue. The precipitated crystals were collected by filtration and then air-dried to obtain 7.38 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9][CH3:10])N.[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[S:9][CH3:10]
Reactant: O=S(=O)(O)O
Reactant: CSc1ccc(N)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(O)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
The product from stage (ii) (11.5 g, 66.2 mmol) was dissolved in the minimum THF (˜15 mL) and water (500 mL) was added with vigorous stirring, followed by conc H2SO4 (25 mL). The mixture was cooled in an ice-water bath and a solution of NaNO2 (5.0 g, 72.5 mmol) in iced water (10 mL), was added via pipette under the surface of the reaction mixture. The reaction was stirred at 0° C. for 1.5 h and the resulting yellow/brown solution was decanted from the remaining solid into a dropping funnel containing ice (˜200 g). This solution was added at a steady rate over 7 min to a vigorously stirred mixture of Cu(NO3)2 (230 g, 0.99 mol) and Cu2O (8.52 g, 67.4 mmol) in water (1 L) at room temperature. After the addition was complete the mixture was stirred for a further 15 min before being extracted with ether (500 mL). The residual red/brown solid in the reaction flask was taken up in MeOH (100 mL) and diluted with ether (300 mL) before being poured into the aqueous layer from above. The ether layer was separated and the combined organic layers were extracted with 1M NaOH (3×100 mL). The aqueous extracts were acidified with conc. HCl and then extracted with ether (2×150 mL). The ether layers were then washed with brine, dried (MgSO4) and the solvent was removed in vacuo to give the phenol (5.465 g, 47%) as a brown crystalline solid; δH (400 MHz, CDCl3) 2.44 (3H, s), 5.08 (1H, br), 6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d); MS m/z (ES−) 173 (M−H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[N:5](C(=O)C(F)(F)F)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCN(C(=O)C(F)(F)F)c2cc(NC(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)CCNc2cc(NC(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)ccc21
Temperature: 60 °C

Procedure:
A suspension of N-(4,4-dimethyl-1-trifluoroacetyl-1,2,3,4-tetrahydroquinol -7-yl)-4-(3-trifluoromethyl-2-pyridyl)-piperazine-1-carboxamide (50 mg, 0.0955 mmol) and potassium carbonate (40 mg, 0.287 mmol) in methanol (5 ml) and water (5 ml) was heated at 60° C. for 4 h. After this period, the solvents were evaporated in vacuo and the residue partitioned between DCM (50 ml) and water (30 ml). The aqueous layer was re-extracted with DCM (3×50 ml) and then the combined organic layers dried (Na2SO4) and the solvents evaporated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.45 (dd, 1H), 7.90 (dd, 1H), 7.00-7.05 (m, 2H), 6.70 (d, 1H), 6.70 (d, 1H), 6.43 (dd, 1H), 6.32 (br-s, 1H), 3.60-3.65 (br, 4H), 3.20-3.30 (m, 6H), 1.65-1.70 (m, 2H), 1.26 (s, 6H). MS (ES): MH+ 434.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)N(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C(C)C)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 7.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-isopropyl-N-methylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.4 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([Br:21])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][N:11](CC2C=CC(OC)=CC=2)[C:10]1=[O:31].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([Br:21])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:31]
Reactant: COc1ccc(CN2Cc3c(Br)cc(OC)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C

Procedure:
A solution of 1-(2,6-dichlorophenyl)-3-(4-methoxyphenyl)methyl-5-bromo-7-methoxy-3,4-dihydro-2(1H)-quinazolinone (30.91 g, 0.0592 mol) (INTERMEDIATE 22) and anisole (28 ml, 0.258 mol) in 350 mL trifluoroacetic acid under a nitrogen atmosphere was refluxed for 2 h. The solution was cooled to RT and concentrated. The residue was partitioned between 500 mL NaHCO3 and 500 mL EtOAc. The organic phase was washed with water (500 mL) and brine (500 mL) and concentrated. The NaHCO3 and brine phases contained a suspension of precipitated product. This material was collected by filtration and combined with the crude. The combined crude was suspended in ethyl ether, filtered and washed with ethyl ether and hexanes to give 1-(2,6-dichlorophenyl)-5-bromo-7-methoxy-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): δ 3.68 (s, 3H), 4.64 (s, 2H), 5.46 (s, 1H), 5.62 (d, 1H, J=2.3 Hz), 6.79 (d, 1H, J=2.5 Hz), 7.36 (t, 1H, J=8.1 Hz), 7.50 (d, 2H, J=8.2 Hz). MS(ES) 401 (M+1); LC 1: 3.18 min.
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][C@@H:7]1[CH2:11][N:10](CC2C=C(C3C=CC=C([N+]([O-])=O)C=3)C(OC)=CC=2)[C:9](=[O:30])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[H-].[Na+]>O>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][C@@H:7]1[CH2:11][NH:10][C:9](=[O:30])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesis of ((S)-4-(tert-Butyl-dimethyl-silanyloxy)-1-(6-methoxy-3′-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one (I-213). Into a 250 mL round-bottomed flask with a stir bar was added I-212 (2.57 g, 11.95 mmol), THF (150 mL), and the solution was cooled to 0° C. NaH (0.56 g, 14.12 mmol) was added and the suspension was stirred at room temperature for 30 minutes. To this, I-70 (3.50 g, 10.86 mmol) was added and the reaction was stirred for 20 hours at room temperature after which time 50 mL of water was added and the product was extracted with ethyl acetate. The organics were concentrated to yield 8.9 g of I-213, which was used as is in the next reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCc2cc(Cl)ccc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2cc(Cl)ccc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonyl-5-chlorobenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxy-5-chlorobenzyloxy)phenylacetic acid as a colorless solid, m.p. 197°-201° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][C:4]=1[CH2:17][CH2:18][CH3:19].C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[C:9]([C:8]1[CH:25]=[CH:24][C:23](=[O:26])[N:7]2[C:3]([CH3:2])=[C:4]([CH2:17][CH2:18][CH3:19])[NH:5][C:6]=12)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCc1nc(CC(=O)c2ccccc2)[nH]c1C
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCCc1[nH]c2c(C(=O)c3ccccc3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 25 with 300 mg (1.08 mmol) of 2-(5-Methyl-4-propyl-1H-imidazol-2-yl)-1-phenylethanone hydrochloride (example XX), 60 mg (1.11 mmol) of sodium methylate and 90.5 mg (1.08 mmol) methyl propiolate.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33](Cl)[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[OH:27])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:32]=[CH:31][N:30]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Yield: 38.6 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((2-hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (183 mg, 0.36 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (84 mg, 0.54 mmol), and N,N-diisopropylethylamine (380 μl, 2.18 mmol) in tert-butanol according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification System to give 69 mg (38% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1cc(O)c2cc(-c3ccc(F)cc3)oc2c1
Yield: 80 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(4-fluorophenyl)ethanone: Yield 80% following procedures A.2 and A.5; m.p. 189-190° C.; IR 3332, 1614, 1500, 1243, 1125, 1072 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.85 (s, 1H), 9.36 (s, 1H), 7.82 (dd, J=8.7 Hz, 5.4 Hz, 2H), 7.27 (t, J=8.9 Hz, 2H), 7.21 (s, 1H), 6.42 (s, 1H), 6.19 (d, J=1.7 Hz, 1H); 13C-NMR (126 MHz, δ ppm, CD3OD) 163.85 (d, J=246.0 Hz), 158.8, 158.0, 153.3, 152.5, 129.0 (d, J=3.3 Hz), 127.1 (d, J=8.1 Hz), 116.8 (d, J=22.2 Hz), 112.9, 99.7, 98.9, 90.9.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[C:44]([NH:61][CH:62]2[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:64][CH2:63]2)=[C:45]2[CH:51]=[CH:50][N:49]([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[C:55]1([S:52]([N:49]2[C:46]3=[N:47][CH:48]=[C:43]([NH:42][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])[C:44]([NH:61][CH:62]4[CH2:63][CH2:64][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:66][CH2:67]4)=[C:45]3[CH:51]=[CH:50]2)(=[O:53])=[O:54])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CCC(C)CC(=O)O
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: CCC(C)CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
Racemic 3-methylpentanoic acid (0.180 ml, 1.4 mmol), HATU (0.53 g, 1.4 mmol), and diisopropylethylamine (0.46 ml, 2.7 mmol), were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (0.54 g, 1.3 mmol, prepared as described in Example 118) in DMF (20 ml) at 25° C. The reaction mixture was stirred for 4 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×200 ml). The organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 3-methyl-pentanoic acid {1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-amide (0.706 g, 110%) as an off-white solid. LCMS (Method G, ESI): RT=0.73 min, m+H=523.4. This material was used in the next step below without further characterization.