Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.CSC.B.[OH-].[Na+].C(OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC(=O)O)c1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A magnetically stirred solution of 3-(3-methoxyphenyl)propionic acid (71.38 g, 396.0 mmol) in 1.00 L of anhydrous tetrahydrofuran (THF) at room temperature was treated dropwise with a solution of borane-dimethyl sulfide (2.0M in THF, 680 mmol), stirred 1 h, heated at reflux for 2 h, cooled to room temperature, and stirred 12 h. The solution was poured over ice (300 g), treated with 6 N NaOH (500 mL), and stirred 1 h. The suspension was treated with diethyl ether (500 mL), the layers were separated, and the aqueous layer extracted with fresh diethyl ether (2×400 mL). The combined organic extracts were washed with water (500 mL), saturated sodium chloride solution (2×500 mL), dried (K2CO3), filtered, and concentrated in vacuo to give a clear liquid. Kugelrohr distillation (0.1 torr, 120° C.) gave 63.89 g (97%) of the alcohol: 1H NMR (CDCl3) δ 7.21 (t, J=8 Hz, 1H), 6.81-6.72 (m, 3H), 3.80 (s, 3H), 3.68 (t, J=7 Hz, 2H), 2.68 (t, J=8 Hz, 2H), 1.95-1.85 (m 2H), 1.40 (bs, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:28](O)(=O)[CH3:29]>>[CH2:28]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24])[CH3:29]
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C(C)C
Yield: 60 %

Procedure:
Compound 122 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (50 mg, 0.14 mmol) and NaBH4 pellets (>10 equiv) in 2 mL acetic acid to afford 30 mg (ca. 60%) of (3R)-4-ethyl-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (30 mg, 0.08 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (0.02M) heated at 90° C. for 4 h to afford 15 mg (57%) of Compound 122, a yellow solid, after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.87 (bs, 1H), 7.13 (d, J=9.3, 1H), 7.12 (s, 1H), 6.96 (d, J=8.9, 1H), 4.49 (d, J=10.8, 1H), 3.69 (dd, J=10.7, 2.7, 1H), 3.49 (m, 1H), 3.24 (m, 1H), 2.88 (bd, J=7.9, 1H) 1.83 (m, 1H), 1.64 (t, J=7.1, 3H), 0.98 (d, J=10.6, 3H), 0.96 (d, J=10.6, 3H).
Reaction SMILES: [N+]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:12]=[C:13]([N+:15]([O-])=O)[CH3:14])([O-])=O.CCOC(C)=O.C(O)(=O)C>[Pd].CCO>[CH3:14][C:13]1[NH:15][C:4]2[C:5]([CH:12]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[O:10][CH3:11]
Reactant: COc1cccc(C=C(C)[N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc2cc(C)[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
To a 2 L hydrogenation flask were added 1-(2-Nitro-3-methoxyphenyl)-2-nitropropene (44 g, 0.1850 mol), 10% Pd/C (4.4 g, 50% water wet), EtOAc (600 mL), acetic acid (90 mL) and absolute EtOH (75 mL). The reaction mixture was hydrogenated at <60 psi for 3 h and then filtered. The cake was washed with EtOAc (3×100 mL). The filterate was concentrated to remove EtOAc and EtOH. DI water (200 mL) was then added slowly. The resulting slurry was stirred for 0.5 h at RT and filtered. The cake was washed with 1:2 HOAc/H2O (2×30 mL) 1:4 HOAc/H2O (50 mL), water (2×80 mL) and suction dried for 18 h to give 2-methyl-7-methoxyindole (8.3 g, 62% yield). 1H NMR (CDCl3) δ2.42 (s, 3H), 3.94 (s, 3H), 6.18 (pseudo t, J=1.1 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H), 6.97 (pseudo t, J=7.7 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 8.10 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.[N:28]([C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33](OC)=[O:34])=[C:29]=[S:30]>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]2[C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=[C:11]2[NH:10][CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:1]3[C:33](=[O:34])[C:32]4[C:31](=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28][C:29]3=[S:30])[CH2:5][CH2:6]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10.9 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in 150 parts of tetrahydrofuran was added dropwise a solution of 6 parts of methyl 2-isothiocyanatobenzoate in 30 parts of tetrahydrofuran at room temperature: slightly exothermic reaction, the temperature rose to 30° C. Upon completion, stirring at room temperature was continued for one hour. The reaction mixture was evaporated. The residue was stirred in trichloromethane. The formed precipitate was filtered off and crystallized from 2-propanone. The product was filtered off and dried, yielding 5.2 parts of 3-[2-[4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl]ethyl]-1,2-dihydro-2-thioxo-4(3H)-quinazolinone; mp. 198.5° C. (compound 131)
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][N:14]2C(OC(C)(C)C)=O)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9](=[O:32])[CH:10]2[CH:15]([NH:14][CH2:13][CH2:12][NH:11]2)[C:16]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C2C(=O)N(Cc3ccccc3)C(=O)C21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C2NCCNC2C(=O)N1Cc1ccccc1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of 650 mg (1.5 mmol) of 8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonane-7,9-dione in tetrahydrofuran (10 ml) was added 4N hydrogen chloride solution in ethyl acetate (10 ml) with stirring. After 30 minutes at 50° C., a 2.5N aqueous solution of sodium hydroxide (17 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 85 mg (yield: 24%) of 8-benzyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dione as a colorless oil.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:32][CH2:33][CH3:34])[C:9]2[C:18]3[CH:17]=[C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:31]=1)[CH3:4].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[C:25]([O:24][C:23](=[O:29])[NH:22][CH2:21][CH2:20][O:19][C:16]1[CH:15]=[CH:14][C:13]2[N:12]=[C:11]([NH2:2])[C:10]3[N:31]=[C:7]([CH2:6][O:5][CH2:3][CH3:4])[N:8]([CH2:32][CH2:33][CH3:34])[C:9]=3[C:18]=2[CH:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: [NH4+]
Reactant: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Reaction time: 16 h

Procedure:
Ammonium hydroxide (50 mL) was added to a solution of tert-butyl 2-[(2-ethoxymethyl-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate (9.7 g, 22 mmol) in dichloromethane (120 mL), and the mixture was cooled to 10° C. p-Toluenesulfonyl chloride (4.16 g, 21.8 mmol) was added in small portions, while maintaining the reaction temperature below 15° C. The reaction was stirred for 16 hours; a tan precipitate formed. Dichloromethane (500 mL) was added, and the precipitate was isolated by filtration and washed with diethyl ether to provide 3.98 g of tert-butyl[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamate as a fine powder. The organic layer was washed sequentially with ammonium hydroxide, water, and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to provide 4.4 g of tert-butyl 2-[(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate as a peach-colored powder.
Reaction SMILES: C([Si](C(C)C)(C(C)C)N1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1)(C)C.[O:30]1C=CC(B(O)O)=C1>>[O:30]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Reactant: OB(O)c1ccoc1
Product: CCOC(=O)c1cn2cc(-c3ccoc3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with furan-3-boronic acid.
Reaction SMILES: [C:1]([C:5]1[O:6][CH2:7][C:8](=[O:40])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:19]([NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH2:24][CH:25]([C:31]([O:33]C)=[O:32])[CH2:26]4)=[O:20])=[CH:14][CH:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([C:5]1[O:6][CH2:7][C:8](=[O:40])[N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:19]([NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH2:24][CH:25]([C:31]([OH:33])=[O:32])[CH2:26]4)=[O:20])=[CH:16][CH:17]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(C(C)(C)C)OCC4=O)cc3)C3CCCC3)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C1=NN(Cc2ccc(C(C(=O)Nc3cccc4c3CC(C(=O)O)C4)C3CCCC3)cc2)C(=O)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
167 mg (0.306 mmol) of methyl 4-{[{4-[(2-tert-butyl-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}(cyclopentyl)acetyl]amino}-2,3-dihydro-1H-indene-2-carboxylate (Example 108A) were dissolved in 14 ml of dioxane/water (3:1 v/v), and 0.46 ml of 1 N aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature overnight. The mixture was then acidified with 1 N hydrochloric acid and extracted repeatedly with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC. This gave 68 mg (42% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2.[Cl-].[Li+].O.Cl>CC(N(C)C)=O>[OH:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2
Reactant: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(-n2cnc3cc(OC)cc(O)c3c2=O)cc1
Temperature: 135 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
A suspension of 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone (2.40 g, 7.68 mmol), as prepared in Example 18 or 19 and anhydrous lithium chloride (6.51 g, 153.6 mmol) in anhydrous dimethylacetamide (51.2 mL) was warmed to 135° C. After 3 to 5 min the trimethoxy compound goes into solution, then after approximately 10 min a voluminous precipitate formed. The precipitate redissolved after 20 min and the resulting solution was stirred at 135° C. for an additional 2.5 h. Upon cooling to room temperature, the reaction was poured into water (100 mL) and acidified with 1.0N HCl which gave a white precipitate. The mixture was extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to remove the methylene chloride, leaving a white precipitate in dimethylacetamide. Filtration provided 1.10 g (48% yield) of 5-hydroxy-7-methoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone, as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([NH:18][CH2:19][C:20]([O:22]C)=O)=[O:17])=[C:4]2[CH:3]=[CH:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C[Al](C)C.O>O1CCCC1>[CH2:24]([NH:31][C:20]([CH2:19][NH:18][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:17])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: NCc1ccccc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a solution of methyl ({[3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)thiophen-2-yl]carbonyl}amino)acetate (50 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added a pre-mixed solution of benzylamine (25 uL, 0.23 mmol) and trimethylaluminum (2.0 M toluene, 91 uL, 0.18 mmol). The solution was stirred at room temperature for 10 minutes then water was added resulting in precipitation. The precipitate was collected by filtration and dried under vacuum to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (benzylcarbamoyl-methyl)-amide (55 mg, 90%) (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.31 (1H, s) 8.46 (1H, t, J=6.08 Hz) 8.39 (1H, t, J=5.69 Hz) 8.03 (1H, d, J=5.37 Hz) 7.81 (1H, d, J=5.42 Hz) 7.51 (1H, d, J=5.42 Hz) 7.33 (1H, dd, J=3.20, 2.71 Hz) 7.28 (4H, d, J=0.05 Hz) 7.16-7.25 (1H, m) 6.85 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.47, 1.90 Hz) 4.30 (2H, d, J=5.95 Hz) 3.89 (2H, d, J=5.71 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][C:6]=2[N:18]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([NH:1][C:2]1[C:3]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][C:6]=2[N:18]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N=C=O
Reactant: CN(C)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CN(C)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1

Procedure:
Following the procedure of Example 21, 1.62 g of 7-amino-6-(2,6-dichlorophenyl)-2-(3-dimethylamino-propylamino)-pyrido[2,3-d]pyrimidine from Example 27 was reacted with 0.48 g of t-butyl isocyanate to give the title compound; mp gradually dec above 130° C.
Reaction SMILES: [CH:1]12[CH:9]([CH2:10][C:11](Cl)=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH2:26][CH3:27]>>[CH:1]12[CH:9]([CH2:10][C:11]([NH:14][N:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]3[CH2:26][CH3:27])=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(Cl)CC1C2CCCC1CCC2
Reactant: CCc1nc2ccccc2c(=O)n1N
Product: CCc1nc2ccccc2c(=O)n1NC(=O)CC1C2CCCC1CCC2

Procedure:
The product from Example 56D and 3-amino-2-ethylquinazolin-4(3H)-one (Aldrich) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.5 Hz, 1 H) 1.40-1.59 (m, 4 H) 1.63-1.97 (m, 10 H) 1.99-2.09 (m, 1 H) 2.51-2.56 (m, 2 H) 2.56-2.67 (m, 1 H) 2.67-2.80 (m, 1 H) 7.53 (t, J=7.0 Hz, 1 H) 7.67 (d, J=7.8 Hz, 1 H) 7.80-7.89 (m, 1 H) 8.11 (dd, J=8.1, 1.4 Hz, 1 H) 10.95 (s, 1 H); MS (ESI+) m/z 354 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]2[C:15]3[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:33]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1)Nc1cc(C(F)(F)F)ccc1F
Yield: 73 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a white solid (49 mg, 73%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]#[N:21]>CN(C)C=O.O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]#[N:21])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: N#CCCl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
10.88 g of a 50% sodium hydride suspension in mineral oil are diluted with 230 ml of absolute dimethylformamide and treated within 30 minutes with a solution of 50 g of p-(p-chlorophenoxy)phenol in 230 ml of absolute dimethylformamide while the temperature rises slightly. The mixture is then stirred at room temperature for 30 minutes. A solution of 18.8 g of chloroacetonitrile in 200 ml of absolute dimethylformamide is added dropwise while cooling the mixture in a water-bath. The mixture is stirred at 50° C. overnight, then cooled and diluted with 1 liter of water. This mixture is extracted five times with 200 ml of ethyl acetate each time. The organic phases are washed twice with 100 ml of 2-N sodium carbonate solution, once with 100 ml of saturated sodium chloride solution and then dried over magnesium sulfate and evaporated. The crude product (80 g of a dark oil) is purified by chromatography on silica gel using toluene for the elution to yield 45 g of [p-(p-chlorophenoxy)phenoxy]acetonitrile (76%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=[O:11])=[O:10]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([OH:11])=[O:10]
Reactant: Clc1cccc(Br)c1
Reactant: O=C=O
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The mixture of 500 mg of 3-bromochlorobenzen and 3 ml of tetrahydrofuran was cooled down to −78° C. and 1.3 ml of 2.0M lithiumdiisopropylamide heptane/tetrahydrofuran/ethylbenzene was added. After stirring it for 2 hours, the mixture was put into dry ice and washed and extracted as described in Referencial Example 1 to obtain a crude material. The crude material was washed with a mixed solvent of hexane-ethyl acetate to obtain the said compound.
Reaction SMILES: [NH2:1][CH2:2]/[C:3](/[CH3:29])=[CH:4]/[C:5]1[CH:26]=[C:25]([F:27])[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:7]([F:28])[CH:6]=1.Cl.[N:31]1([CH:36](N)[NH2:37])C=CC=N1>C1COCC1>[F:28][C:7]1[CH:6]=[C:5](/[CH:4]=[C:3](\[CH3:29])/[CH2:2][NH:1][C:36]([NH2:37])=[NH:31])[CH:26]=[C:25]([F:27])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])(=[O:17])=[O:18])=[CH:12][CH:11]=1
Reactant: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCN(C)C)cc2)c(F)c1)CN
Reactant: NC(N)n1cccn1
Agent: Cl
Solvent: C1CCOC1
Product: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCN(C)C)cc2)c(F)c1)CNC(=N)N
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To a solution of (E)-4-(4-(3-amino-2-methylprop-1-enyl)-2,6-difluorophenoxy)-N-(2-(dimethylamino)ethyl)benzenesulfonamide (Intermediate 93.4, 39.3 mg, 0.092 mmol) in dry THF (460 uL, 0.2M) under N2 was added TEA (0.276 mmol, 27.9 mg) and (1H-pyrazol-1-yl)methanediamine hydrochloride (0.102 mmol, 14.9 mg). The resulting solution was stirred for 1 hour, at which point LCMS indicated complete conversion. The solvent was removed and the resulting residue brought up in 1:1 ACN:water and purified by preparative HPLC to give 16.9 mg of the title compound (26%) as a TFA salt. 1H-NMR (400 MHz, CD4OD): δ 7.87 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 3.92 (s, 2H), 3.62 (m, 2H), 3.29 (m, 2H), 3.17 (t, 2H), 2.01 (s, 6H), 1.91 (s, 3H). MS (m/z): 468.12 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:31][CH2:32][S:33][CH3:34])[NH:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:9][C:8]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH:36](=O)[CH2:37][CH2:38][CH3:39]>>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:31][CH2:32][S:33][CH3:34])[NH:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:9][C:8]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: CCCC=O
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNCCN2CCCCC2)cc1-c1ccccc1C
Product: CCCCN(CCN1CCCCC1)Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2C)c1

Procedure:
The desired compound was prepared using the method described in Example 403H starting with the compound prepared in Example 1196A and butyraldehyde. m/e (ESI) 552 (MH−)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.O.C1(C)C=CC=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Oc1ccnc2cc(Cl)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccnc2cc(-c3ccccc3C(F)(F)F)ccc12

Procedure:
Combine 7-chloroquinolin-4-ol (1000 mg, 5.55 mmol,) 2-(trifluoromethyl)phenylboronic acid (1583 mg, 8.33 mmol) and toluene (50 mL), and bubble nitrogen into the solution for 10 minutes. Add palladium acetate (25 mg, 0.11 mmol), 2-(dicyclohexylphosphino)biphenyl (78 mg, 0.22 mmol), and K3PO4 (2353 mg, 11.1 mmol) and heat at 90° C. for 16 hours. Let cool, add water (25 mL) and EtOAc (50 mL), and remove any insoluble material by filtration. Separate the EtOAc layer, and extract the aqueous layer twice with EtOAc (25 mL each). Combine the EtOAc extracts, dry (Na2SO4), and evaporate. Purify by silica gel chromatography (94% CH2Cl2/5% MeOH/1% NH4OH) to provide 7-(2-trifluoromethyl-phenyl)-quinolin-4-ol as a white solid.