Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][NH:1][C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[CH:4][CH:3]=3)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2cn[nH]c2c1
Product: O=C(CNc1ccc2cn[nH]c2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 6-aminoindazol and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[C:13]#[N:14])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Co]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)/C(=C/C#N)CC2
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)/C(=C/CN)CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-(6-methoxyindan-1-ylidene) acetonitrile (5.0 g, 27 mmol.) in ethanol (50 mL) were added a saturated ammonia/ethanol solution (250 mL) and Raney cobalt (10 g). The mixture was stirred for 5 hours at room temperature under hydrogen atmosphere (5 kgf/cm2). The Raney cobalt was filtered off, and the solvent was distilled off under reduced pressure to leave (E)-2-(6-methoxyindan-1-ylidene)ethylamine. This oily residue was dissolved in ethanol (20 mL). The solution was cooled to -40° C., to which was added a saturated hydrogen chloride/ethanol solution. The resulting crystalline precipitate was collected by filtration to obtain the title compound (yield 4.3 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Li]C(CC)C.[O:26]=[C:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:5]2=[C:4]([C:27]2([OH:26])[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Cl)nc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc(Cl)nc21
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a colorless solution of 6-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.63 mmol) in THF (16 mL) was dropwise added sec-BuLi at −78° C. under N2 over 6 min, and the resulting tan solution was stirred for 2 hr. Tert-butyl 4-oxopiperidine-1-carboxylate (1.13 g, 5.70 mmol) in THF (3 mL) was dropwise added over 10 min to give a light tan solution at −78° C. under N2, and continued stirring for 2 hr. The reaction was quenched with sat. NH4Cl (30 mL), extracted with Et2O (2×50 mL). The combined organic phase was washed with brine (30 mL), dried (MgSO4), concentrated on rotary vacuo and purified on Biotage Flash Collector eluting with 20˜50% EtOAc/Hexanes (800 mL) to give the expected product, tert-butyl 4-(6-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-hydroxypiperidine-1-carboxylate (400 mg, 48%), as a light yellow solid. 1H-NMR (400 MHz, CHLOROFORM-D) δ ppm 1.25 (t, J=7.68 Hz, 18 H) 1.64 (s, 9 H) 1.94 (dt, J=15.17, 7.65 Hz, 5 H) 2.33-2.44 (m, 2 H) 3.42 (s, 2 H) 4.24 (d, J=7.05 Hz, 2 H) 6.88 (d, J=3.53 Hz, 1 H) 7.38-7.41 (m, 3 H); Mass spec. 508.25 (MH+) calc. for C26H42ClN3O3Si 507.27.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C:9]1([CH2:36][CH3:37])[C:21]2[CH:20]=[C:19]([N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][C:12](Br)=[CH:13][CH:14]=2)[CH3:8].O1C2C=CC=CC=2N=C1.[I-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:67]1([C:73]2O[C:75]3[CH:81]=[CH:80][CH:79]=[CH:78][C:76]=3[N:77]=2)C=CC=CC=1>C1(C)C=CC=CC=1.[Cu].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:7]([C:9]1([CH2:36][CH3:37])[C:21]2[CH:20]=[C:19]([N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][C:12]([C:73]1[NH:77][C:76]3[CH:75]=[CH:81][CH:80]=[CH:79][C:78]=3[CH:67]=1)=[CH:13][CH:14]=2)[CH3:8]
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: c1ccc(-c2nc3ccccc3o2)cc1
Agent: [Cu]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC1(CC)c2cc(-c3cc4ccccc4[nH]3)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reaction time: 18 h
Yield: 65 %

Procedure:
A mixture of cesium carbonate (6.5 g. 20 mmol, dried at 190° C. under 1 mm), 9,9-diethyl-N,N-diphenyl-7-bromo-2-fluoreneamine (7.4 g., 16 mmol), benzoxazole (2.4 g., 20 mmol), copper(l) iodide (0.38 g., 2 mmol), palladium (II) acetate (0.075 g., 0.334 mmol), triphenyl phosphine (0.15 g., 0.6 mmol) and DMF (30 ml) was kept at 115° C. for 18 hours under an atmosphere of nitrogen, then cooled, diluted with toluene and filtered. The filtrate was washed with water, dried and concentrated. The residue was chromatographed on alumina. Earlier fractions gave 0.25 g., m.p. 102-104° C., identified as 2-phenyl benzoxazole (m/z 195). Elution with heptane-toluene (3:1), followed by crystallization, gave 5.14 g. (65% yield) of bright yellow crystals, m.p. 193-194° C. A sample for analysis was obtained by sublimation under 0.5 mm vacuum at a bath temperature of 210° C. Mass Spec: mlz 506 (M+). Analysis: Calculated for C36H30N2O: C, 85.34; H, 5.97; N, 5.53. Found: C, 85.25; H, 5.97; N, 5.55.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([F:40])=[C:34]([CH:39]=3)[C:35]([O:37]C)=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([F:40])=[C:34]([CH:39]=3)[C:35]([OH:37])=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(Cc1ccc(F)c(C(=O)O)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 86.4 %

Procedure:
To a solution of methyl 5-{[({4-[(4-butylphenyl)ethynyl]phenyl}sulfonyl)(hexyl)amino]methyl}-2-fluorobenzoate (66 mg; 0.12 mmol) in THF (4 mL) were added lithium hydroxide monohydrate (49 mg; 1.17 mmol) and water (1 mL). The reaction mixture was stirred at 100° C. for 2500 s under MW. The mixture was poured into HCl 1N (10 mL) and extracted with EtOAc (2×75 mL). Combined organic layers were washed with brine (125 mL), dried over magnesium sulfate and filtrated. The solvent was removed under reduced pressure to give 57 mg (88.6%) of the title compound as a white powder. HPLC: Rt=5.71 min (purity=98.9%), LC/MS: M−(ESI): 548.3.1H NMR (MeOD) δ: 7.87 (d, J=8.6 Hz, 3H), 7.72 (d, J=8.6 Hz, 2H), 7.69 (m, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 7.18 (s, 1H), 4.39 (s, 2H), 3.75 (m, 1H), 3.55 (t, J=4.3 Hz, 1H), 3.16 (t, J=7.3 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H), 1.63 (q, J=7.5 Hz, 3H), 1.35 (m, 4H), 1.15 (m, 4H), 0.95 (t, J=7.3 Hz, 3H), 0.82 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:19](O)=[O:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH3:35].Cl>C1COCC1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:19](=[O:20])[NH2:35])([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@@](NC(=O)OCc1ccccc1)(C(=O)O)C(=O)OCC
Reactant: N
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@](NC(=O)OCc1ccccc1)(C(N)=O)C(=O)OCC
Yield: 84 %

Procedure:
A solution of (R)-1-ethyl hydrogen 3-benzyloxycarbonylamino-3-ethoxycarbonylsuccinate (1.8 g) in THF (20 mL) was added with triethylamine (0.96 mL) and isobutyl chloroformate (0.84 mL, 0.87 g) in this order at −15° C. with stirring, and the mixture was stirred for 5 minutes. A solution of 25% aqueous ammonia (0.47 mL) was dropped into the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 1 hour, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (1.51 g, yield: 84%) as colorless crystals. Optical rotation [α]D25 was −5.7° (c 0.52, ethanol) and optical purity was 96.1% ee.
Reaction SMILES: [C:1]1([C:7]2[N:17]3[C:18]4[N:10]([C:11](=S)[NH:12][C:13](=[O:19])[C:14]=4[CH:15]=[N:16]3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].OO.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH3:27][CH:26]([CH3:28])[CH2:25][NH:29][C:11]1[N:10]2[C:18]3[N:17]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][CH2:9]2)[N:16]=[CH:15][C:14]=3[C:13](=[O:19])[N:12]=1
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1ccccc1)=CC2
Reactant: CC(C)CN
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(=O)c2cnn3c2n1CC=C3c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg of 4,5-dihydro-8-phenyl-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 7) in 10.0 ml of N,N-di-methylformamide was added 1.8 ml of 1N sodium hydroxide. The reaction mixture was cooled to 0° C. in an ice bath, then 0.6 ml of 30% hydrogen peroxide was added to the mixture dropwise. The reaction mixture was stirred at 0° C. for about 30 minutes, then 1.0 ml of isobutylamine was added in one portion and the mixture was allowed to warm to room temperature, then was stirred for 2 hours. The solid was collected and washed with water, then ether to give 253 mg of the desired product as a white solid, m.p. 265°-268° C. (dec). Following the procedure of Example 44 and reacting 4,5-dihydro-8-phenyl-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one with the appropriate primary aliphatic amine or cyclic secondary amine, the products of Examples 45-51 were obtained as set forth in Table V.
Reaction SMILES: [C:1](=[O:14])(OC1C=CC=CC=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:15][C:16]([NH2:20])([CH3:19])[CH2:17][NH2:18]>CCO>[NH2:20][C:16]([CH3:19])([CH3:15])[CH2:17][NH:18][C:1](=[O:14])[O:2][C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Reactant: CC(C)(N)CN
Solvent: CCO
Product: CC(C)(N)CNC(=O)OC(C)(C)C
Yield: 37 %

Procedure:
Tert-butyl phenyl carbonate (0.421 mL, 2.270 mmol) was added to a solution of 2-methylpropane-1,2-diamine (200 mg, 2.270 mmol) in EtOH (4.5 mL) and the reaction mixture was heated at reflux overnight. The mixture was concentrated and the residue diluted in water. The mixture was acidified with 2N HCl to pH 4 and washed with DCM. The aqueous layer was treated with 1M NaOH (2 mL) and extracted with DCM. The combined organic layers were dried with MgSO4, filtered and concentrated to afford tert-butyl 2-amino-2-methylpropylcarbamate (158 mg, 37% yield) as a colorless oil. MS (apci) m/z=188.9 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:28][N:29]([CH3:42])[CH2:30][CH2:31][NH:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[N:36]=1)=[O:34]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([C:33](=[O:34])[NH:32][CH2:31][CH2:30][N:29]([CH3:28])[CH3:42])[N:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN(C)CCNC(=O)c1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)NCCN(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-bromo-pyridine-2-carboxylic acid (2-dimethylamino-ethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](OCC)=[O:15].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][OH:15]
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 5-(2,4-dichlorophenyl)isoxazole-4-carboxylate (8.60 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 65 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(2,4-dichlorophenyl)-4-isoxazolylmethanol (7.09 g, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 76–77° C.
Reaction SMILES: [Cl-].[NH4+].O.[Cl:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([N+:15]([O-])=O)=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=1[C:11]([F:14])([F:12])[F:13]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cnc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water (40 mL), and the mixture was stirred at room temperature for 5 min. A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.8 g) in methanol (40 mL) was added, and the mixture was stirred at room temperature for 1 hr. Reduced iron (2.3 g) was added, and the mixture was further stirred at the same temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and 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 (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as a solid (yield 1.0 g, 65%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[C:19]([O:21]C)=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)O)cc2OCc2ccccc2)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 12.8 eq) of sodium hydroxide and 200 mg (0.39 mmol, 1 eq) of methyl (E)-3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 125 mg of (E)-3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=115-116° C.). Yield=64%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:50])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:45])(=[O:44])[NH:28][C:29](=[O:43])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:17][CH:16]=3)[C:10]([CH2:46][CH2:47][CH2:48][CH3:49])=[N:9]2)[CH:7]=1.[C:51](Br)(=[O:54])[CH2:52][CH3:53]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:46]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:45])(=[O:44])[NH:28][C:29](=[O:43])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:51](=[O:54])[CH2:52][CH3:53])[CH:3]=[CH:4][C:5]=2[Cl:50])[N:9]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Oc2ccccc2)cc1
Yield: 65 %

Procedure:
By the procedure of Example 69, 2-[5-amino-2-chlorophenyl]-5-n-butyl-2,4-dihydro-4-[[2'-[N-(2-phenoxybenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Step B) was reacted with propionyl bromide in the presence of DMAP. The crude product was reconcentrated from toluene and flash chromatographed on silica gel (gradient elution with 1-2% MeOH in CH2Cl2) to give a 65% yield of the title compound as a stiff foam, mp 113°-116° C.; homogeneous by TLC in 9:1 CH2Cl2 ; mass spectrum (FAB) m/e 764 (M+1)+.
Reaction SMILES: I[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:2]3[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[C:7]4[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:32]=2)[N:27]=1
Reactant: Cc1ccc2c(Oc3cccc(C(F)(F)F)c3)nccc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Oc5cccc(C(F)(F)F)c5)nccc34)ccc2n1
Temperature: 150 °C

Procedure:
5-Iodo-6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinoline (0.170 g, 0.396 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.124 g, 0.436 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.0139 g, 0.0198 mmol), and sodium carbonate (0.0840 g, 0.792 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30-70% EtOAc in hexanes. The clean fractions were reduced in vacuo and the residue triturated with ether to give N-methyl-6-(6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-yl)quinazolin-2-amine as a light yellow solid. MS(M+H)+ 461.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH3:38][O:39][C:40]([C:42]1[S:43][C:44]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:45][C:46]=1[NH:47][CH:48]1[CH2:57][CH2:56][C:51]2([O:55][CH2:54][CH2:53][O:52]2)[CH2:50][CH2:49]1)=[O:41].C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:38][O:39][C:40]([C:42]1[S:43][C:44]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)=[CH:45][C:46]=1[N:47]([CH:48]1[CH2:49][CH2:50][C:51]2([O:55][CH2:54][CH2:53][O:52]2)[CH2:56][CH2:57]1)[C:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10])=[O:41]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CCC2(CC1)OCCO2
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To trans 4-methyl-cyclohexanecarboxylic acid (148 mg, 1.044 mmol) and triphenylphosphine (274 mg, 1.044 mmol) dissolved in 1,2-dichloroethane (1.5 ml) was added N-chlorosuccinimide (145 mg, 1.084 mmol). After 15 minutes of stirring at room temperature, a solution of 3-(1,4-Dioxa-spiro[4.5]dec-8-ylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (300 mg, 0.803 mmol) in 1,2-dichloroethane (1.5 ml) was added. The resulting mixture was then stirred for 18 h at 90° C. and then cooled to room temperature. It was then diluted with ethyl acetate (10 ml) and a solution of saturated NaHCO3 (10 ml) was added. The aqueous phase was separated and washed with ethyl acetate (2×10 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0% to 30% EtOAc/Hexane) to obtain 265 mg (66%) of 3-[(1,4-Dioxa-spiro[4.5]dec-8-yl)-(trans 4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[C:37]([F:41])=[CH:38][CH:39]=2)[CH:34]=[CH:33]1)(C(C)(C)C)(C)C>>[F:41][C:37]1[C:36]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][CH:33]=[CH:34]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCOCC3)ccc2n1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCOCC3)ccc2n1

Procedure:
4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)morpholine (0.1 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 94.7 mg of 146 following reverse phase HPLC purification. MS (Q1) 449.2 (M)+
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(O)cc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: CCc1ccc(Oc2cccc(Oc3ccc(CCC(=O)O)c(C)c3)c2)cc1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethylphenol as in Example 18 to afford 0.020 g (14%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C24H24O4 377.1753, found 377.1747.