Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[N:40]3)=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:23][N:22]([CH3:24])[C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([CH2:14][C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:42]=[C:41]5[C:36]([CH:37]=[CH:38][CH:39]=[N:40]5)=[CH:35][CH:34]=4)=[CH:3][CH:4]=3)[C:12](=[O:13])[NH:11][N:10]=2)[CH2:16]1)=[O:21]
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CN(C)C(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)C(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of (3S)-3-{[4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-N,N-dimethyl-1-pyrrolidinecarboxamide (0.342 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.353 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (25 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-65% acetonitrile/water 0.1% NH4OH) was utilized to purify the title compound (65 mg, 42%). MS(ES)+ m/e 442.8 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.C(OC([NH:13][C:14]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15]1)=O)(C)(C)C.[CH3:21]O>>[NH2:13][C:14]1([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16][CH2:17]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1(N)CCC1
Temperature: 0 °C
Yield: 75 %

Procedure:
Concentrated H2SO4 (10 ml) was added at 0° C. to a solution of 1-(tert-butoxy-carbonylamino)-cyclobutane-1-carboxylic acid (9.29 mmol, 1 equiv.) in MeOH (30 ml), and the reaction was refluxed for 2 hours at 0° C. The solvent was removed under reduced pressure. The residue was taken up in distilled water, adjusted to pH 8-9 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with distilled water (2×150 ml) and saturated NaCl solution (2×50 ml) and dried over sodium sulfate. The solvent was concentrated under reduced pressure to yield the desired product in the form of a white solid. Yield: 75%
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([NH:10][CH:11]([CH3:14])[CH2:12][CH3:13])=[N:7][C:8]=1[CH3:9])#[N:2].[Se](=O)=[O:21]>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([NH:10][CH:11]([CH3:14])[CH2:12][CH3:13])=[N:7][C:8]=1[CH:9]=[O:21])#[N:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1NC(C)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C#N)c(C=O)nc1NC(C)CC

Procedure:
26.1 g of 5-cyano-6-methyl-2-[(1-methylpropyl)amino]-3-pyridine-carboxylic acid, ethyl ester (0.1 mol) and 13 g of selenium dioxide are refluxed together in dioxane for 24 hours. After this time the selenium is filtered off and the solvent removed in vacuo. The resulting oily residue is crystallized with ether. Yield 19 g (69%); m.p. 37°-38° C. (methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([O:16]CC)=[O:15])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: CCOC(=O)c1cc2c(c(OC)c1)NC(=O)CC2
Solvent: CO
Product: COc1cc(C(=O)O)cc2c1NC(=O)CC2
Yield: 99.4 %

Procedure:
By using 0.85 g of 8-methoxy-6-ethoxycarbonyl-3,4-dihydrocarbostyril and in the same manner as in Reference Example 10, 0.75 g of 8-methoxy-6-carboxy-3,4-dihydrocarbostyril was obtained as colorless needle-like crystals (recrystallized from methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[CH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[C:15](O)(=[O:17])[CH3:16].C(C=O)=O>CCOC(C)=O>[OH:14][C:12]1[C:11]([C:15](=[O:17])[CH3:16])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:13]=1
Reactant: CC(=O)O
Reactant: COc1cccc(NN=CC(C)=O)c1
Agent: O=CC=O
Solvent: CCOC(C)=O
Product: COc1cccc(-n2cc(O)c(C(C)=O)n2)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
A mixture of 2-oxopropanal (3-methoxyphenyl)hydrazone (2.88 g, 14.5 mmol), acetic acid (20 mL) and glyoxal (6.3 g, 5.0 mL, 43 mmol) were heated at reflux overnight. The reaction was cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaCl. The black sludge was removed by decantation and the filtrate was washed with more saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purify by CombiFlash (80 g column, 0-50% heptane/EtOAc gradient) to afford 1-[4-hydroxy-1-(3-methoxyphenyl)-1H-pyrazol-3-yl]ethanone (330 mg, 10%).
Reaction SMILES: [C:1]12[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:8][C:7]1[C:2]2=[C:3](O)[N:4]=[CH:5][N:6]=1.O=P(Cl)(Cl)[Cl:17]>O1CCOCC1>[Cl:17][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[C:1]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:8]2
Reactant: Oc1ncnc2sc3ccccc3c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Clc1ncnc2sc3ccccc3c12
Temperature: 90 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaen-3-ol (2.0 g, 9.89 mmol, 1.00 equiv) in 1,4-dioxane (15 mL) and POCl3 (4.5 g, 29.35 mmol, 2.97 equiv) under nitrogen. The resulting solution was stirred for 4 h at 90° C. The excess amount of POCl3 was removed under reduced pressure and the residue was diluted with DCM. The resulting mixture was poured into a cooled saturated aqueous sodium bicarbonate, extracted with DCM, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10) to afford 3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene (0.9 g, 41%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:39]C(=O)OC(C)(C)C)[CH2:16][C:17]([N:19]3[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]4[N:29]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:28]5[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=5[N:26]=4)[CH2:20]3)=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C(Cl)Cl>[NH2:39][C@H:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]2[N:29]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:28]3[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=3[N:26]=2)[CH2:20]1)=[O:18]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(N4CCC(O)CC4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(N4CCC(O)CC4)cc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
tert-Butyl (R)-1-(4-(4-hydroxypiperidin-1-yl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (0.325 mmole, 206 mg) in DCM (10 mL) was added TEA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (10-15% CH3CN in H2O) to afford (R)-3-Amino-4-(4-(4-hydroxypiperidin-1-yl)phenyl)-1-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butan-1-one (234) (0.024 mmole, 13 mg, two-step yield: 7.5%). ESI-MS: m/z 534.7 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.20-1.43 (m, 5H) 1.78-2.39 (m, 4H) 2.69-3.11 (m, 4H) 3.10-3.17 (m, 1H) 3.15-3.24 (m, 3H) 3.27 (s, 3H) 3.35-3.55 (m, 2H) 3.66-3.78 (m, 2H) 3.80-3.89 (m, 1H) 3.90-4.00 (m, 2 H) 4.37-4.46 (m, 1H) 4.48-4.58 (m, 1H) 4.59-4.67 (m, 2H) 4.67-4.76 (m, 1H) 7.30-7.35 (m, 1H) 7.38-7.46 (m, 3H) 7.55-7.67 (m, 2H) 7.73-7.82 (m, 1H) 7.83-7.93 (m, 1H).
Reaction SMILES: CO.[CH3:3][O:4][C@@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]1OS(C)(=O)=O.C[O-].[Na+]>O>[CH3:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CO[C@@H]1c2ccccc2C[C@H]1OS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
A stirrer, thermometer and reflux condenser were mounted to a 500-ml four-necked flask which was filled with 200 ml of methanol and 12.1 g (0.05 mol) of trans-1-methoxy-2-methane sulfonyloxy indane, and cooled in an ice-salt bath to 0° C. The cream-colored slurry was stirred while 27 g (0.5 mol) of sodium methoxide was added. The reaction liquid was heated to 70° C., stirred for 6 hours, cooled to 25° C., 200 ml of water was added, and extraction was performed twice with 200 ml of methylene chloride and the methylene chloride layer was dried with anhydrous sodium sulfate and vacuum-concentrated to obtain 7.17 g of a reddish-brown oil of 1-methoxyindene (yield of 98.2%). The purity of this compound according to gas chromatography (GC) was 90.9% (surface area percentage). Its physical properties are given below.
Reaction SMILES: C(N)C.[CH3:4][Si:5]([C:8]#[CH:9])([CH3:7])[CH3:6].[CH2:10]([S:17]/[C:18](/I)=[CH:19]\[CH:20]=[C:21](/[S:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)\[Sn:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>C1C=CC=CC=1.[Cu]I.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>[CH2:42]([S:41]/[C:21](/[Sn:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:20]\[CH:19]=[C:18](\[S:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:9]#[C:8][Si:5]([CH3:7])([CH3:6])[CH3:4])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C#C[Si](C)(C)C
Reactant: I/C(=C/C=C(\SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCN
Solvent: ClCCl
Solvent: c1ccccc1
Product: C[Si](C)(C)C#C/C(=C\C=C(/SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 38 h
Yield: 86.3 %

Procedure:
A mixture of EtNH2 (1 mL) and trimethylsilylethyne (32 mL, 0.23 mmol) were added to a solution of 5 (0.148 g, 0.190 mmol), CuI (1.81 mg., 0.0095 mmol) and (Ph3P)2PdCl2 (6.67 mg, 0.0095 mmol) in benzene (3 mL) under argon. The resulting yellow-green solution was stirred at room temperature for 38 h, and then concentrated in vacuo. The residue was mixed with ether (20 mL) and water (5 mL), the layers were separated and the aqueous layer was extracted by ether (2×10 mL). The combined ether layers were washed with NH4Cl solution (2×25 mL) and water (10 mL), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (1:6 CH2Cl2 :hexanes) of the dark, oily residue gave 7 as a yellow solid (122 mg, yield 86%): mp 122°-123° C.; 1H NMR δ 6.9-7.8 (m, 27 H), 4.06, 37.27, 0.03; Anal. Calcd for C41H40S2SiSn, C, 66.21; H, 5.42. Found, C, 66.42; H, 5.55.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:25][CH3:26])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]([C:19]([O:21]CC)=O)[C:11]2=[O:24])(=O)C.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:19]([C:12]2[C:11](=[O:24])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:7]([CH2:25][CH3:26])[CH2:6][CH2:5][OH:4])[CH:9]=3)[N:14]([CH3:18])[CH:13]=2)=[O:21])=[CH:30][CH:29]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2ccc(N(CC)CCOC(C)=O)cc2c1=O
Product: CCN(CCO)c1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 190 °C

Procedure:
To a flask containing ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 16 (0.22 g) is added p-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 190° C. overnight. The reaction is cooled to room temperature. The residue is adsorbed onto silica and chromatographed on silica eluting with 4% to 8% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.12 g of the title compound as a off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]#[N:28]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[CH:24]=[N:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: N#Cc1[nH]cnc1N
Product: Cc1ccc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)cc1C(F)(F)F
Yield: 38.6 %

Procedure:
Reaction of 1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (298 mg, 1.0 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (143 mg, 39%). MS (ISP) 371.1 [(M+H)+]; mp 220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@H:10]2[CH2:15][O:14][C:12](=[O:13])[CH2:11]2)[CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.[H-].[Na+].CO.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@H:10]2[CH2:15][O:14][C:12](=[O:13])/[C:11]/2=[CH:24]/[C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(C[C@H]2COC(=O)C2)cc2c1OCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(/C=C2/C(=O)OC[C@@H]2Cc2cc(OC)c3c(c2)OCO3)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.2 %

Procedure:
A solution of (R)-3-[1-(5-methoxy-3,4-methylenedioxyphenyl)methyl]butanolide (21.0 g, 0.084 mol) and 3,4,5-trimethoxybenzaldehyde (26.0 g, 0.133 mol) in toluene (350 ml) was cooled to 0° C. under an argon stream, followed by the addition of sodium hydride (60%, 9.1 g, 0.228 mol) and methanol (0.33 ml, 0.0082 mol). After stirred at 0° C. for 15 minutes and then at room temperature for 18 hours, the reaction mixture was ice cooled and then acidified with 2N-HCl. After the addition of ethyl acetate (100 ml), the organic layer was separated. The water layer was extracted with ethyl acetate (50 ml×2). The extracts were combined with the previously-obtained organic layer. The organic layer was washed successively with water, saturated NaHCO3 and saturated NaCl, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus obtained (52.9 g) was purified by column chromatography (silica gel: "MERCK #9385", 500 g, eluent: 1:2 mixed solvent of ethyl acetate and hexane), whereby 16.62 g of the title compound were obtained as colorless oil (yield: 46%). [α]27D : -53.7° (C=1.04, CHCl3)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH3:17])[C:14](=O)[CH3:15]>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:10]=[C:14]([CH3:15])[C:13]2([CH3:17])[CH3:12]
Reactant: CC(=O)C(C)C
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2
Temperature: 10 °C

Procedure:
To 4-methoxyphenyl hydrazine hydrochloride (4.84 g) was added 3-methyl-2-butanone (6.4 ml) and acetic acid (45 ml). The mixture was heated to 10° C. for 2.5 hours after which time the solvent was removed by rotary evaporation. Flash column chromatography gave the product (4.66 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A room temperature solution of Example 1A (10.0 g, 43.4 mmol) and saturated LiOH (50 mL) in THF (100 mL) was stirred for 16 hours, slowly adjusted to pH 2-4 with 6M HCl, diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use. MS (ESI(−)) m/e 215 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[O:31][N:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:36])[O:31][N:30]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Yield: 54 %

Procedure:
3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (90 mg, 0.264 mmol) was reacted with phenyl 3-isopropylisoxazol-5-ylcarbamate as prepared in Example 122A (78 mg, 0.317 mmol) to afford 1-(3-isopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (70 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ 10.30 (brs, 1H), 9.14 (brs, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.38-7.44 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 5.99 (s, 1H), 4.32-4.35 (m, 2H), 3.99 (s, 3H), 3.77-3.78 (m, 2H), 3.35 (s, 3H), 2.90 (septet, J=9 Hz, 1H), 1.19 (d, J=9 Hz, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[Si:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
N,N-dimethylformamide (70 ml), was mixed with 5.00 g (36.7 mmol), of 4′-hydroxyacetophenone, 6.64 g (44.1 mmol), of tert-butyldimethylchlorosilane, and 6.00 g (88.1 mmol), of imidazole and the mixture was stirred for 12 hours at room temperature. The reaction mixture was poured onto ice water to stop the reaction and extracted with 100 ml of ethyl acetate. The organic extract was washed with 100 ml of water ten times and then with saturated saline and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform 100%), to obtain 5.23 g (yield: 56.9%), of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:26](OC)(OC)(OC)[CH2:27][CH2:28][CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH2:27]([C:26]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCCC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)c1ccccc1
Yield: 87.7 %

Procedure:
A solution of 6-(3-aminoquinolin-4-ylamino)-1-phenylhexan-1-one (2.09 g, 6.25 mmol) and trimethyl orthovalerate (1.52 g, 9.37 mmol) in toluene (50 mL) was heated at reflux under a Dean-Stark trap for 2 hours, then concentrated under reduced pressure to provide 6-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (2.19 g) as a dark red oil that was used directly in the next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:30]=[CH:29][C:14]2[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C@@H:18]3[C@H:23]([NH2:24])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:55]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][C:57](O)=[O:58]>C(Cl)Cl>[CH3:66][C:63]([O:62][C:60](=[O:61])[NH:55][CH2:56][C:57]([NH:24][C@H:23]1[C@@H:18]2[N:19]([C:13]3[CH:12]=[C:11]([Cl:10])[CH:30]=[CH:29][C:14]=3[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=32)[CH2:20][CH2:21][CH2:22]1)=[O:58])([CH3:64])[CH3:65]
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: CC(C)(C)OC(=O)NCC(=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: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reaction time: 3 h
Yield: 104.1 %

Procedure:
DIPEA was added (pH=9) to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) in 1 mL of CH2Cl2 with HATU (12.5 mg, 0.03 mmol) and Boc-Gly-OH (10.3 mg, 0.03 mmol). The resulting mixture was stirred for 3 h, washed with 5% aqueous sodium bicarbonate and H2O, dried (Na2SO4) and evaporated to give [[[(trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]carbonyl]methyl]carbamic Acid 1,1-dimethylethyl Ester (14.3 mg, 100%). Data: (m/z)=405 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([C:19](OC)=[O:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>ClCCl.[H-].C([Al+]CC(C)C)C(C)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([CH2:19][OH:20])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cccc(OCc3ccccc3)c2CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: OCC1=Cc2cccc(OCc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
Under an argon atmosphere, to a solution of 2.79 g of 5-(benzyloxy)-2-(methoxycarbonyl)-3,4-dihydronaphthalene in 30 ml of dry dichloromethane, 24 ml of diisobutylaluminum hydride (1M toluene solution) was added dropwise at −70° C. or lower, followed by stirring for 20 minutes. To the reaction solution, 26 ml of an aqueous 10% sodium hydroxide solution was added dropwise and, after heating to room temperature, the mixture was extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.25 g of the desired compound as a colorless crystal having a melting point of 59 to 61° C.