Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][N:24]=1>>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:28]=1
Reactant: COc1ccnc(Cl)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: COc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-methoxy-pyrimidine. MS (ESI) mass calcd. for C22H22N4O2S, 406.50; m/z found, 407.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29]O)[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][O:15][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Product: COC(=O)c1ccc(C(C)(C)C)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Yield: 32.1 %

Procedure:
In a manner substantially equivalent to Example 21-C, methyl 4-tert-butyl-2-hydroxybezoate (2.08 g, 10.0 mmol) and 1-Boc-3-hydroxymethylpiperidine (2.15 g, 10.0 mmol) were reacted to give the desired product (1.30 g, 32.1%).
Reaction SMILES: [NH:1]1[C:6](=O)[CH2:5][O:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.B.CSC>O1CCCC1>[NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cnccc2N1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: c1cc2c(cn1)OCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred solution of 1H-pyrido-[3,4-b][1,4]oxazine-2-(3H)one (3 g, 21 mmol) in tetrahydrofuran (150 ml) was added rapidly a borane/dimethyl sulfide solution (52 ml of a 2M solution in THF, 5 eq) at 25° C. over 15 minutes. The reaction mixture was stirred at 25° C. for 2 hours and quenched with 5 ml of water. The solvent was removed in vacuo using a rotary evaporator and the residue treated with aqueous 1M HCl with stirring. The water was removed and the residue chromatographed on silica gel using CH2Cl2 /MeOH/NH4OH (90/10/1) to give 2 g (70%) of titled product. m.p. 167°-169° C. The structural assignment is supported by the proton NMR spectrum.
Reaction SMILES: [C:1]([CH:5]1[NH:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]2[NH:17][C:16]3=[CH:18][CH:19]=[N:20][C:15]3=[CH:14][N:13]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC[O:23]C(C)=O.[ClH:27]>CO>[OH2:23].[ClH:27].[C:1]([CH:5]1[NH:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]2[NH:17][C:16]3=[CH:18][CH:19]=[N:20][C:15]3=[CH:14][N:13]=2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3nccc-3[nH]2)CC(C(C)(C)C)N1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing 1-(tert-butyl)vinylpyrrolidine (freshly prepared before use) (1.20 g, 7.73 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.60 g, 7.73 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (1.3 mL, 7.73 mmol), piperidine (Aldrich Chemical Company) (1.2 mL, 12.4 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (23 mL of a 2M solution in DMF). The crude residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 448 mg (21%) of the free base as a cream colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.36 (s, 9), 1.63 (br s, 6), 2.38 (s, 3), 3.60 (br s, 4), 6.05 (d, 1, J=1.6), 10.20 (s, 1). MS m/z: 273 (M+1). To a hot solution of 6-(tert-butyl)-2-methyl-4-piperidylpyrrolo[3,2-d]pyrimidine (0.45 g, 1.65 mmol) in 10:1 EtOAc:MeOH (30 mL) was added 1N etheral HCl (Aldrich Chemical Company) (1.70 mL, 1.65 mmol). Crystallization occurred as the mixture cooled and the precipitate was collected by filtration, washed with Et2O (3×10 mL) and dried under vacuum to give 420 mg (83%) of the title compound as a white colored solid. Mp: 256-258° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.41 (s, 9), 1.67 (m, 6), 2.54 (s, 3), 3.98 (t, 4, J=5.2), 6.26 (s, 1), 11.14 (s, 1), 14.32 (s, 2). MS m/z: 273 (M+1). Anal. Calcd for C16H25ClN4.0.25H2O: C, 61.41; H, 8.20; N, 17.91; Cl, 11.33. Found C, 61.41; H, 8.11; N, 17.90; Cl, 11.39.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Agent: Br
Product: Oc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Reaction time: 0.1 h

Procedure:
The mixture of (4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine and hydrobromic acid (48%) was subjected to the microwave at 150° C. for 6 mins to yield 2-[(4-bromophenyl)amino]benzoxazol-5-ol. MS: MH+=305
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[O:14]1CCOCC1.O>>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH:1]=[O:14])=[N:3][CH:4]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCO1
Reactant: Cc1ccc(-c2ccccc2)cn1
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)cn1
Temperature: 110 °C
Yield: 14 %

Procedure:
To a solution of 2-methyl-5-phenyl-pyridine (800 mg, 4.73 mmol) (Koyama, J. et al. Heterocycles, 1994, 38, 1595-1600) in mixture of dioxane/water (20 mL:2 mL) was added SeO2 (577 mg, 5.20 mmol). The reaction mixture was heated to 110° C. overnight. Then the reaction mixture was cooled and concentrated in vacuo. Purification by flash column chromatography on silica gel using 1:4 hexanes/EtOAc afforded 5-phenyl-pyridine-2-carbaldehyde as a pale yellow solid (124 mg, 14%). 1H NMR (CDCl3) δ 7.49-7.52 (m, 3H), 7.63-7.66 (m, 2H), 8.05 (s, 2H), 9.02 (d, 1H, J=3.0 Hz), 10.12 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[O:15][C:16]1[CH:17]=[C:18]([N:23](C(C)(C)C)C(=O)[O-])[CH:19]=[CH:20][C:21]=1[CH3:22])(=[O:3])[CH3:2].[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[O:15][C:16]1[CH:17]=[C:18]([NH2:23])[CH:19]=[CH:20][C:21]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(Oc3cc(N(C(=O)[O-])C(C)(C)C)ccc3C)ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c(Oc3cc(N)ccc3C)ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
3-(8-Acetylaminoquinolin-4-yloxy)-4-methylphenyl-t-butylcarbamate (120 mg, 0.26 mmol) was dissolved in a 1:1 (by volume) mixture of dichloromethane and trifluoroacetic acid, which was then stirred at room temperature for one hour. When the reaction was completed, the resultant was neutralized with 1 M sodium hydroxide. The resultant was extracted with dichloromethane and water, and combined organic layers were dried with anhydrous sodium sulfate, and then filtered. After the solvent was removed by vacuum distillation, filtered a brown solid product to obtain 86 mg of the desired compound (yield 88.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:22]([C:21]1[CH:20]=[N:19][C:18]([NH2:17])=[CH:26][CH:25]=1)=[O:23])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Reactant: Nc1ccc(C(=O)O)cn1
Product: CC(C)(C)OC(=O)N1C2CCCC1CN(C(=O)c1ccc(N)nc1)C2
Yield: 71.8 %

Procedure:
Following general amide formation method 1, 3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170 mg, 0.751 mmol, 1.1 eq) was combined with 6-amino-nicotinic acid (94 mg, 0.683 mmol, 1.0 eq) which gave 3-(6-amino-pyridine-3-carbonyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170 mg) in 72% yield. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.50 (s, 9H) 1.55-1.72 (m, 2H) 1.74-1.98 (m, 4H) 3.20 (qd, J=7.41, 4.55 Hz, 3H) 3.65-3.82 (m, J=13.20, 6.66, 6.66, 4.29 Hz, 2H) 4.18 (br. s., 1H) 4.28 (br. s., 1H) 4.66 (br. s., 1H) 4.85 (br. s., 1H) 6.58 (d, J=8.59 Hz, 1H) 7.57 (dd, J=8.59, 2.02 Hz, 1H) 8.04 (s, 1H) 8.16 (d, J=2.02 Hz, 1H) MS m/z 291.4 (M+H)+.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[NH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.Cl>FC(F)(F)CO>[I:2][C:3]1[C:4]2[NH:9][C:14]3[CH2:15][CH2:16][NH:11][CH2:12][C:13]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCNCC1
Reactant: NNc1ccccc1I
Agent: Cl
Solvent: OCC(F)(F)F
Product: Ic1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 69 %

Procedure:
To a solution of 2-iodophenyl hydrazine hydrochloride (1.0 eq.) and 4-piperidone (1.0 eq.) in 2,2,2-trifluoroethanol was added 12 N HCl (2.0 eq.). The reaction mixture was heated at 60–65° C. for 3 h and cooled to rt. then filtered. The residue was purified by column chromatography to provide 6-iodo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole in 69% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=O)[N:6]2[CH2:15][CH2:16][CH2:17][CH:5]2[C:4]1=[O:18])[CH3:2].C(N1C(=O)OC(=O)C2=CC=CC=C12)C.N1CCC[C@H]1C(O)=O.C1C=CN2C(=O)C3C=CC=CC=3NC(=O)C=12>CO>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][N:6]2[CH2:15][CH2:16][CH2:17][CH:5]2[C:4]1=[O:18])[CH3:2]
Reactant: CCN1C(=O)C2CCCN2C(=O)c2ccccc21
Agent: CCn1c(=O)oc(=O)c2ccccc21
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=c1[nH]c2ccccc2c(=O)n2cccc12
Solvent: CO
Product: CCN1C(=O)C2CCCN2Cc2ccccc21

Procedure:
When (+) 10-ethyl-1,2,3,11a-tetrahydro-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11(10H)-dione, melting point 138° -140°C., (prepared as described above by reacting N-ethylisatoic anhydride with L-proline) is substituted for (+)-1,2,3,11 a-tetrahydro-10-methyl-[5H-pyrrolo [2,1-c] [1,4] benzodiazepin-5,11 -(10H)-dione in the procedure of Example 1, the above compound is obtained. The hydrochloride salt melts at 233°-235°C., [α]D 25 + 415° (0.9% in methanol).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:12]2[S:29][C:28]([NH2:30])=[N:27][C:13]=2[N:14]=[C:15]([S:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH3:19])[N:16]=1.[NH2:31][C@H:32]([CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:33][OH:34].O>CN1C(=O)CCC1>[NH2:30][C:28]1[S:29][C:12]2[C:11]([NH:31][C@H:32]([CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:33][OH:34])=[N:16][C:15]([S:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH3:19])=[N:14][C:13]=2[N:27]=1
Reactant: CC(C)(F)C[C@@H](N)CO
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](Sc1nc(N[C@@H](CO)CC(C)(C)F)c2sc(N)nc2n1)c1ccccc1F
Temperature: 120 °C
Reaction time: 22 h
Yield: 12.5 %

Procedure:
DIPEA (2.09 mL, 12.0 mmol) was added to 7-chloro-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (1.36 g, 4.0 mmol) and (2R)-2-amino-4-fluoro-4-methylpentan-1-ol (4 mmol) in NMP (3 mL). After stirring the reaction mixture at 120° C. for 22 h it was poured into water and the precipitate was collected by filtration. The solid was purified by flash column chromatography (a stepwise gradient of 5%-10% MeOH in CHCl3) and preparative HPLC to give the title compound (0.22 g, 13% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M117) (0.46 g, 0.85 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (280 mg, 80%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(C(C)O)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solution of methyl 4-acetylbenzoate (1.78 g, 10 mmol) in ethanol (100 mL) was added sodium borohydride (0.76 g, 20 mmol) in portions at 0° C. The mixture was stirred for 30 minutes and warmed to 20° C. Then the mixture was stirred at the same temperature for 12 hours. After that, the mixture was concentrated in vacuo to give methyl 4-(1-hydroxyethyl)benzoate (1.54 g, 85%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1>>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([CH:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:14]1
Reactant: O=Cc1ccccc1
Reactant: CC1=NC(C)(C)CO1
Product: CC1(C)COC(C=Cc2ccccc2)=N1

Procedure:
4,4-Dimethyl-2-(2-phenylethenyl)-2-oxazoline (P-1886) was prepared by reacting benzaldehyde with 2,4,4,-trimethyl-2-oxazoline. The product had a boiling point of 112° at 0.45mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:14]=[CH:15][C:16]([C:18](O)=[O:19])=[CH:17][C:12]=2[C:11]2[C:10](=[O:21])[NH:9][CH:8]=[CH:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH:1]([C:4]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:24])=[O:19])=[CH:17][C:12]=2[C:11]2[C:10](=[O:21])[NH:9][CH:8]=[CH:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2cc[nH]c(=O)c2c2cc(C(=O)O)ccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc[nH]c(=O)c2c2cc(C(N)=O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridine-9-carboxylic acid (78 mg, 0.28 mmol) in DMF (1.0 mL) was added 1,1′-carbonylbis(1H-imidazole) (CDI, 68 mg, 0.42 mmol). The reaction mixture was stirred for 1 hour at room temperature. Ammonium hydroxide (0.19 mL, 1.3 mmol) was added, and the resulting mixture was stirred for 15 minutes. The reaction mixture was diluted with DMF and purified directly by preparative reverse phase HPLC, eluting with an acetonitrile/water (with 0.05% TFA modifier) gradient to afford 6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridine-9-carboxamide. 1H NMR (500 MHz, DMSO-D6) δ 11.86 (s, 1H), 10.46 (s, 1H), 8.50 (d, 1H), 8.20 (s, 1H), 8.09 (d, 1H), 7.61 (s, 1H), 7.56 (t, 1H), 6.78 (d, 1H), 4.12 (septet, 1H), 1.37 (d, 6H). LRMS (ESI) calc'd for (C16H15N3O2) [M+H]+, 282.1; found 282.1.
Reaction SMILES: C[O:2][C:3]([C@:5]1([CH3:25])[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[S:11](=[O:24])(=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])=[O:4].Cl>[OH-].[Na+]>[Cl:21][C:15]1[C:14]([CH3:22])=[C:13]([NH:12][S:11]([N:6]2[CH2:7][CH2:8][C@@H:9]([OH:10])[C@@:5]2([CH3:25])[C:3]([OH:4])=[O:2])(=[O:23])=[O:24])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: COC(=O)[C@]1(C)[C@H](O)CCN1S(=O)(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(NS(=O)(=O)N2CC[C@@H](O)[C@@]2(C)C(=O)O)ccc(C#N)c1Cl
Yield: 65.8 %

Procedure:
A solution of 3C (120 mg, 0.309 mmol) in 8 mL of 1.6 N NaOH was stirred at rt overnight. The reaction mixture was acidified to pH 2 with 10% HCl and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (76 mg) as an orange oil. 1H NMR (CD3OD) δ 1.58 (s, 3H), 1.98-2.04 (m, 1H), 2.13-2.19 (m, 1H), 2.43 (s, 3H), 3.49-3.54 (m, 1H), 3.65-3.70 (m, 1H), 4.12 (t, J=6.1, 1H), 7.59 (d, J=8.3, 1H), 7.65 (d, J=8.8, 1H); 13C NMR (CD3OD) δ 15.33, 23.61, 31.78, 48.13, 74.81, 81.10, 109.72, 117.40, 122.04, 130.98, 132.84, 137.85, 143.90, 175.19; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.55 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.40 min retention time (89%); MS (ES) m/z 374 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)C.C1COCC1>[CH2:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(c1ccccc1)c1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Brc1cccc(Cc2ccccc2)c1
Temperature: 40 °C

Procedure:
(3-Bromo-phenyl)-phenyl-methanol (from previous step) was dissolved in diethyl ether (10 mL) and the solution was added dropwise to a suspension of lithium aluminum hydride (0.607 g, 16 mmol) and aluminum chloride (2.11 g, 16 mmol) stirring in THF (15 mL). The reaction was heated to 40° C. for 1 hour then cooled to 0° C., quenched with H2O, and submitted to standard aqueous workup. The crude product was purified via silica gel chromatography (0-5% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl.ClCCC1N=CNC=1>CN(C=O)C>[C:6]1(=[O:7])[NH:2][C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: ClCCc1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21

Procedure:
7 g of N-hydroxyphthalimide was dissolved in 120 ml of DMF and then 9.8 g of potassium carbonate and 300 mg of 18-Crown-6(Merck & co, Ltd.) were added thereto. A mixture of 4.3 g of 4-(2-chloroethyl)imidazole hydrochloride and 30 ml of DMF was added to the mixture under stirring. The resulting mixture was stirred for 15 hours at 50° C. After cooling, the insoluble material was removed by filtration and the filtrate was evaporated and then chloroform was added to the residue. The mixture was washed with SSB and SSC and dried with sodium sulfate and concentrated to dryness. The residue was washed with ether to give 2.9 g of N-(2-imidazol-4yl)ethoxy)phthalimide with mp 145°-146° C. as a hygroscopic colorless powder.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](=[CH:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][C:5]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>CO.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:6]=2)[CH:13]=1
Reactant: COC(=O)C1=C(Oc2ccccc2)CC(=COc2cccnc2)C=C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(COc2cccnc2)cc1Oc1ccccc1
Yield: 92.1 %

Procedure:
To a solution in methanol (15 mL) of 4-(3-pyridyloxymethylene)-2-phenoxybenzoic acid methyl ester (2.46 g), prepared as in Example 157E, was added a solution of 5% aqeuous KOH (2.00 g) in water (3 mL). The reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in water. The aqueous phase was acidified with acetic acid with cooling and stirring. The resulting solid was filtered, washed with water, and dissolved in THF. The THF solution was dried over Na2SO4, filtered, and concentrated in vacuo to give 4-(3-pyridyloxymethyl)-2-phenoxybenzoic acid (2.17 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:18])=[CH:20][CH:21]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCCCC3)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (50 mg, 0.16 mmol) obtained in Example 21 and piperidine (0.021 ml, 0.21 mmol) in methylene chloride (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol), and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was purified by a silica gel column chromatography (hexane:ethyl acetate=1:2) to yield the title compound (30 mg, 0.08 mmol, yield 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[NH3:19]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:19][C:10](=[O:9])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=c1oc(-c2ccc(Br)cc2)cc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2ccccc12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a suspension of 3-(4-bromo-phenyl)-isochromen-1-one (1.05 g, 3.50 mmol) in DMF (7 ml) is added aqueous ammonia (25% by weight, 7 ml) and the mixture is stirred at 80° C. for 3 days. The reaction mixture is diluted with water. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 3-(4-bromo-phenyl)-2H-isoquinolin-1-one as brown powder; HPLC/MS 1.96 min (A), [M+H] 300/302;
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][C:11]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][C:11]1[CH:12]=[CH:13][C:14]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:22][CH2:23]2)=[O:17])=[CH:15][C:10]=1[CH2:9][NH:7][CH3:6]
Reactant: CC(C)N1CCN(C(=O)c2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(C(=O)N2CCN(C(C)C)CC2)ccc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of [2-(3,4-dichloro-phenoxy)-5-(4-isopropyl-piperazine-1-carbonyl)-benzyl]-methyl-carbamic acid tert-butyl ester (212.5 mg, 0.40 mmol) in DCM (2 mL) was added TFA (1 mL). After 30 min, the mixture was concentrated and the residue was purified by FCC to give the desired product (119.3 mg, 69%). MS (ESI): mass calcd. for C22H27Cl2N3O2, 435.15; m/z found, 436.3 [M+H]+. 1H NMR (CDCl3): 7.50 (d, J=2.0, 1H), 7.38 (d, J=8.8, 1H), 7.30 (dd, J=8.3, 2.1, 1H), 7.06 (d, J=2.8, 1H), 6.88 (d, J=8.3, 1H), 6.82 (dd, J=8.8, 2.8, 1H), 3.81-3.69 (m, 4H), 3.53-3.37 (m, 2H), 2.78-2.68 (m, 1H), 2.64-2.43 (m, 4H), 2.43 (s, 3H), 1.93 (br s, 1H), 1.04 (d, J=6.5, 6H).