Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CCC>[C:19]1([N:25]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][CH:4]=[C:3]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:2]3=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cncc(-c2ccccc2)c1Cl
Reactant: NNc1ccccc1
Solvent: CCCCO
Product: O=c1c2c[nH]cc(-c3ccccc3)c-2nn1-c1ccccc1
Yield: 9.4 %

Procedure:
A mixture of ethyl 4-chloro-3-phenyl-5-pyridinecarboxylate (0.300 g, 1.15 mmol) and phenylhydrazine (0.125 ml, 1.27 mmol) in 1-butanol (25 ml) was stirred at reflux under nitrogen for 24 h. More phenylhydrazine (0.125 ml, 1.27 mmol) was added and the mixture was stirred at reflux for a further 3 days. The solvent was removed in vacuo and dichloromethane, followed by hydrogen chloride in diethyl ether, was added. The solution was filtered, and the filtrate was washed with aqueous NaHCO3 and evaporated in vacuo to give 31 mg (9%) of the title compound as a yellow solid; mp 280-285° C.; 1H NMR (250 MHz, DMSO-d6) δ7.18 (1H, t, J 7.4 Hz), 7.41-7.56 (5H, m), 7.91 (1H, s), 8.17 (2H, d, J 7.1 Hz), 8.22 (2H, d, J 7.5 Hz), 8.58 (1H, s), 12.60 (1H, br s); MS (ES+) m/z 288 [MH]+. Anal. found: C, 70.03; H, 5.00; N, 13.41. C18H12N3O.1.3H2O requires: C, 69.80; H, 4.75; N, 13.56%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][CH2:18][CH2:19][SH:20]>>[C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14][S:20][CH2:19][CH2:18][NH2:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCS
Reactant: OCc1ccc(Nc2ccccc2)nc1
Agent: Cl
Product: NCCSCc1ccc(Nc2ccccc2)nc1

Procedure:
Following the procedure given in part C of Example 3, the title compound was prepared from 6-phenylamino-3-pyridinemethanol and 2-aminoethanethiol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:18]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=3[CH:18]=2)=[N:21][CH:22]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)N1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CC(C)N1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isopropyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield an off-white solid (67%). mp 195° C.; LCMS: m/z=509.27 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.47 (m, 1H), 7.34 (m, 1H), 7.25 (m, 1H), 6.23 (m, 2H), 4.61 (m, 1H), 4.26 (m, 1H), 3.00 (s, 1H), 2.85 (d, 1H, J=11.9 Hz), 2.66 (s, 3H), 2.47 (d, 1H, J=8.1 Hz), 2.31 (m, 1H), 2.15 (m, 3H), 1.80 (m, 1H), 1.56 (m, 1H), 1.45 (m, 3H), 1.36 (s, 3H), 1.24 (m, 4H), 0.99 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:24]([O:26]C)=[O:25])=[CH:12][C:13]=3[N:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:24]([OH:26])=[O:25])=[CH:12][C:13]=3[N:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCc1ccccc1-3
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
To a solution of methyl 12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylate (337 mg, 0.93 mmol) in tetrahydrofuran (3 ml) and methanol (3 ml) was added 4N aqueous sodium hydroxide solution (3.0 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was acidified with 2N hydrochloric acid. The precipitated solid was collected by filtration and dried in vacuo to give 12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic acid (298 mg, yield 92.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25]([OH:26])=[C:24]([O:27][CH3:28])[C:23]([O:29][CH3:30])=[CH:22][C:21]=1[CH3:31].N(S([O-])(=O)=O)(S([O-])(=O)=[O:35])[O].[K+].[K+].O.P(O)(O)([O-])=O.[K+]>CN(C)C=O.CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:35])[C:21]=1[CH3:31]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1080 h
Yield: 60.1 %

Procedure:
The above 18-acetoxy compound was deacetylated by the corresponding procedure of Reference Example 2 and the resultant 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methylphenol (0.5 g) is dissolved in dimethylformamide (1 l). To this solution is added potassium nitrosodisulfonate (13 g), 700 ml of water, 100 ml of methanol and monopotassium phosphate (1 g), and the mixture is stirred at room temperature for 45 days. The product is extracted in the conventional manner and recrystallized from ether-hexane. The above procedure yields 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (V, n=17) as yellow needles (0.31 g), m.p. 81° C.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].OC[CH2:9][N:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH:11]1C>>[C:1]([O:6][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][N:10]([CH3:11])[CH3:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)[O-]
Reactant: CC1CC(C)(C)CN1CCO
Product: C=C(C)C(=O)OCC(C)(C)CN(C)C

Procedure:
Methacrylate of N-hydroxyethyl-2,4,4-trimethyl-pyrrolidine
Reaction SMILES: [F:1][C:2]1[C:3]([O:12]C)=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][OH:11])[C:3]=1[OH:12]
Reactant: COc1c(F)cc(F)cc1CCO
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: OCCc1cc(F)cc(F)c1O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 2-(3,5-difluoro-2-methoxyphenyl)ethanol (850 mg, 4.52 mmol) in DCM (30 mL) at 0° C. was added 1M BBr3 (13.55 mL, 13.55 mmol) solution. The resulting mixture was slowly warmed to room temp and stir for 3 h. water (dropwise) was then added and after the bubbling stops mixture was diluted with DCM and washed with water, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-50%, EtOAc/hexane) to afford 2,4-difluoro-6-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol, 57.2% yield) as clear viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.14 (br. s., 1H), 6.80-6.73 (m, 1H), 6.66 (dt, J=8.8, 2.4 Hz, 1H), 4.01-3.95 (m, 2H), 2.93 (t, J=5.5 Hz, 2H), 2.32 (br. s., 1H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:28][CH2:27][CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: NCCOc1ccccc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 96.8 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.106 g, 1.050 mmol) and 2-phenoxyethylamine (0.144 g, 1.050 mmol) in MeCN (3 mL) was heated at in a microwave reactor 120° C. for 5 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 65:35 mixture of heptane and EtOAc as eluant to give the title compound (0.262 g, 97%); 1H NMR (500 MHz, CDCl3): δ 7.57-7.54 (m, 2H), 7.49-7.45 (m, 3H), 7.32-7.27 (m, 2H), 7.02-6.97 (m, 1H), 6.86-6.83 (m, 2H), 5.71-5.66 (br m, 1H), 4.46-4.39 (m, 1H), 3.89 (t 2H), 3.27 (q 2H), 1.60 (d 6H); 13C NMR (125 MHz, CDCl3): δ 158.5, 158.2, 135.6, 131.7, 130.0, 129.8, 129.1, 125.1, 121.8, 114.7, 108.0, 65.8, 47.8, 43.6, 20.4; Mass Spectrum: M−H′ 387.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9]COCCOC)[C:3]=1[CH2:16][CH2:17][CH:18]1[O:23][C:22](=[O:24])[CH2:21][CH:20]([OH:25])[CH2:19]1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH2:16][CH2:17][CH:18]1[O:23][C:22](=[O:24])[CH2:21][CH:20]([OH:25])[CH2:19]1
Reactant: COCCOCOc1cc(Cl)cc(Cl)c1CCC1CC(O)CC(=O)O1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Zinc bromide (2.4 g, 10 mmole) was added to a solution of 6-{2-[2,4-dichloro-6-(2-methoxyethoxymethoxy) phenyl]ethyl}-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (780 mg, 2 mmole) in methylene chloride (12 ml). The resulting mixture was stirred at 20° C. for 2 hours, then quenched with saturated sodium bicarbonate solution (50 ml) and diluted with ether (200 ml). The ethereal layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on a 50 mm low-pressure column with 6 inches of silica gel (230-400 mesh). The column was eluted with 470 ml of methylene chloride-acetone (4:1, v:v). The next 330 ml provided the title compound as a golden glass (100 mg., 16%): pmr (CDCl3)δ2.62 (2H, d), 4.29 (H, m), 4.78 (H, m), 6.87 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CO.CC(C)=O.[OH-].[K+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:40])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-benzoic acid tert-butyl ester (1.07 g, 1.82 mmol) in a 1:1 MeOH/acetone solution (40 mL total) was added 4 mL of a 50% KOH (aq) solution. The reaction mixture was stirred for 20 hours at ambient temperature. Glacial acetic acid was added dropwise until the solution had a pH=6. The product was extracted into ethyl acetate and dried over Na2SO4. The material was adsorbed onto silica gel and purified by flash chromatography in an ethyl acetate and hexane gradient, affording 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid tert-butyl ester as a colorless oil that started to crystallize into a white solid (1.97 g, quantitative yield). 1H NMR (500 MHz, CDCl3) δ 11.34 (s, 1H), 8.50 (s, 2H), 8.21 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.75 (m, 2H), 7.55 (m, 2H), 7.40 (t, J=6.0 Hz, 1H), 7.10 (m, 2H), 3.88 (s, 3H), 1.25 (s, 9H). MS: m/e 401.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[I-:24].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][I:24])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nnc(CI)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.9 h

Procedure:
5-Chloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (346 mg. 0.001 mole) is added to a stirred solution of sodium iodide (300 mg., 0.002 mole) in acetone, and the resulting mixture is stirred at ambient temperature for 6 hours 54 minutes and poured into ice water. This mixture is extracted with chloroform. The extract is washed with brine, dried and concentrated. The residue is crystallized from methylene chloride-ethyl acetate to give: 0.227 g. of melting point 185.5°-192° (decomposition) of 5-chloro-2-[3-(iodomethyl)-5-methyl-4H-1,2,4-triazol-4-triazol-4-yl]benzophenone. The analytical sample has a melting point of 185°-200° C. (decomposition).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCC1c2c(C)cccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCC1c2c(C)cccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 26.4 %

Procedure:
The title compound was prepared from 6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-7-methyl-5,6-dihydrophenanthridine (0.45 g, 1.1 mmol), tetrabutylammonium iodide (1.00 g, 2.71 mmol), and 1 M boron trichloride in dichloromethane (8.0 mL, 8.0 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (3:7 to 1:1 gradient), followed by re-crystallization from a mixture of ethyl acetate-hexane, to yield 4-[(6-ethyl-7-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.11 g, 25%), m.p. 167-169° C.;
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[C:5]2[CH:19]=[CH:20][C:21]3[C:26]([C:4]=2[NH:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=3.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C1(NC(C2C=CC(N3C(=O)CC(=O)NC4C5C(C=CC3=4)=CC=CC=5)=CC=2)=O)C=CC=CC=1>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:14]([C:13]1[CH:12]=[CH:11][C:10]([N:6]2[C:7](=[O:9])[CH2:8][C:2](=[O:1])[NH:3][C:4]3[C:26]4[C:21]([CH:20]=[CH:19][C:5]2=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:17]=1)=[O:16]
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Reactant: NCc1ccccc1Cl
Agent: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(C(=O)NCc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 15 %

Procedure:
By using 4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid obtained in Example 102, (4), and 2-chlorobenzylamine, the title compound (yield 15%) was obtained in the same manner as that of Example 102, (5).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[S:3][C:4]([C:7](=[O:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:6]=2)=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)CC(=O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)s1
Temperature: 90 °C
Yield: 64.1 %

Procedure:
To a solution of 2-bromo-5-(3,3-dimethylbutyryl)-thiophene (187 mg, 0.7 mmol) in dioxane (7 mL) add a solution of aqueous 2M Na2CO3 (0.9 mL), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (216 mg, 0.8 mmol) and tetrakis(triphenylphosphine)-palladium(0) (41 mg, 0.03 mmol). Heat the mixture at 90° C. overnight. Cool at room temperature, add water and extract with EtOAc. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (174 mg, 63%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CC(N(C)C)=O.[Br-].[CH:21]1([Zn+])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: [Zn+]C1CCCCC1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (6 g, 24.00 mmol), DMA (30 mL), cuprous iodide (0.914 g, 4.80 mmol) and 1,1′-bis(diphenylphosphino) ferrocenedichloro palladium(II) dichloromethane complex (1.756 g, 2.400 mmol) was bubbled with nitrogen for 5 min. before 0.5 M THF solution of cyclohexylzinc bromide (100 mL, 50.0 mmol) was added over 20 min. via cannula at room temperature. The black reaction mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. EtOAc (50 mL), water (100 mL) and saturated aqueous ammonium chloride solution (30 mL) were added. The solid was filtered off over a celite pad and washed with ethyl acetate (3×20 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL). The combined organic solutions were washed with 1 N aqueous HCl (2×40 mL) and then brine (40 mL), dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (silica gel column, 20→100% ethyl acetate in hexanes) afforded 4-cyclohexyl-3-(trifluoromethyl)benzonitrile (2.77 g, 10.94 mmol, 45.6% yield) as a solid. The compound had an HPLC retention time=3.44 min. (condition C); LC/MS [M+H2O]+1=272.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH2:13].CC([O-])(C)C.[K+].[Cl:20][CH2:21][C:22](OCC)=[O:23].O>C1COCC1>[Cl:20][CH2:21][C:22]([NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=2)[N:9]=[CH:8][CH:7]=1)=[O:23]
Reactant: CCOC(=O)CCl
Reactant: COc1ccc2nccc(N)c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nccc(NC(=O)CCl)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a solution of 6-methoxy-1,5-naphthyridin-4-amine (553 mg, 3.116 mmol) in THF (45 mL) was added t-BuOK (390 mg, 1.1 eq) at 0° C. The resulting brown suspension was stirred at rt for 1.5 h and then added dropwise to a solution of ethyl chloroacetate (0.337 mL, 1 eq) in THF (30 mL) at −5° C. The mixture was allowed to warm to rt and was further stirred for 3 h. Water was added and the solvent was removed under reduced pressure. The resulting precipitate was filtered and further dried at HV to afford the title intermediate as a beige solid (357 mg, 45% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19]C)=[C:6]([CH:18]=1)[CH2:7][CH:8]1[CH2:11][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[CH2:7][CH:8]1[CH2:11][N:10]([C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[CH2:9]1
Reactant: COc1ccc(Br)cc1CC1CN(C(=O)C(F)(F)F)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N1CC(Cc2cc(Br)ccc2O)C1)C(F)(F)F
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 1-[3-(5-bromo-2-methoxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone (66 mg, 0.19 mmol) in dry DCM (10 mL) at 0° C. was added BBr3 (1.0 M in DCM, 370 mL, 0.37 mmol). After warming to rt overnight, saturated NaHCO3 solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated to provide the title compound (59 mg, 92%). MS (ESI): mass calcd. for C12H11BrF3NO2, 337.0; m/z found, 338.0 [M+H]+. 1H NMR (CDCl3): 7.23-7.10 (m, 2H), 6.70 (t, J=8.7 Hz, 1H), 4.53-4.40 (m, 1H), 4.27-4.11 (m, 2H), 3.97 (dd, J=10.7, 6.0 Hz, 1H), 3.17-3.01 (m, 1H), 3.01-2.78 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7](I)=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[OH-].[Cs+]>O1CCCC1.O.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]>[OH:1][C:2]1[C:3]([C:10](=[O:12])[CH3:11])=[CH:4][CH:5]=[C:6]([OH:9])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1ccc(O)c(I)c1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(O)c(-c2ccccc2)c1O
Reaction time: 15 h

Procedure:
To a solution of 1-(2,4-dihydroxy-3-iodo-phenyl)-ethanone (1.0 g, 3.59 mmol; 581938, may be prepared as described in G. Batu and R. Stevenson, J. Org. Chem. 1979, 44, 3948) in tetrahydrofuran/water (15 mL/3 mL) at room temperature is added phenyl boronic acid (0.877 g, 7.19 mmol), Pd(dppf)2Cl2 (0.088 g, 0.107 mmol), and cesium hydroxide monohydrate (1.81 g, 10.8 mmol). After stirring for 15 hours, the mixture is filtered through a pad of Celite®, washing with ethyl acetate. The residue is diluted with 30 mL of 1N hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with brine; dried over magnesium sulfate; filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography, eluting with 30% ethyl acetate/hexanes to give the title compound as a colorless solid: MS (m/z) 228 (M+); 1H NMR (DMSO-d6) δ 13.1 (s, 1H), 10.6 (bs, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.41-7.28 (m, 5H), 6.61 (d, J=8.8 Hz, 1H), 2.58 (s, 3H); Rf=0.58 in 40% ethyl acetate/hexanes.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=2)[CH:12]([CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.Cl>C1COCC1.CO.O1CCOCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)[CH:12]([CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)O)cs2)C(COc2cccnc2)C1
Reaction time: 5 h

Procedure:
Lithium hydroxide (15.5 mg, 0.649 mmol) was added to a solution of methyl 2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate (0.282 g, 0.649 mmol) in THF (2 mL), MeOH (2 mL), and H2O (1 mL). After 5 h, 4M HCl in 1,4-dioxane (0.200 mL) was added, and the reaction mixture was concentrated under reduced pressure. The material was used without further purification. LC-MS: RT=6.35 min, [M+H]+=421.7.