Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28](O)([CH3:31])([CH3:30])[CH3:29]>C(N(CC)CC)C.CCOC(C)=O>[C:28]([O:14][C:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH2:2])=[CH:4][CH:5]=1)=[O:15])([CH3:31])([CH3:30])[CH3:29]
Reactant: Nc1ccc(C(=O)O)c2ccccc12
Reactant: CC(C)(C)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(N)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
3.6 g (16 mmol) of 4-Amino-naphthalene-1-carboxylic acid hydrochloride, (T. Nakayama et al, Chem. Pharm. Bull, 1984, 32, 3968-3980), was suspended in 44 mL of tert-butyl alcohol and 3.3 mL of triethylamine. To this was added 3.1 g (19 mmol) of carbonyldiimidazole. An exothermic reaction was noted, and the brown solution was stirred at room temperature for 12 h. After this time, the reaction was diluted with EtOAc, filtered through diatomaceous earth and concentrated in vacuo. Purification on silica gel, eluting with 20% EtOAc-hexanes provided 1.1 g of 4-amino-naphthalene-1-carboxylic acid tert-butyl ester as an off-white solid (29%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH2:17])=[N:11][NH:12]2>N1C=CC=CC=1>[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:11][NH:12]2
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2cccc(I)c12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cccc(I)c12
Temperature: 5 °C
Reaction time: 50 h

Procedure:
0.20 cm3 of butyryl chloride is added to 500 mg of 4-iodo-1H-indazole-3-amine, described previously, in 15 cm3 of pyridine, and cooled to about 5° C. The reaction medium is allowed to return to about 19° C. over 50 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of ethyl acetate, 15 cm3 of tetrahydrofuran and 15 cm3 of distilled water. The organic phase is dried over magnesium sulphate and then filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of dichloromethane and filtered. The insoluble material is taken up in 10 cm3 of methanol and filtered off and the filtrate is evaporated under reduced pressure, to give after drying (90 Pa; 50° C.), 70 mg of N-[4-iodo-1H-indazol-3-yl]butanamide in the form of an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([O:21]C)=[O:20].[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)O

Procedure:
Compound 3 (0.10 g, 0.33 mmol), NaOH (0.7M, 2.4 ml) and ethanol (2.4 ml) were refluxed until the solid dissolved. The red solution was cooled and acidified with concentrated HCl to precipitate the product as a yellow solid. Yield 0.09 g, (88%). 1H NMR (DMSO): δ 12.19 (bs, 1H, OH); 10.18 (s, 1H, NH); 8.15 (d, 1H, J=1.9 Hz); 7.52 (d, 1H, J=1.9 Hz); 7.36 (d, 1H, J=1.9 Hz); 6.78 (d, 1H, J=1.9 Hz); 3.93 (s, 3H); 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.COCCOC.C(Cl)Cl.CCOC(C)=O.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[C:31]#[N:32])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: N#CC(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone (2.43 g, 8.5 mmol), prepared as described in Procedure 2, in DME (60 mL), was added TosMIC (2.23 g, 11.4 mmol). The reaction mixture was cooled in an ice bath. A solution of potassium tert butoxide (1.0 M potassium ten butoxide in tert butanol, 22.8 mmol) in tert butanol/DME (22 mL t-BuOH, 20 mL DME) was added via a funnel at a slow stream. Upon completion of addition, the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water (approx 50 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic portions were washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (120 g) with elution at 40 mL/min gradient 0 to 15% EtOAc in hexane over 30 min (RT=23-29 min) 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile (1.8 g, 72% yield) was isolated as a yellow oil. LCMS: RT=1.73 min [M+H] 298.99 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.98 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 5.35 (s, 1 H), 7.31 (d, J=7.91 Hz, 1 H), 7.38 (d, J=8.79 Hz, 1 H), 7.46-7.47 (m, 2H), 7.50 (s, 1 H), 8.46 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:30]1([S:36][CH2:37][CH:38]([CH3:42])[C:39](O)=[O:40])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:39](=[O:40])[CH:38]([CH3:42])[CH2:37][S:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(CSc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(CSc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 0.5 h

Procedure:
To a cold solution of 19.9 g (0.1M) of N-cyclopentyl glycine-t-butyl ester in 200 ml THF was added 26 g dicyclohexyl carbodiimide. After stirring for 1/2 hour, a solution of 19.6 g (0.1M) of 3-phenylthio-2-methyl propanoic acid in 50 ml THF was added and stirring continued for 16 hours. It was then filtered, solvent removed, dissolved in ether, washed well with water, filtered, dried over MgSO4, and evaporated to dryness leaving an oily residue which was purified by HPLC using ethyl acetate-hexane (3:17) as eluent.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:6]=2[O:5]1)[CH3:2].[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C=O)C>[CH2:18]([O:13][C:12]1[C:6]2[O:5][CH:4]([O:3][CH2:1][CH3:2])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: CCOC1Oc2cccc(O)c2O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cccc2c1OC(OCC)O2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 37 (4.0 g, 22.0 mmol) in DMF (7 mL) was added dropwise over 5 min to a suspension of sodium hydride (1.32 g, 33.0 mmol 60% dispersion in oil) in DMF (15 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min, then allyl bromide (2.93 g, 2.09 mL, 24.2 mmol) was added and the reaction mixture was allowed to warm to rt over 16 h. The reaction mixture was then cooled to 0° C., water was added dropwise, then the reaction mixture was extracted with t-BuOMe (3×). The organic phase was washed successively with water and brine, dried (Na2SO4) and evaporated to dryness to give 4.8 g of crude product. Purification by column chromatography (SiO2 2:98 EtOAc:cyclohexane) gave 38 compound (3.3 g, 68%):
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:21]#[N:22].[Cl-].[Ca+2].[Cl-].O.N>S([O-])([O-])(=O)=O.[Cu+2].O.CN1CCCC1=O>[C:21]([C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:22]
Reactant: CCOc1ccc2c(c1)CCc1c(Cl)cccc1S2
Reactant: N#C[Cu]C#N
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ccc2c(c1)CCc1c(C#N)cccc1S2
Reaction time: 15 h
Yield: 29.8 %

Procedure:
The mixture of 520 mg of 9-chloro-10,11-dihydro-2-ethoxydibenzo[b,f]thiepin, 0.1 g of copper sulfate, 1 g of copper cyanide and 20 ml of N-methylpyrrolidone was refluxed with stirring for 15 hrs., while preventing the moisture with calcium chloride. After cooling, to this was added 20 ml of conc. ammonia water and 100 ml of water, and the mixture was extracted. The extract was washed with water, dried over anhydrous potassium carbonate and, the solvent was evaporated to obtain the residue. This was chromatographed on silica gel, eluted with the mixed solvent of benzene and n-hexane (4:1) and there was obtained 150 mg of 9-cyano-10,11-dihydro-2-ethoxydibenzo[b,f]thiepin having a melting point of 124° to 126° C. as colorless powdered crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22]4[N:23]3[N:26]=[N:27][N:28]=4)=[CH:18][C:17]=2[O:29][CH3:30])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.[ClH:37].CO>CCOC(C)=O>[ClH:37].[ClH:37].[CH3:30][O:29][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[N:23]1[N:26]=[N:27][N:28]=[C:22]1[CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-n1nnnc1CC2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)-n1nnnc1CC2
Reaction time: 24 h
Yield: 61 %

Procedure:
To a stirred solution of Compound 7 (110 mg, 0.23 mmol) in AcOEt (6 ml) was added an excess amount of HCl-MeOH, and stirred for 1 day. After the solvent was evaporated, the residual solid was recrystallized from MeOH-Et2O. The crystals precipitated were collected by filtration, washed with Et2O, and dried in vacuo at 30° C. to give Compound 8 (65 mg, 0.14 mmol, 61%) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=3[CH2:35]O)[CH:12]=2)[N:7]=1>ClCCl>[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=3[CH2:35][Cl:3])[CH:12]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
67 μl of thionyl chloride in 2 ml of dichloromethane are added dropwise to 200 mg of [2-amino-6-(2-hydroxymethyl-4,5-difluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 2 ml of dichloromethane, and the mixture is stirred at 25° C. for 2 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, and the operation is repeated. The residue is employed in the subsequent reactions without further treatment.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)NO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)NOC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4-Chlorobenzoyl chloride (1.10 mL, 8.57 mmol) is added slowly to a solution of ethyl hydroxycarbamate 6 (1.00 g, 9.52 mmol) and triethylamine (1.19 mL, 8.57 mmol) in diethyl ether (30 mL) at 0° C. then stirred at room temperature for 30 min. The reaction is quenched with HCl (1 M; 10 mL) then water (100 mL) is added and extracted with diethyl ether (100 mL). The organic layer is washed with sat. NaHCO3 (50 mL), water (50 mL), dried with MgSO4 and concentrated. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 9:1 then 8:2) to yield 7 (1.54 g) as an off-white solid. M.p. 79° C. (determined by differential scanning calorimetry, sharp onset); FTIR (neat, cm−1) 3210, 3094, 2990, 1765, 1708, 1588, 1495, 1487, 1473, 1443, 1401, 1368, 1298, 1283, 1249, 1235, 1177, 1121, 1107, 1090, 1054, 1016, 996, 876, 852, 771, 747, 728, 681; 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 8.02 (dt, J=2.1, 8.7 Hz, 2H), 7.46 (dt, J=2.1, 8.7 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.1, 156.6, 140.9, 131.3, 129.1, 125.2, 63.0, 14.3; HRMS (ES+) m/z calcd for C10H10ClNO4 (M+Na)+ 266.0191, found 266.0199.
Reaction SMILES: [NH2:1][O:2]C1CCCCO1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([OH:29])=O)=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C.CO>[OH:2][NH:1][C:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16])[CH2:19][CH2:20]2)=[O:29]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
NH2OTHP (0.12 g, 0.99 mmol) was added to a solution of 16 (0.25 g, 0.82 mmol), PyBOP (0.46 g, 0.87 mmol), triethylamine (0.28 ml, 1.98 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 1.5 h before it was quenched with water, followed by extraction with EtOAc (15 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2:CH3OH=30:1:1% NH3(aq)) to give a white solid, which was treated with TFA (2.7 ml, 36.35 mmol) in the presence of CH3OH (52 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give a white residue, which was recrystallized by CH3OH to afford Compound 18 (0.25 g). 1H NMR (500 MHz, CD3OD): δ 2.95 (d, J=8.49 Hz, 2H), 3.97 (d, J=8.52 Hz, 2H), 7.48-7.52 (m, 3H), 7.57-7.63 (m, 3H), 7.82 (d, J=7.71 Hz, 2H). HRMS (EI) for C15H14N2O4S (M+): calcd, 318.0674. found, 318.0672.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[CH:4]=[N:3]1)[C:11](=[O:15])[C:10]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2([NH:26]S(C(C)(C)C)=O)[CH2:25][CH2:24][CH2:23]2)=[N:20][CH:21]=1)=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:8]3.[ClH:39].O1CCOCC1>CO>[ClH:39].[NH2:26][C:22]1([C:19]2[N:20]=[CH:21][C:16]([C:10]3[C:11](=[O:15])[C:12]4[C:7]([O:8][C:9]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]3=[CH:14][CH:13]=4)=[CH:17][CH:18]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(NS(=O)C(C)(C)C)CCC5)nc4)c(-c4ccccc4)oc3c21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)nc4)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {1-[5-(1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-pyridin-2-yl]-cyclobutyl}-amide (34 mg, 0.0645 mmol) in MeOH (6 mL) was added a solution of HCl in dioxane (4 M, 0.32 mL, 1.28 mmol). The reaction mixture was stirred at RT for 30 min before evaporating to dryness. The resulting residue was dissolved in a mixture of MeOH (1 mL), water (4 mL) and then chromatographed on a 5 g C18 cartridge {gradient 20 to 60% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (24.3 mg, 82%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.78 (br s, 3H), 8.41 (dd, J=2.2 and 0.8 Hz, 1H), 8.29 (s, 1H), 7.89-7.81 (m, 3H), 7.75 (d, J=8.3 Hz, 1H), 7.59-7.57 (m, 2H), 7.51-7.41 (m, 3H), 4.41 (s, 3H), 2.60-2.55 (m, 4H), 2.26-2.15 (m, 1H), 2.05-1.94 (m, 1H). LCMS (Method E): =3.22 min, [M+H]+=423.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([C:7]1[N:8]([CH2:20][CH2:21][C:22](OCC)=[O:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:5][CH3:6]>C1COCC1>[CH3:1][N:2]([CH3:3])[C:22](=[O:23])[CH2:21][CH2:20][N:8]1[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=[C:7]1[CH2:4][CH2:5][CH3:6]
Reactant: CNC
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)N(C)C
Temperature: 110 °C

Procedure:
Dimethylamine (15 mL of a 40% aqueous solution) was added to a solution of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.02 g, 12.9 mmol, prepared in Part B of Example 18) in THF (7 mL), and the reaction mixture was heated at 110° C. overnight in a pressure vessel. The reaction was allowed to cool to ambient temperature and concentrated under reduced pressure to provide 4.1 g of N,N-dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide as a dark brown solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([CH:3]=[CH:4][NH:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1ccc(NCC(OC)OC)cc1OCCN(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2cc[nH]c2cc1OCCN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A stirred solution of N-[3-(2-dimethylaminoethoxy)-4-methoxyphenyl]aminoacetaldehyde dimethyl acetal (D15, 5.3 g, 0.018 mole) in trifluoroacetic acid (22 ml) at -5° C. under argon was treated dropwise over 40 minutes with trifluoroacetic anhydride (22 ml). After a further 30 minutes the dark solution was treated with more trifluoroacetic acid (33 ml) and then heated under reflux for 7 hours. The solution was concentrated in vacuo and the residue basified with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated in vacuo and the residue dissolved in methanol (100 ml), treated with potassium carbonate (10 g) and stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, the residue treated with water (60 ml) and extracted with ethyl acetate (2×70 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown solid (3.5 g, 83%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>CO.C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([O:18][CH3:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-benzyl-4,5-dichloro-2H-pyridazine-3-one (22.31 g, 87.47 mmol), prepared as described in Example 244A, in dry MeOH (175 mL) at 0° C., was added dropwise a solution of sodium methoxide in methanol (25% weight in MeOH, 25 mL). The mixture was slowly warmed up to room temperature and stirred for 18 h. The reaction mixture was diluted with methylene chloride (200 mL) and filtered. The filtrate was concentrated to afford the title compound, 2-benzyl-4-chloro-5-methoxypyridazin-3(2H)-one (22.2 g) which was >95% pure as judged by HPLC and was used in the next reaction, Example 354B, without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[I-].[K+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCOCC1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(C)CC3)CC2)nc1N
Yield: 33.1 %

Procedure:
A suspension of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (32 mg, 0.066 mmol, Example 272), potassium iodide (50 mg, 0.3 mmol), N-methylpiperazine (500 mg, 5.0 mmol, Aldrich) in dioxane (15 mL) was heated at reflux under nitrogen for 16 hours. The reaction was diluted with methylene chloride (40 mL) and washed (2×) with water. The organic layer was separated and dried (Na2SO4). The residue was purified by silica gel chromatography (methanol/methylene chloride) and triturated from ethyl ether and filtered to give (4-amino-2-[1-[3-(4-methyl-piperazin-1-yl)-propane-1-sulfonyl]-piperidin-4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (12 mg, 33% yield). HRMS, observed: 550.2612; Calcd for (M+H)+: 550.2607
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([O:9]N)[CH:6]=[CH:7][CH:8]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[C:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:12]=3[O:9][C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NOc1cccc(Br)c1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2oc3cc(Br)ccc3c2C1
Yield: 11 %

Procedure:
The product of step B was reacted with tert-butyl 4-oxopiperidine-1-carboxylate then Boc protected following the procedure of Example 29, step B to give tert-butyl 7-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (181 mg, 11%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J=1.6 Hz, 1H), 7.34 (dd, J=8.3 Hz, 1.8 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 4.53 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.52 (s, 9H); ESI MS m/z 352 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([Li])[CH2:13][CH2:14]C.C(Br)C=C.[Cl-].[NH4+]>CCCCCC.C(OCC)(=O)C.[Cu]I.C(OCC)C>[CH2:14]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]=[CH2:12]
Reactant: Brc1cnc2ccccc2c1
Reactant: [Li]CCCC
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCc1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In an amount of 24.8 mg of copper(I) iodide was added with 9 ml of diethyl ether and 343.5 μl of 3-bromoquinoline, then added dropwise with 1.6 ml of a 1.57 M solution of n-butyllithium in hexane at −78° C., and stirred at −78° C. for 30 minutes. This reaction mixture was added with 71.4 μl of allyl bromide, stirred at −78° C. for 30 minutes, then warmed to 0° C., added with 20 ml of saturated aqueous ammonium chloride, diluted with 20 ml of ethyl acetate, and successively washed twice with 20 ml of saturated aqueous ammonium chloride and once with 20 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to ethyl acetate/hexane (1:1)) to obtain 130 mg of the title compound.