Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12](N)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[I-:16].[K+].N(OC(C)(C)C)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[N:13][C:12]([I:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [I-]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: CC(C)(C)ON=O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1cc(Oc2ccc(I)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
A mixture of 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (1.00 g, 4.51 mmol) and potassium iodide (3.74 g, 22.5 mmol) in DCM (15 mL) was treated dropwise with t-butyl nitrite (4.65 g, 45.1 mmol) and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc (75 mL) and washed with 10% Na2CO3 (50 mL), then water (50 mL) and finally brine (50 mL) and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give a thick oily solution. EtOAc (100 mL) was added and the solution was washed with 0.1M sodium thiosulfate (75 mL), brine (50 mL) and dried over sodium sulfate. The solvents were evaporated at reduced pressure, and the residual oil was purified by silica gel chromatography to provide 2-chloro-4-((6-iodopyridin-3-yl)oxy)pyridine (695 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, J=3.0 Hz, 1H), 8.73 (d, J=5.8 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H), 7.91 (dd, J=8.6, 3.1 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.48 (dd, J=5.8, 2.3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1)[CH2:5][CH3:6].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:18][C:19]1[N:20]=[C:21]([O:15][CH2:14][CH2:13][O:12][C:11]2[CH:16]=[CH:17][C:8]([O:7][CH:4]([CH3:3])[CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C)Oc1ccc(OCCOc2cccc(F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium hydride (0.12 g) in 5 ml of THF and 4 ml of HMPA, cooled in an ice bath, is added, dropwise, a solution of 2-[4-(1-methylpropoxy)phenoxy]ethanol (1.00 g) in 5 ml of THF. The mixture is stirred at RT for 2 hours, after which 2,6-difluoropyridine (0.65 g) is added and the mixture is stirred at RT overnight. The THF is removed by rotoevaporation and the product is isolated by column chromatography on silica gel to give 6-fluoro-2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 306 (M+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15])[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH2:16]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]([CH:21]([CH3:23])[CH3:22])[C:4]1=[O:15])[CH3:17]
Reactant: CC(C)I
Reactant: CCC1(CC)C(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(C(C)C)c2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of 3,3-diethyl-5-nitro-1,3-dihydro-indol-2-one (11.7 g, 49.95 mmol) in anhydrous N,N-dimethylformamide (DMF) (60 ml) was treated with sodium hydride (1.558 g, 64.93 mmol). The resulting suspension was stirred for 1 h at 60° C. A solution of 2-iodo-propane (4.99 ml, 8.49 g, 49.95 mmol) was added. The mixture was kept at 60° C. for further 3 h, allowed to cool to room temperature poured into ice water. The precipitate was filtered off, washed with water and dried to yield 12.6 g 3,3-diethyl-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (45.60 mmol, 91%)
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Br[CH2:20][C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>C1COCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]#[C:21][CH2:20][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[CH:24][CH:25]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Fc1ccc(C#CCBr)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of trimethyl(prop-1-ynyl)silane (2.19 g, 19.50 mmol) in 22 mL of THF at −78° C., was added dropwise n-BuLi 2.5M in hexane (7.8 mL, 20 mmol). After stiffing 2 hours at −78° C., 1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THF was slowly added and the resulting mixture was stirred for 1h at −78° C. and warmed to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.57 g of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (99%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=3)[CH2:9][CH:2]12.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][O:32][C:33]2[CH:34]=[C:35]([NH2:38])[NH:36][N:37]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:38][C:35]4[NH:36][N:37]=[C:33]([O:32][CH2:31][C:25]5[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:23]([O:22][CH3:21])[CH:24]=5)[CH:34]=4)=[O:16])=[CH:18][CH:19]=3)[CH2:9][CH:2]12
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CC3CCCNC3C2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CC5CCCNC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 30.5 %

Procedure:
4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as for Example 115, but starting from methyl 4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)benzoate (0.221 g, 0.85 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine HCl (0.243 g, 0.85 mmol) and 2M trimethylaluminium in toluene (1.06 ml, 2.13 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.124 g, 30.5%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[NH:16][N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:20])[CH:3]=1.[N+:21]([C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(O)=O.CO>[F:20][C:4]1[CH:3]=[C:2](/[N:1]=[CH:29]/[C:27]2[O:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)c(F)c1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Yield: 81 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 0.28 g, 1 mml) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9e, 324 mg, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][NH2:6].[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[C:17]=[O:18].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][NH:6][C:17]([NH:16][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[O:18]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCCC2)c(F)c1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 3-fluoro-4-(1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.47 (s, 1H), 8.62 (s, 1H), 8.58 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.57 (t, 1H), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz), 2.98 (m, 4H), 2.79 (s, 3H), 1.67 (m, 4H), 1.53 (m, 2H); MS (ESI) 393 (M+H)+; Anal. Calcd for C23H25FN4O.1.5HCl: C, 61.78; H, 5.97; N, 12.53. Found: C, 61.40; H, 6.04; N, 12.18.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]=[C:6](C(Cl)(Cl)Cl)[N:5]=2)[CH2:3][CH2:2]1.[NH3:18]>O1CCCC1.O>[NH2:18][C:6]1[N:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]=1
Reactant: N
Reactant: ClC(Cl)(Cl)c1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1

Procedure:
71.2 g of 2-cyclopropyl-4,6-bis-trichloromethyl-1,3,5-triazine are dissolved in 70 ml of tetrahydrofuran, and at room temperature are added, with stirring, 300 ml of a concentrated aqueous ammonia solution. The reaction mixture is stirred for 30 minutes; it is then diluted with water, and the formed emulsion is extracted with ether. The ether phases are collected, dried, filtered and subsequently concentrated by evaporation. The residue crystallises and there remain 48 g of the crystalline title product, m.p. 111°-114° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[NH:6][CH:5](SC)[N:4]([NH2:11])[C:3]1=[O:12].C(O)(=O)C.[CH3:17][NH2:18]>C(O)(C)C>[CH3:1][N:2]1[C:7](=[O:8])[NH:6][CH:5]([NH:18][CH3:17])[N:4]([NH2:11])[C:3]1=[O:12]
Reactant: CSC1NC(=O)N(C)C(=O)N1N
Reactant: CN
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CNC1NC(=O)N(C)C(=O)N1N
Reaction time: 10 h
Yield: 88 %

Procedure:
18.8 g (0.1 mole) of 1-methyl-3-amino-4-methylmercaptotetrahydro-1,3,5-triazine-2,6-dione (prepared according to Example 2) were idssolved in 200 ml of isopropanol with addition of 6 g of glacial acetic acid and a pinch of ptoluenesulphonic acid and the mixture was saturated with methylamine gas at room temperature. The batch was left to stand for about 10 hours and was evaporated in vacuo, and the resudue was recrystallized from isopropanol. 15 g (88%) of 1-methyl-3-amino-4-methylamino-tetrahydro-1,3,5-triazine2,6-dione were obtained as a colorless powder; melting point 225°-227° C.
Reaction SMILES: O(C([NH:8][C@@:9]1([CH3:16])[C:13]2([CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10]1)=O)C(C)(C)C.F[C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]2[C@@H:29]2[CH2:31][C@@H:30]2[F:32])=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl.CS(C)=O>[NH2:8][C@@:9]1([CH3:16])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:18]2[C:27]([CH3:28])=[C:26]3[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]3[C@@H:29]3[CH2:31][C@@H:30]3[F:32])=[CH:20][CH:19]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CNCC12CC2
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(N2CC3(CC3)[C@](C)(N)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 75 °C
Reaction time: 120 h

Procedure:
A mixture of (7S)-7-(tert-butoxylcarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (523 mg, 2.31 mmol), 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (538 mg, 1.927 mmol), triethylamine (0.537 mL, 3.85 mmol), and dimethyl sulfoxide (6 mL) was stirred in nitrogen atmosphere in an oil bath at 75° C. for 5 days, and in an oil bath at 85° C. for 2 days. To the reaction mixture was added 10% aqueous solution of citric acid (10 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2) to obtain a pale yellow foam solid. The purified pale yellow foam solid was dissolved in concentrated hydrochloric acid (8 mL) at room temperature, and after transferring the resulting acidic aqueous solution using 6N hydrochloric acid to a separatory funnel, solution was washed with chloroform (50 mL×8). To the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath, and hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3), and lower layer of a mixed solvent chloroform, methanol, and water (chloroform:methanol:water, 7:3:1) (100 mL). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by recrystallization from ethanol-isopropanol system, and the crystals were dried under reduced pressure to obtain 332 mg (2 steps, 42%) of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[Br:18].Cl[CH2:20][CH:21](OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Br:18][C:3]1[C:2]2[N:7]([CH:20]=[CH:21][N:1]=2)[N:6]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(-c2cc(Br)c(N)nn2)cc1
Reactant: CCOC(CCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cc(Br)c3nccn3n2)cc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of methyl 4-(6-amino-5-bromopyridazin-3-yl)benzoate (1.64 g, 5.32 mmol), 2-chloro-1,1-diethoxyethane (0.984 g, 6.39 mmol) and PTSA (1.215 g, 6.39 mmol) in isopropanol (50 mL) was heated to 80° C. for 40 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHCO3 solution (50 mL), extracted with dichloromethane (50 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give methyl 4-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (640 mg, 36%) as a white solid. LC-MS: [M+H]+, 333.9, tR=1.637 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:18][C:19]1[CH:20]=[C:21]([NH2:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[O:17][C:14]3([NH:28][C:21]=2[CH:20]=1)[CH2:15][CH2:16][N:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[CH2:12][CH2:13]3
Reactant: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N2CCC3(CC2)Nc2cc(Cl)ccc2C(=O)O3)cc1
Yield: 94 %

Procedure:
A mixture of 5.82 g (0.023 mol) of the compound of (B), 4 g (0.023 mol) of 4-chloroanthranilic acid, 75 ml of toluene, and 0.1 of p-toluenesulfonic acid is stirred at reflux with the azeotropic removal of water for 5 hours. After cooling, the resulting precipitate is collected, and washed with cold toluene to give 8.8 g (94%) of title compound: m.p. 193°-194° C.; IR (KBr) 3350, 1695, and 1600 cm-1 ; NMR (DMSO-d6) δ 7.84-7.70 (m, 2H), 7.76 (d, 2H), 7.16 (d, 2H), 6.90-6.84 (m, 1H), 3.78-3.66 (m, 2H), 3.48-3.36 (m, 2H), 3.12 (s, 3H), 2.18-2.08 (m, 2H) and 1.96-1.82 (m, 2H); MS m/e 487 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)(=O)=O.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CI>O1CCOCC1>[CH3:21][S:2][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[C:9]=2[CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1Nc2cccnc2Nc2ccc(S(=O)(=O)Cl)cc21
Solvent: CI
Solvent: C1COCCO1
Product: CSc1ccc2c(c1)C(=O)Nc1cccnc1N2

Procedure:
Intermediate 7, freshly prepared from 6 (0.5 g, 2.4 mmol) , was reduced with triphenylphosphine (2.8 g, 11.0 mmol) in dioxane (20 mL) for 2 h at 90° C. See Oae, S.; Togo, H., Bull. Chem. Soc. Jpn., 1983, 56, 3802, which is specifically incorporated by reference herein. The crude 8-thio-derivative was quenched (10 min, 25° C.) with excess methyl iodide (0.5 mL, 8.0 mmol) and crystallized from toluene to yield 50 mg (8% from 6) of 8 as a waxy solid: 1H NMR (CDCl3) δ 2.40 (s, 3 H, CH3), 6.25 (br s, 1 H, NH), 6.66 (d, J=8.3, 1 H), 6.86 (dd, J=7.7, 4.4 Hz, 1 H), 7.06 (d, J=8.2 Hz, 1 H), 7.24 (dd, J= 8.3, 2.3 Hz, 1 H), 7.79 (d, 13 J=2.3 Hz, 1 H), 7.91 (d, J=4.5 Hz, 1 H); MS (CI/NH3) m/e 258 (MH+, base), 243,211, 113.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH:12]=[CH:11]N=[CH:9]2)=[O:7])=[C:4]([Cl:15])[CH:3]=1.CN[CH:18]1[CH2:23]CC[CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH:12]2[CH2:11][CH2:20][CH2:19][CH2:18][CH2:23]2)[CH3:9])=[O:7])=[C:4]([Cl:15])[CH:3]=1
Reactant: Nc1ccc(C(=O)n2ccnc2)c(Cl)c1
Reactant: CNC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc(N)cc1Cl)C1CCCCC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A mixture of 15 gm of N-(4-amino-2-chloro-benzoyl)-imidazole (m.p. 122°-127° C) and 150 ml of N-methyl-cyclohexylamine was stirred at 130° C for 4 hours. Subsequently, chloroform was added to the reaction mixture, and the resulting mixture was extracted twice with 300 ml of water. The organic phase was dried with sodium sulfate and evaporated. The oily residue was purified by chromatography on a silicagel column with chloroform/methanol (6:1), and the combined eluate fractions containing the desired product were evaporated. The residue was crystallized from isopropanol, yielding 4-amino-2-chloro-N-cyclohexyl-N-methyl-benzoic acid amide, m.p. 166°-170° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH3:18])[CH:14]([CH3:17])[CH2:15][CH3:16])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH3:18])[CH:14]([CH3:17])[CH2:15][CH3:16])[N:12]=1
Reactant: CCC(C)N(C)c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Phosphoryl chloride (1.33 mL) was added dropwise to DMF (5 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 6-chloro-N-methyl-N-(1-methylpropyl)pyrazin-2-amine (1.43 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 80° C. for 18 hr, water (5 mL) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10'50% ethyl acetate/hexane) to give the title compound (1.43 g, 88%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].CCN(CC)CC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nccn1Cc1cc(Cl)cc(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylamine was dissolved in CH2Cl2 and Et3N was added followed by benzoyl chloride. The reaction mixture was stirred at room temperature for 2 h and washed with 1N HCl, saturated NaHCO3 and water. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH to afford N-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-benzamide (40 mg, 56%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([OH:27])=O)=[CH:5]1.C([N:30](CC)CC)C.ClC(OCC)=O.N>CN(C)C=O.C(OCC)(=O)C>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([NH2:30])=[O:27])=[CH:5]1
Reactant: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(=O)O)cn(CCF)c3c2)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(N)=O)cn(CCF)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
The 1-(2-fluoroethyl)-7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (174 mg, 0.450 mmol) obtained in (B) was dissolved in dimethylformamide (3 ml), added with triethylamine (0.126 ml, 0.900 mmol) and ethyl chloroformate (0.086 ml, 0.900 mmol) under ice cooling, and then the mixture was stirred for 1 hour. The reaction mixture was warmed to room temperature, stirred for 30 minutes and further stirred at 0° C. for 1 hour. The reaction mixture was added with concentrated aqueous ammonia (0.15 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated to obtain the title compound (164 mg, 94%) as pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[C:10](=[O:35])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[C:42]([O:46][CH3:47])(=[O:45])[CH:43]=[CH2:44].O>CN(C)C=O>[O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)[C:10](=[O:35])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:44][CH2:43][C:42]([O:46][CH3:47])=[O:45]
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCn1c(=O)n(CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
2,4-Dioxo-3-[3-(4-diphenylmethoxypiperidino)propyl]-1,2,3,4-tetrahydroquinazoline (3.50 g) obtained in Example 79 and potassium carbonate (1.24 g) were suspended in N,N-dimethylformamide (50.0 ml), and then methyl acrylate (1.01 ml) was added. The reaction mixture was stirred at 120° C. for 20 hours, poured onto an iced water, and then extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (3:1, v/v) to give the title compound (1.73 g, 42%) as a crystal. This product was used in the next reaction without further purification.