Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])C1C=CC=CC=1.C([O:32][CH2:33][CH3:34])(=O)C>CN(C)C=O.C(N(CC)CC)C>[NH:18]1[C:22](=[O:26])[CH2:23][CH2:25][C@H:34]1[C:33]([NH:24][C@H:23]([C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([OH:9])=[O:28])=[O:27])=[O:26])[CH3:25])=[O:32]
Reactant: CCOC(C)=O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (2.46 g, 6 m mole) was dissolved in dimethylformamide (10 ml, and triethylamine (0.84 ml, 6m mole) was added thereto under cooling to neutralize it and then benzyloxycarbonyl-L-pyroglutamic acid N-hydroxysuccinimide ester (2.38 g, 6.6 m mole) was added thereto. The mixture was stirred for 2 days while the solution had been adjusted to a pH of about 7 with triethylamine and then ethyl acetate (150 ml) was added thereto. The solution was washed with 1N hydrochloric acid, 5% aqueous sodium bicarbonate and water in order. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the thus obtained residue, n-hexane was added to form a powder. This powder was purified by column chromatography. (Silica gel, developing solvent; chloroform:ethanol:ethyl acetate=5:1:5). The fractions of the main ingredient were collected together and then concentrated. To the residue, n-hexane was added to precipitate the powder. They were dissolved in methanol (50 ml) and then hydrogen gas passed through the solution in the presence of palladium-carbon as a catalyst for 4 hours. The catalyst was separated by filtration and the solvent was distilled off. The thus obtained residue was recrystallized with methanol-ether to give L-pyroglutamyl-L-alanyl-L-prolyl-L-proline (880 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[NH2:19]OS(O)(=O)=O>CN(C=O)C>[NH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Cl:1])=[CH:3]1
Reactant: Clc1c[nH]c2ccccc12
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nn1cc(Cl)c2ccccc21
Temperature: 0 °C
Yield: 40.4 %

Procedure:
To a stirred solution of 12.6 g of 3-chloroindole in 125 ml of dry DMF at 0° C. was added 0.5 g of milled K2CO3 in 20 ml of dry DMF, followed by 30 g of KOH in 20 ml of dry DMF. The mixture was cooled to about 0° C. after which was added 13.3 g of NH2OSO3H such that the temperature did not rise above 0° C. When addition was complete, a second charge of 2.22 g of NH2OSO3H was added. When addition was complete a third 2.22 g charge of NH2OSO3H was added. The mixture was poured into ice/water/toluene, extracted into toluene, washed with water and concentrated to provide 5.6 g of an oil which crystallized on standing overnight.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:9]2)C.[O:23]=[S:24]1(=[O:31])[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[C:16]1([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([CH2:5][C:4]([OH:3])=[O:22])=[CH:14][C:13]=3[NH:15][CH:27]2[CH2:28][CH2:29][S:24](=[O:31])(=[O:23])[CH2:25][CH2:26]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCS(=O)(=O)CC1
Reactant: CCOC(=O)Cc1cc(N)c2[nH]c(-c3ccccc3)cc2c1
Product: O=C(O)Cc1cc(NC2CCS(=O)(=O)CC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-(2-Phenyl-7-amino-1H-indol-5-yl)acetic acid ethyl ester prepared as an intermediate in the process of Example 31 and 1,1-dioxo-tetrahydro-thiopyran-4-one were reacted according to the same procedures as Step B of Example 1 and Example 30 to give the title compound.
Reaction SMILES: [Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16].CCN(CC)CC>ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:16]#[C:15][CH2:14][CH2:13][OH:17])=[CH:7][CH:6]=1
Reactant: CC(Br)COc1ccc(I)cc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)COc1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 4-(2-Bromopropoxy)-1-iodobenzene (10 g, 29 mmol), 3-butyn-1-ol (2.6 mL, 37 mmol), CuI (980 mg, 5.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (3.6 g. 5.2 mmol) in dichloromethane (40 mL) was added Et3N (6.0 mL, 44 mmol) dropwise. The reaction was stirred overnight at room temperature under Ar. The solvent was evaporated under reduced pressure and ethyl acetate was added to dissolve the compound, the solution was filtered over celite to remove most of the Pd. The crude product was purified by silica gel chromatography, eluted with hexane/ethyl acetate (2:1). 2.6 g of the title compound were obtained as a light brown solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][CH:30]=[CH:31][N:32]=2)=[CH:24][C:23]=1[F:33])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].[CH3:34][Mg]Br.C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)=[CH:24][C:23]=2[F:33])[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[C:1]([OH:3])([CH3:34])[CH3:2])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: C[Mg]Br
Reactant: CC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(-c2ncco2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)[C@@H]1CCCC[C@H]1N(Cc1ccc(-c2ncco2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 13 %

Procedure:
N-((1R,2R)-2-acetylcyclohexyl)-4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)benzenesulfonamide (150 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5.0 mL) and a solution of 1.4M methyl magnesiumbromide in 3:1 toluene/tetrahydrofuran (2.0 mL, 2.8 mmol) was added. After 1 h, TLC indicated conversion to a new product. The reaction mixture was quenched with methanol followed by saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to give a mixture of starting material and product. The crude mixture was purified by flash chromatography on silica gel twice using a gradient of 15-50% ethyl acetate/hexanes followed by 10-35% ethyl acetate/hexanes to give 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(2-hydroxypropan-2-yl)cyclohexyl)benzenesulfonamide as a colorless oil (20 mg, 13% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.66-7.78 (m, 4H), 7.62 (dd, J=10.83, 1.51 Hz, 1H), 7.52 (t, J=7.81 Hz, 1H), 7.35-7.45 (m, 2H), 7.21-7.28 (m, 3H), 4.44-4.56 (m, 2H), 3.87 (d, J=3.02 Hz, 1H), 3.06 (s, 1H), 1.85 (d, J=8.31 Hz, 2H), 1.62-1.69 (m, 2H), 1.52-1.61 (m, 3H), 1.49 (br. s., 1H), 1.18 (s, 3H), 1.05-1.16 (m, 7H). MS [M+H+Na]+=529.19.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:9]
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)O
Reactant: NNC(N)=S
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 250 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 28.2 grams (0.120 mole) of 2-(2,4-dichlorophenoxy)propanoic acid, (10.9 grams, 0.120 mole) of thiosemicarbazide and 90 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (20.2 grams, 0.13 mole) was slowly added (for 38 minutes) while maintaining the temperature within 90°-95° C. The resulting mixture was refluxed for 115 minutes, and then evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane). One hundred (100) milliliters of water was added and 50 percent NaOH solution was also added until the pH of the solution was 10. An oil formed, which was extracted with a mixture of CH2Cl2, CHCl3 and diethyl ether, and the organic phase was dried over anhydrous MgSO 4, filtered and topped on a roto-vac at 70° C. to a grey sludge. Upon addition of diethylether, a first crop of crystals formed which were removed by filtration and then dried in a vacuum oven at 80° C. to crystals containing 5-[1-(2,4-dichlorophenoxy)ethyl-2-amino-1,3,4-thiadiazole (9.7 grams). Addition of hexane to the filtrate produced a second crop of crystals which were filtered off, dried in a vacuum oven at 80° C. to 10.1 grams of crystals. The first and second crop of crystals were combined, and recrystallized from the minimum amount of an ethanol water mixture, suction filtered, and dried in a vacuum oven at 80° C. to 17.1 grams of a grey powder of 5-[1-(2,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 119°-123° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])=[O:7].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC=CC=1>C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[O:19][CH2:18][CH2:17][O:7]1
Reactant: OCCO
Reactant: COc1ccc(Cl)cc1C(=O)CCCCCl
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cl)cc1C1(CCCCCl)OCCO1
Yield: 95.4 %

Procedure:
A mixture of 5-chloro-1-(5-chloro-2-methoxyphenyl)-1-pentanone (2 g, 7.66 mmol), prepared as in Example 7, ethylene glycol (1.25 g, 20 mmol), 2-napthalenesulfonic acid (50 mg, 0.24 mmol) and toluene (approximately 80 mL) was heated 4-5 hours at reflux (removing water with a Dean-Stark trap) and then additional ethylene glycol (1 g, 16 mmol) was added. The mixture was heated approximately 16 hours at reflux and then washed with saturated sodium bicarbonate, water (3×) and brine (1×), dried (K2 CO3), filtered and concentrated to give 5-chloro-1-(5-chloro-2-methoxyphenyl)-1,1-ethylenedioxypentane (2.23 g, 7.31 mmol) as an oil.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]([CH3:12])[N:6]=1.C1(C)C=CC=CC=1>O>[Cl:4][C:5]1[N:6]=[C:7]([CH3:12])[N:8]=[C:9]([S:2][CH3:1])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1nc(C)nc(Cl)n1
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Sodium methanethiolate (0.49 g, 7.0 mmol) was added portionwise at 0° C. to a stirred cloudy solution of 2,4-dichloro-6-methyl-1,3,5-triazine (7) (1.04 g, 6.3 mmol) in toluene (10 mL, 94 mmol) over 15 min. After addition, the pale yellow mixture was stirred at the same temperature for another 1 h, and water (10 mL) was added. The separated aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography (hexanes to 70% DCM in hexanes) to give 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (0.87 g, 78% yield) as a white solid. MS (API-ES) m/z 176 (M+H)+; 1H NMR (d6-DMSO, 400 MHz) δ 2.55 (s, 3H) 2.51 (br. s., 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:22][CH2:23][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)([OH:9])[CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
To a solution of (4-fluorophenyl)(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (4.0 g, 21.84 mmol) in dry THF (150 mL) was added EtMgBr (1 M in THF, 150 mL) at 0° C. under nitrogen. The mixture was stirred at RT for 3 h, then quenched with NH4Cl solution and extracted with ethyl acetate (200*3 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-flash with dichloromethane:methanol=10:1 to give the title compound (440 mg, 10%) as a yellow solid. MS (ES+) C17H21FN4O requires: 316. found: 317 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][OH:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Cl)ccc1NCCO
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 1,4-dichloro-2-nitrobenzene (I-1, Aldrich, Wis.; 38.4 g, 0.2 mol) and 2-aminoethanol (24.4 g, 0.4 mol, 2 eq.) in n-butanol (100 mL) was refluxed overnight. The solvent was evaporated and the residue was dispersed in petrol ether (600 mL) and stirred overnight. The solids were filtered to give intermediate I-2 as a yellow powder (37 g, 86%). 1H-NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 8.19˜8.20 (d, 1H, J=2.4 Hz), 7.39˜7.42 (dd, 1H, J1=2.4 Hz, J2=9.2 Hz), 6.87˜6.90 (d, 1H, J=9.6 Hz), 3.95˜3.98 (t, 2H, J=5.2 Hz), 3.49˜3.53 (dd, 2H, J1=4.8 Hz, J2=10.4 Hz). MS (ESI): m/z 217 (M+H+).
Reaction SMILES: [CH3:1][P:2]1(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49](OC(=O)C)[CH:50]=[CH2:51])=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1.C([O-])(=O)C>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49]=[CH:50][CH2:51][N:5]5[CH2:6][CH2:7][P:2]([CH3:1])(=[O:8])[CH2:3][CH2:4]5)=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reactant: CP1(=O)CCNCC1
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCN4CCP(C)(=O)CC4)[nH]c(=O)c3c2n1C
Reaction time: 0.33 h
Yield: 10.2 %

Procedure:
To a glass scintillation vial was added 4-methyl-[1,4]azaphosphinane 4-oxide (100 mg, 0.75 mmol). To a separate glass vial was added tris(dibenzylacetone)dipalladium (28 mg, 0.031 mmol), triphenylphosphine (30 mg, 0.12 mmol), and THF (2.5 mL). The resulting solution was stirred for 20 minutes, then acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.270 g, 0.621 mmol) was added as a solution in THF (7.0 mL), followed by TEA (0.90 mL, 12.2 mmol). Of the resulting solution, 2.4 mL (0.15 mmol total allylic acetate) was transferred to the vial containing 4-methyl-[1,4]azaphosphinane 4-oxide. The solution was stirred at room temperature for 20 h. The solvent was removed in vacuo and the resulting solid redissolved in MeCN (2 mL) and DMSO (2 mL). The solution was filtered, then purified directly by preperative reverse-phase HPLC (0% to 100% MeCN:H2O+0.1% formic acid) to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ5[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (32 mg, 42%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.33 (br s, 1H), 10.68 (br s, 1H), 7.79 (d, 1H, J=8.6 Hz), 7.72 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.9 Hz, J2=9.8 Hz), 7.25 (td, 1H, J1=3.1 Hz, J2=8.6Hz), 7.19-7.15 (m, 2H), 6.54-6.48 (m, 1H), 4.18 (s, 3H), 4.10-4.00 (br s, 2H), 3.80-3.30 (br m, 4H), 3.16 (s, 3H), 2.36 (s, 3H), 3.31 (s, 3H), 2.30-2.10 (br m, 4H), 1.7-1.6 (br r, 3H); ESMS (m/z): found, 508.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1.BrC1C=C(C)C=C2C=1C(O)=CC=N2.O=P(Cl)(Cl)[Cl:29]>C(#N)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:29])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Br)cc2nccc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cc1cc(Br)c2c(O)ccnc2c1
Solvent: CC#N
Product: Cc1cc(Br)cc2nccc(Cl)c12
Temperature: 90 °C
Yield: 49.5 %

Procedure:
To a vial charged with a mixture of 7-bromo-5-methylquinolin-4-ol and 5-bromo-7-methylquinolin-4-ol (0.09 g, 0.378 mmol) was added acetonitrile (1.890 ml) followed by the addition of POCl3 (0.035 ml, 0.378 mmol). The mixture was heated to 90° C. for 1.5 hr. The mixture was dried under reduced pressure and the crude residue purified with a 25 g Interchim HP spherical silica column (15 μm spherical) (0 to 50%, 10% DCM throughout) providing adequate separation of regioisomers. The major, first eluting isomer was isolated cleanly to yield 7-bromo-4-chloro-5-methylquinoline (48 mg, 0.187 mmol, 49.5% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.02 (s, 4H) 7.46 (d, J=4.69 Hz, 1H) 7.50 (dd, J=2.01, 0.93 Hz, 1H) 8.15-8.19 (m, 1H) 8.67 (d, J=4.70 Hz, 1H). m/z (ESI) 256.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1.S(Cl)([Cl:39])=O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:39])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Solvent: c1ccncc1
Product: Cc1cc(C(Cl)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Yield: 75 %

Procedure:
At room temperature, 8.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-(benzoylamino)benzamide and 1.0 g of pyridine were introduced to 40 ml of thionyl chloride. Then, the temperature was elevated, and the mixture was stirred under reflux conditions. After the loss of the starting material was confirmed through TLC, the reaction solution was cooled and was concentrated under reduce pressure. Thus obtained residue was purified by silica gel chromatography (eluent:hexane:ethyl acetate=3:1) to give 6.2 g (yield 75%) of the title compound as a powder form.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([F:27])[CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)(=O)=O>CN(C)C=O>[F:27][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=3)[CH2:23][CH2:22]2)=[C:18]2[C:13]=1[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19]2
Reactant: Cc1ccc2c(N3CCNCC3)ccc(F)c2n1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)ccc(F)c2n1
Temperature: 100 °C
Yield: 46 %

Procedure:
N,N-Diisopropylethylamine (0.25 mL; 3 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)-8-fluoro quinoline (0.170 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.17 g; 1 eq) in dimethylformamide (4.0 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 46% yield (0.126 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CC[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>CC#N>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:4]4[CH2:1][CH2:2][CH:30]([CH2:29][NH:26][CH2:27][CH3:28])[CH2:5]4)[C:12]=3[C:14]([F:15])([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C(F)(F)F)C1
Yield: 193.1 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid (0.20 g, 0.61 mmol) 3-((N-ethylamino)methyl)pyrrolidine (0.20 g, 1.6 mmol) and NEt3 (0.20 g, 2 mmol) were refluxed with stirring under N2 in CH3CN (2 mL) for 2 hours. When the reaction mixture had cooled to 20° the yellow solid was collected by vacuum filtration, washed with water (5 mL) and ether (5 mL), and then dried at 110°/0.2 mm to give 1-cyclopropyl-7-(3-((N-ethylamino)methyl)pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid (0.26 g, 97%) as a light yellow solid; mp 239°-241° C. C21H23N3O3F4 requires C, 57.14; H, 5.22; N, 9.52; F, 17.23%. Found, C, 56.77; H, 4.98; N, 9.34; F, 16.95%. Nmr (TFA) δ 9.37 (1H, s, H2), 8.09 (1H, d, J=13.8 Hz, H5), 7.2-7.5 (2H, br s, NH+2), 4.45-4.55 (1H, m, H1 pyrrolidinyl), 4.1-4.4 (2H, m, H5 pyrrolidinyl), 3.9-4.1 (2H, m, H1 cyclopropyl+pyrrolidinyl), 3.3-3.65 (4H, m, CH2s ethylaminomethyl), 2.9-3.1 (1H, m, H3 pyrrolidinyl), 2.5-2.65 (1H, m, H4 pyrrolidinyl), 1.9-2.1 (1H, m, H4 pyrrolidinyl), 1.5-1.8 (5H, m and t, J=7.1 Hz, cyclopropyl and CH3), 0.95-1.4 (2H, m, cyclopropyls). Ir (KBr) 1629, 1456, 1360 cm-1. MS 442 (4, M H⊕), 441 (4, M⊕).
Reaction SMILES: C(O)(=[O:3])C.[C:5]1([S:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OO.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[C:14]1([S:13][CH2:12][S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:3])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(SCSc2ccccc2)cc1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=S(CSc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
5 ml of acetic acid was added to 1.538 g of bis(phenylthio)methane, 0.75 ml of an aqueous solution of hydrogen peroxide (concentration: 30%) was added thereto, and then the mixture was stirred for 1 hour at room temperature. After 100 ml of methylene chloride, 6 g of potassium carbonate and a small amount of water were thereto, the resultant mixture was dried with anhydrous sodium sulfate. The product was concentrated under reduced pressure, and then the leavings were separated by means of column-chromatography (silica gel, methylene chloride). Thus 1.585 g of phenyl phenylthiomethyl sulfoxide was obtained as a colorless liquid. The yield was 96.6%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:31])[C:20]1[C:25]([O:26][CH2:27][CH3:28])=[CH:24][C:23]([CH3:29])=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][C:23]([CH3:29])=[CH:24][C:25]([O:26][CH2:27][CH3:28])=[C:20]2[C:19]=1[OH:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)cc(C)nc1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2nc(C)cc(OCC)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-ethoxy-6-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;