Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][N:13]=1>N1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([C:16]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[C:4]#[N:5])=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(N)c(C#N)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)c(C#N)c1
Yield: 18.1 %

Procedure:
A mixture of 2-amino-5-methyl-benzonitrile (80 mg, 0.61 mmol) and 6-chloronicotinoyl chloride (162 mg, 0.92 mmol) in anhydrous pyridine (5 ml) was refluxed for 4 hours. The mixture was diluted with 50 ml of hexane:ethyl acetate (1:1), wash with 2 N HCl (25 ml), water (25 ml), followed by saturated aqueous NaCl (25 ml), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (2:1) to give 30 mg (18% yield) of the title compound as pale pink solid. 1H NMR (DMSO-d6): 10.82 (s, 1H), 8.99 (d, J=2.4 Hz, 1H), 8.38 (dd, J=2.4, 8.1 Hz, 1H), 7.78-7.73 (m, 2H), 7.61-7.48 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]1(C)C=CC=C[CH:14]=1>S(Cl)(Cl)=O>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([Cl:11])=[N:10][C:2]=1[Cl:1])[CH3:14]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A suspension of 2,6-dichloro-5-fluoronicotinic acid (43 g, 205 mmol) in thionyl chloride (200 mL) and toluene (200 mL) was refluxed for 3 h to yield a clear solution. The solution was cooled and the solvent was evaporated under vacuum. The residue was cooled in an ice bath and cold anhydrous ethanol was added slowly. After stirring 15 min at 0° C., the solution was refluxed for 30 min under argon. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 48.5 g (99%) of 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester (65) as colorless viscous oil. 1H-NMR (DMSO-d6): δ 1.32 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2 Hz, 2H), 8.46 (d, J=8.0 Hz, 1H); EIMS m/z 238 (M).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To the solution of 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (100 mg, 0.23 mmol) in THF (4.5 mL) was added palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (31.8 mg, 0.045 mmol). The reaction mixture was stirred at RT under 1 atm of H2 for 40 h. The reaction mixture was filtered through a pad of celite and washed with THF. The filtrate was washed with a mixture 1 N NaOH and brine. The aqueous layer was extracted with EtOAc and MeOH (3×) and the combined organics were dried and concentrated. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 95% over 15 min then neutralization to provide 1-(4-(3-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as white solid. MS (ESI, pos. ion) m/z: 444.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[C:15](#[N:17])[CH3:16].[H-].[Na+].CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([CH2:16][C:15]#[N:17])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 47.4 g of ethyl 2,4-dichloro-5-fluoro-benzoate and 8.2 g of anhydrous acetonitrile are added dropwise to a suspension of 6.1 g of 80% strength sodium hydride in 100 ml of anhydrous tetrahydrofuran under reflux in the course of about 1 hour. The mixture is heated at the boiling point under reflux for a further hour and cooled to room temperature, and 150 ml of ether are added. The precipitate is filtered off with suction and dissolved in 50 ml of ice-water and the solution is acidified to pH=6 with 10% strength hydrochloric acid. The precipitate is filtered off cold with suction, rinsed with ice-water and dried in vacuo at 40° C. 16 g of 2,4-dichloro-5-fluoro-benzoylacetonitrile of melting point 96°-98° C. are obtained.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[CH:9][N:8]=[C:7]([NH:20][CH3:21])[N:6]=2)[CH2:3][CH2:2]1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O>[CH:22]1([NH:28][C:13]2[N:12]=[C:11]([C:10]3[C:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)=[N:6][C:7]([NH:20][CH3:21])=[N:8][CH:9]=3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CNc1ncc(-c2ccnc(S(C)=O)n2)c(CC2CC2)n1
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Product: CNc1ncc(-c2ccnc(NC3CCCCC3)n2)c(CC2CC2)n1
Temperature: 160 °C
Yield: 69.8 %

Procedure:
To a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-1) (50 mg, 0.165 mmol) in DMSO (1 mL), cyclohexylamine (94 μL, 0.824 mmol) was added, and the reaction was heated in the microwave at 160° C. for 10 minutes. The crude reaction was purified by reverse-phase HPLC [30-100% organic phase with 3% n-propanol modifier over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 10% MeOH/DCM] to obtain the pure desired product as a white solid (39.0 mg, 69.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.04-0.20 (m, 2H) 0.37 (d, J=7.58 Hz, 2 H) 0.99-1.19 (m, 2 H) 1.19-1.36 (m, 4 H) 1.59 (d, J=11.62 Hz, 1 H) 1.65-1.80 (m, 2 H) 1.88 (d, J=8.59 Hz, 2 H) 2.72-2.90 (m, 5 H) 3.63-3.80 (m, 1 H) 6.68 (d, J=5.05 Hz, 1 H) 6.96 (d, J=8.08 Hz, 1 H) 7.29 (br. s., 1 H) 8.24 (d, J=5.05 Hz, 1 H) 8.36 (br. s., 1 H). HRMS (ES+) for C19 H26N6.H+ [MH+]: calcd, 339.2297. found, 339.2312. UV-LC: 100% UV purity at 254/214 nm; tR=6.70 minutes over 7.75 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][NH:38][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[N:2]([CH3:22])[CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cnc(NCCC2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Temperature: 97 °C

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid dimethylamide (473 mg, 1.43 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (814 mg, 3.56 mmol) and diisopropylethylamine (0.747 mL, 4.29 mmol) in 1,4-dioxane (5 mL) is heated at 97° C. under nitrogen for 2 days. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with MeOH in dichloromethane 0-2%, to give 4-{2-[4-(6-dimethylcarbamoyl-benzo[b]thiophen-2-yl)-5-methylpyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester. The intermediate is then subject to deprotection by dissolving in dichloromethane (20 mL) and treating with triethylsilane (0.9 mL) and TFA (4 mL). The resultant yellow solution is stirred at room temperature for 1 hour. After concentration and subsequent chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 3-12%, the fractions containing the desired product are collected and concentrated to give yellow foam. This foam is dissolved in MeOH (20 mL), treated with 0.5 N LiOH (20 mL) then concentrated to give the crude product of the title compound as yellow foam. It is used for next reductive methylation without further purification.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)[CH:7]2[CH2:6][C:5]2[CH:32]=[CH:33][C:2](/[CH:36]=[CH:35]/[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[CH:3][CH:4]=2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Yield: 90.4 %

Procedure:
The title compound was prepared as described in Example 135, using 1-(4-bromobenzyl)-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (1.22 g, 2.43 mmol) and ethyl acrylate (0.50 g, 5.0 mmol) to provide the title compound (1.146 g, 90% yield): 1H NMR (CDCl3) 7.65 (d, 1H), 7.33-7.44 (m, 7H), 7.02 (d, 2H), 6.92 (m, 2H), 6.69-6.78 (m, 5H), 6.39 (d, 1H), 5.03 (s, 2H), 4.76 (t, 1H), 4.26 (q, 2H), 3.55 (m, 1H), 3.48 (m 1H), 3.18 (dd, 1H), 2.95 (m, 2H), 2.67 (dt, 1H), 1.31 (t, 3H); ES-MS m/z 522 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].O=[C:16]([CH:20]=[N:21][OH:22])[CH:17]=[N:18][OH:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:16]([CH:20]=[N:21][OH:22])[CH:17]=[N:18][OH:19]
Reactant: O=C(C=NO)C=NO
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: ON=CC(C=NO)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 2,6-dichloro-4-trifluoromethylphenylhydrazine (34 g), 2-oxopropanedial 1,3-dioxime (17 g) and ethanol (300 ml) was heated under reflux for 31/2 hours. The solvent was evaporated under reduced pressure and the residue triturated with light petroleum (bp 40°-60°) and filtered to give 2-oxopropanedial 2-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 1,3-dioxime. This product (36 g) was stirred in acetic anhydride (350 ml) and acetic acid (220 ml) at room temperature for 45 mins. The mixture was poured into water and filtered and the residue dried in vacuo at 40° to give 2-oxopropanedial 1-acetyloxime 2-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 3-oxime.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: [O-][n+]1c(Cl)cccc1Oc1ccccc1

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.47 g (0.0050 moles of phenol was reacted with 0.200 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 6 hours to give 2-chloro-6-phenyloxypyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 3.5 hours to give 1-hydroxy-6-phenyoxypyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCl to pH 3. The water solution was extracted with dichloromethane (2×25 ml) and was dried over sodium sulfate. The dichloromethane solution was stripped in vacuo to give 1.29 g which was purified with Flash Chromatography(9:1 ethyl acetate:methanol):0.82 (65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1.Cl[CH2:19][C:20]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:21]=1[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][N:12]1[C:11](=[O:16])[CH:10]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:19][C:20]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:21]=3[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:3][C:4]=2[F:17])[C:13]1=[O:14]
Reactant: Cn1c(=O)cnn(-c2ccc(O)cc2F)c1=O
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2ncc(=O)n(C)c2=O)c(F)c1
Yield: 78.9 %

Procedure:
By the method of Example 1, Step I, 0.47 g (0.002 mole) of 2-(4-hydroxy-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5-dione and 0.73 g (0.003 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate were reacted in the presence of 0.41 g (0.003 mole) of anhydrous potassium carbonate in 30 mL of N,N-dimethylformamide, yielding 0.70 g of methyl 2-[2-[4-(4-methyl-1,2,4-triazine-3,5-dion-2-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The IR and NMR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH=8.0 Hz); 2.30 (s, 3H); 3.40 (s, 3H); 3.78 (s, 3H); 4.84 (q, 1H, JHH=8.0 Hz); 5.18 (dd, 2H, JHH=10 Hz); 6.58 (s, 1H); 6.8-7.3 (m, 5H); 7.54 (s, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].[CH2:22](O)[CH3:23]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([O:17][CH2:22][CH3:23])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C(C)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C

Procedure:
Two hundred grams of 2-(3-phenoxyphenyl)propionic acid, prepared according to Example 2, were dissolved in 1500 ml. of ethanol, and hydrogen chloride gas was passed into the ethanolic solution until it was saturated. The reaction mixture was then refluxed with stirring overnight after which a large portion of the ethanol was evaporated in vacuo, and the remaining reaction mixture was poured into ice water. The reaction mixture was basified with 10 percent sodium hydroxide, and extracted twice with ethyl ether. The combined ether extracts were washed twice with water and dried over sodium sulfate. The ethyl ether was evaporated, leaving crude ethyl 2-(3-phenoxyphenyl)propionate as an oily residue. The preparation was repeated with an additional 200 g. of 2-(3-phenoxyphenyl)propionic acid. The crude residues were combined and distilled through a 15 cm. Vigreux column to yield 339.9 g. of ethyl 2-(3-phenoxyphenyl)propionate, b.p., 128°-134°C./0.15 mm., nD25 = 1.5458.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:12][C:13](Br)=[C:14]([CH3:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:1]1([S:7]([NH:10][C:11]2[S:12][C:13]([C:25]3[CH:26]=[CH:27][O:23][CH:24]=3)=[C:14]([CH3:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(Br)c1C
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(-c2ccoc2)c1C
Temperature: 150 °C
Yield: 36.2 %

Procedure:
A mixture of ethyl 2-benzenesulphonylamino-5-bromo-4-methylthiophene-3-carboxylate (Intermediate 34, 0.134 g), 3-furan boronic acid (0.056 g) and potassium carbonate (0.114 g) in dioxane (1.3 ml) and water (0.33 ml) was degassed and placed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.019 g) was added and the mixture was heated in the microwave at 150° C. for 15 minutes. The solvent was removed and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-benzenesulphonylamino-5-(furan-3-yl)-4-methyl-thiophene-3-carboxylate (0.047 g) as a white solid.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1.[O:18]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)[CH2:19]1.C(#N)C>C(N(CC)CC)C>[CH3:17][O:16][CH2:15][C:4]1[CH:3]=[C:2]([N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:20]2[CH2:21][CH2:22][O:18][CH2:19]2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Reactant: c1c[nH]c(C2CCOC2)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCc1cc(-n2ccnc2C2CCOC2)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 74.6 %

Procedure:
To a mixture of 6.0 g of methyl 4-fluoro-2-(methoxymethyl)-5-nitrobenzoate, 3.5 g of 2-(tetrahydrofuran-3-yl)-1H-imidazole, and 60 mL of acetonitrile was added 6.9 mL of triethylamine, followed by stirring at 70° C. for 5.5 hours. The reaction mixture was concentrated, and water and ethyl acetate were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 6.65 g of methyl 2-(methoxymethyl)-5-nitro-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[N:3]=[C-:2]1.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27]Br)[CH:15]=1)[CH3:10].[O:30]1CCOCC1>>[CH2:9]([O:11][C:12](=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:30])[CH:15]=1)[CH3:10]
Reactant: O=C1CO[C-]=N1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2CBr)c1
Reactant: C1COCCO1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1cccc(Oc2ccccc2CN2CCOC2=O)c1
Reaction time: 0.17 h

Procedure:
To 2-oxazolidone (0.083 g, 1.0 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (60% in mineral oil; 0.041 g, 1.03 mmol), and the mixture was stirred for 10 minutes. [3-(2-Bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.30 g, 0.86 mmol) was added in 1,4-dioxane, and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by preparative HPLC to give the desired product (0.14 g).
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.N1C=CC=CC=1.Cl>O>[CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1
Reactant: C1CNCCN1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Yield: 74.3 %

Procedure:
A mixture of 1.95 g of 1-methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 3.05 g of anhydrous piperazine and 20 ml of dry pyridine is refluxed for 6 hours. The solvent is stripped off in vacuo, the residue is taken up in 20 ml of water, the pH is brought to 7-8 with half-concentrated hydrochloric acid, with cooling, and the precipitate is filtered off with suction, washed with ice-water and dried at 100° C. in vacuo. 1.8 g of 1-methylamino-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 276°-278° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH3:12][C:13]1[S:14][C:15]([CH:19]=[O:20])=[C:16]([CH3:18])[N:17]=1>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH3:12][C:13]1[S:14][C:15]([CH:19]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[OH:20])=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1nc(C)c(C=O)s1
Agent: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)c2cnnn2C)s1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
1-methyl-1H-1,2,3-triazole was prepared according to the literature reference WO2008/98104. To a 2 L flask containing 1-methyl-1H-1,2,3-triazole (9 g, 108.3 mmol) was added THF (1500 mL) and the solution was cooled to −40° C. To this colorless homogeneous solution was added n-butyllithium (2.5 M in hexanes, 45 mL, 112.5 mmol) dropwise which immediately afforded a dark brown viscous mixture. The mixture was kept between −10 to −20° C. for 60 minutes, then a THF solution of 2,4-dimethylthiazole-5-carbaldehyde (17.2 g, 121.8 mmol in 200 mL THF) was introduced via cannula. Once the aldehyde was added the reaction was allowed to warm to room temperature. After 3 hours, the reaction was quenched by pouring into a saturated solution of aqueous NH4Cl. The aqueous portion was extracted with EtOAc in portions, 7×400 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a brown oil. Chromatography on silica gel (10% acetone-DCM increasing to 50% acetone and increasing to 10% MeOH-DCM) provided the title compound as an amber solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][NH:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][N:24]2[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CC2CNC1CN2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A mixture of 0.28 g (1 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.2 g (1.1 mmole) 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 0.45 ml (3.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10 ml of acetonitrile was heated at reflux for four hours. After cooling to room temperature, the reaction mixture was filtered and the solid washed with ethanol and dried to give 0.27 g of the title compound, mp 275°-280° C.