Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
700 mg (2.024 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid were added to a round 3-neck flask of 50 ml under a nitrogen atmosphere, and then stirred at room temperature for 10 minutes after 30 ml of chloroform and 0.491 ml (3 mmol) of pyridine were added thereto. While the temperature of the inside of the container was kept at −10° C., 0.197 ml (2.024 mmol) of methacryloylchloride was slowly dripped thereinto. After reaction for 3 hours, distilled water was added to the reactants, which were then extracted with dichloromethane, concentrated, and chromatographed (20 gm silica, 7% MeOH/CH2Cl2) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(2-methyl-1-oxo-2-propenyl)-1-piperazinyl]-4-oxo-3-quinoline carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:20]=[C:21]=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.[CH3:25][NH:26][O:27][CH3:28]>C1C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:22])[N:26]([O:27][CH3:28])[CH3:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Reactant: CNOC
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
Five grams of 3-trifluoromethyl-4-(2-naphthyloxy)phenyl isocyanate were dissolved in 100 ml of benzene, and a solution of 2 g of N,O-dimethylhydroxylamine in 50 ml of benzene was added dropwise thereto at a temperature below 30° C. The reaction mixture was allowed to stand at room temperature for 30 minutes, and the solvent was then removed under reduced pressure. The residue was recrystallized from ethanol to obtain 4.2 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea as white needles. M.P. 129°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:7][C:8]=1[CH3:9])[OH:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:14][CH:13]=1.[H-].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na+]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:3]2[C:2]([CH3:1])=[C:8]([CH3:9])[CH:7]=[C:5]([OH:6])[C:4]=2[OH:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:17]=1
Reactant: O=C(O)CCCCCC(O)c1ccc(F)cc1
Reactant: Cc1cc(O)c(O)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Reaction time: 20 h
Yield: 30.7 %

Procedure:
To a solution of 4,5-dimethylcatechol (663 mg) and 7-(4-fluorophenyl)-7-hydroxyheptanoic acid (1.15 g) in toluene (18 ml) was added sodium p-toluene sulfonate monohydride (455 ml) and the reaction was carried out at 100° C. for 20 hours. After cooling in air, the reaction mixture was extracted by addition of water and ethyl acetate. The organic layer was separated, washed in turn with water and saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by subjecting it to silica gel column chromatography and eluting with ethyl acetate/hexane (1:7) to obtain 7-(4-fluorophenyl)-7-(2,3-dihydroxy-5,6-dimethylphenyl)heptanoic acid (530 mg) (Compound 57). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+].Cl.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Brc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: c1cc(OC2CCC3(CC2)OCCO3)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (4.93 g, 31.202 mmol, 1.0 eq.) was dissolved in DMSO (100 ml); potassium tert-butylate (10.5 g, 93.61 mmol, 3.0 eq.) was added at 0° C. and the mixture was stirred for 1 hour at RT. 4-Bromopyridine HCl (9.1 g, 46.803 mmol, 1.5 eq.) was then added at 0° C. and stirring was carried out for 16 hours at RT. After monitoring by TLC, the reaction mixture was concentrated and the residue was taken up in water (200 ml) and extracted with DCM (2×200 ml). The combined org. phases were washed with water (200 ml) and sat. NaCl solution (250 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 40% ethyl acetate in hexane). Yield: 35% (2.6 g, 11.063 mmol)
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[Br:7][C:8]1[N:9]=[CH:10][S:11][C:12]=1[C@@H:13]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[CH2:15][CH2:16]C=C>C(Cl)Cl>[Br:7][C:8]1[N:9]=[CH:10][S:11][C:12]=1[C@@H:13]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])[C@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[CH2:15][CH2:16]/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C=CCC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1scnc1Br
Solvent: ClCCl
Product: COC(=O)/C=C/CC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1scnc1Br
Yield: 85.7 %

Procedure:
A mixture of methyl acrylate (0.16 mL, 1.80 mmol), GrubbsII catalyst (0.025 g, 0.030 mmol) and tert-butyl (1S,2S)-1-(4-bromothiazol-5-yl)-2-(2,3-difluorophenyl)hex-5-enylcarbamate (0.2842 g, 0.600 mmol) in methylene chloride (20 mL) was heat to reflux for 3 h under nitrogen. The solvent was removed under vacuum and the crude product was purified by silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 45% to give the desired product (273.2 mg, 86%): MS (ESI)[M+H+]=533.13. 1H NMR showed inseparable diastereomers with a ratio of 3.5:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=2)=[O:22])[O:27][N:26]=1)[CH3:24]
Reactant: CCc1cc(CN)on1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: CCc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 3-ethyl-5-isoxazolemethanamine as starting materials; LC-MS (UV peak area/ESI) 100%, 440.0985 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)COc1cc(C)ccc1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COc1cc(C)ccc1CCl
Yield: 55.4 %

Procedure:
By the method of Example 1, Step H, 9.21 g (0.044 mole) of methyl (2-hydroxymethyl-5-methylphenoxy)acetate was reacted with 7.40 g (0.062 mole) of thionyl chloride and 5 drops of pyridine in 50 mL of methylene chloride, yielding 5.57 g of methyl (2-chloromethyl-5-methylphenoxy)acetate as an orange liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1cccc(Br)c1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To a solution of 3-bromophenylacetic acid (25.0 g, 116 mmol) in carbon tetrachloride (200 ml) was added N-bromosuccinimide (22.8 g, 128 mmol) at room temperature. The mixture was refluxed for 3 hours and cooled to room temperature. The resulting precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=4/1) to afford bromo-(3-bromo-phenyl)-acetic acid as yellow liquid (27.8 g, 81%).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19])=[CH:11][C:10]=1[S:22]([Cl:25])(=[O:24])=[O:23].ClC(OCC)=O.CN>O1CCCC1.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:21])[N:3]([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[S:22]([Cl:25])(=[O:24])=[O:23]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reaction time: 0.12 h

Procedure:
2.1 g of triethylamine are rapidly added dropwise to a mixture of 6.2 g 4-(4-chloro-3-chlorosulfonylphenyl)-4-oxobutanoic acid and 2.2 g of ethyl chloroformate in 20 ml of absolute tetrahydrofurane at a rate such that the internal temperature is maintained between -5° and -10° C. The mixture is stirred for about 5 to 10 minutes at -5° to 0° C. and 1.55 ml of a 4% strength solution of gaseous methylamine in tetrahydrofurane is rapidly added dropwise. Stirring is continued for 15 to 20 minutes at 10°-15° C., the reaction mixture is poured into water and extracted twice, each time with 80 ml of ethyl acetate. The organic phase is washed once with 50 ml of 0.01 N hydrochloric acid at 0° C. and once with cold bicarbonate solution, dried for one hour over Na2SO4 at 0°-10° C. while stirring with a magnetic stirrer and concentrated on a rotavapor (bath temperature ≤30° C.). The 5-(4-chloro-3-chlorosulfonylphenyl)-5-hydroxy-1-methyl-2-oxo-pyrrolidine is mostly obtained in the form of an amorphous residue. After addition of 20 ml of 40% strength aqueous methylamine solution (cooling) the mixture is stirred overnight at room temperature, concentrated and allowed to crystallize under water. Colorless crystals, melting point 112°-114° C. (from ethanol).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH2:46])=[O:45])=[CH:42][CH:41]=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][C:40]1[CH:48]=[CH:47][C:43]([C:44](=[O:45])[NH2:46])=[CH:42][CH:41]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(C(N)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To the solution of 1 (acetylsalicylic acid, 500 mg, 2.77 mmol) in 15 mL of dimethylformamide, hydroxybenzotriazole (412 mg, 3.05 mmol) and DCC (628 mg, 3.05 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 418 mg, 3.05 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl 2-acetoxybenzoate (5) was obtained (410 mg, 47% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14]COC)([CH2:12][CH3:13])[CH2:10][CH3:11].[Li]CCCC.[B:23](OC(C)C)(OC(C)C)[O:24]C(C)C>C1COCC1>[CH2:10]([C:9]1([CH2:12][CH3:13])[O:14][B:23]([OH:24])[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]1=2)[CH3:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCC(CC)(OCOC)c1ccc(C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(CC)OB(O)c2cc(C)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a solution of 2-bromo-1-(3-(methoxymethoxy)pentan-3-yl)-4-methylbenzene (3.0 g, 10 mmol) in THF (80 mL) cooled at −78° C. was added n-BuLi (12 mL, 30 mmol) dropwise. The mixture was stirred at −78° C. for additional 1 h and then triisopropyl borate (3.76 g, 20 mmol) in 5 mL of THF was added below −70° C. The resulting mixture was kept stirring at −78° C. for 30 min and allowed to warm to rt and stirred overnight. Then it was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to provide the product (0.8 g, 39.2%). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1 H), 7.43 (s, 1 H), 7.23 (s, 1 H), 7.12 (s, 1 H), 2.3 (s, 3 H), 1.83-1.63 (m, 4 H), 0.50 (t, 6 H) ppm.
Reaction SMILES: [F:1][C:2]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])([F:4])[F:3].[C:15]1([CH2:25][C:26]([OH:28])=O)[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=1>>[F:1][C:2]([F:4])([F:3])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:26](=[O:28])[CH2:25][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22](=[O:24])[NH:14][C:11]3[CH:12]=[CH:13][C:8]([S:5]([C:2]([F:4])([F:1])[F:3])(=[O:7])=[O:6])=[CH:9][CH:10]=3)=[CH:19][CH:20]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=C(Cc1ccc(CC(=O)Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Same procedure as Example 20 except 4-aminophenyl trifluoromethyl sulfone and 1,4-phenylenediacetic acid were used. 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 2H, 2×NH), 8.04 (d, J=8.9 Hz, 4H), 7.99 (d, J=8.9 Hz, 4H), 7.84 (d, J=8.9 Hz, 2H), 7.23 (d, J=8.9 Hz, 2H), 3.71 (s, 4H, 2×CH2). MS 609 [M++1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-nitrobenzyl chloride (1 g) and N-methylpiperazine (3 ml) was stirred and heated to 100° C. for 4 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was evaporated to give 3-(4-methylpiperazin-1-ylmethyl)nitrobenzene (1.05 g); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 2.31-2.38 (m, 8H), 3.57 (s, 2H), 7.6 (t, 1H), 7.54 (d, 1H), 8.07-8.13 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH3:12])=[CH:5]2.[N+:13]([O-])([O-:15])=[O:14].[K+].N>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH3:12])=[CH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cnc2ccc(Cl)cc2c1
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cnc2ccc(Cl)c([N+](=O)[O-])c2c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
To a solution of 6-chloro-3-methylquinoline (6.3 g, 35.6 mmol) in concentrated H2SO4 (22 mL) was added dropwise a solution of KNO3 (3.77 g, 37.2 mmol) in concentrated H2SO4 (22 mL) at 0° C. Care was taken that the temperature of the reaction mixture did not rise above 10° C. The reaction mixture was stirred for 1 h at 0° C. and 12 h at room temperature. It was then poured onto ice (150 g) and rendered basic (pH=10) with a 33% aqueous ammonia solution. A dark yellow precipitate was formed, which was filtered off, thoroughly rinsed with water and dried in vacuo to afford the title compound as a brown solid (7.1 g, 31.9 mmol, 90%). 1H NMR (400 MHz, CDCl3, 298 K): δ=8.89 (s, 1H), 8.20 (d, J=9.0 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 2.59 (s, 3H). MS (ES+): 223 (M(C10H735ClN2O2)+H)+.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>Cl>[C:1]1([C:9]2[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=2)([C:9]2[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: O=C1CCC1
Agent: Cl
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC2)cc1

Procedure:
Cyclobutanone (1.2 g, 17 mmol) and phenol (4.8 g, 51 mmol) were stirred in concentrated HCl (7 mL) at 40° C. for 72 h. The resulting slurry was filtered and the filter cake was dissolved in EtOAc and washed with saturated NaHCO3 (aq) and brine. The organic layer was concentrated to give a solid which was recrystallized from EtOAc/CH2Cl2 to provide the title compound. LCMS (ESI, neg. ion): m/z=239 [M−H]−; 479 [2M−H]−. 1H NMR (500 MHz, CD3OD): δ 7.10 (d, J=8.6 Hz, 4H), 6.70 (d, J=8.6 Hz, 4H), 2.65 (t, J=7.5 Hz, 4H), 1.93 (quint, J=7.5 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[N:7]=[C:6]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:5]=1.Cl[CH2:27][C:28]1([CH2:31]C)[CH2:30][O:29]1.O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]([CH2:27][C:28]3([CH3:31])[CH2:30][O:29]3)[CH:14]=2)[N:7]=[C:6]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][N:17]=2)[CH:5]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cn[nH]c2)c1
Reactant: CCC1(CCl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC3(C)CO3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (20.7 mg, 0.52 mmol) was added to a solution of 4-methyl-6-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (150 mg, 0.47 mmol) in DMF (2 mL). The mixture was stirred for ten minutes after which time 2-(chloromethyl)-2-ethyloxirane (150 mg, 1.41 mmol) was added. The mixture was stirred at room temperature for 2 h, water was added, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 4-methyl-6-(1-((2-methyloxiran-2-yl)methyl)-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine. MS ESI calc'd. for C19H19F3N5O [M+H]+ 390. found 390.
Reaction SMILES: [N:1]1([C:6](O)=[O:7])C=CN=[CH:2]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]=1[NH-]>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[N:17]1[C:18]2[C:19](=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:2][NH:1][C:6]1=[O:7]
Reactant: [NH-]c1c(Nc2c(F)cccc2F)cccc1Oc1ccccc1
Reactant: O=C(O)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCc2c(Oc3ccccc3)cccc2N1c1c(F)cccc1F
Reaction time: 4 h

Procedure:
The product of example 1c above, 2-phenoxy-6-(2,6-difluorophenylamino)benzylamine, (0.159 g 0.49 mmol) was dissolved in dry tetrahydrofuran (6 mL) and stirred under argon at room temperature. 1,1′-Carbonyldiimidazole (0.102 g, 0.63 mmol) dissolved in dry tetrahydrofuran (4 mL) was added and the mixture stirred at room temperature, and then heated to reflux The solvent was evaporated in vacuo, to give a crude product which was flash chromatographed on silica gel eluted with 0–3% methanol in methylene chloride to give an intermediate imidazole-1-carboxylic acid[2-(2,6-difluorophenylamino)-6-phenoxyphenylamide. The imidazole-1-carboxylic acid[2-(2,6-difluorophenylamino)-6-phenoxyphenylamide was dissolved in tetrahydrofuran (5 mL) and sodium hydride hydride, dry, 95% (0.025 g, 1 mmol) was added. The resulting mixture was stirred for four hours under argon. The solvent was evaporated and the residue was partioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–20% ethyl acetate in CH2Cl2 to give the title compound as a white amorphous solid. mp 199–201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: CCC(Br)C(=O)OC
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1cncc(Cl)c1)C(=O)OC
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-3-pyridinol (10.0 g) was dissolved in anhydrous N,N-dimethyl formamide (150 ml) containing anhydrous potassium carbonate (21.2 g) and methyl 2-bromobutyrate (16.4 ml). The mixture was stirred at 70° C. for 1.5 hours and allowed to cool to ambient temperature. The mixture was poured into water, extracted with diethyl ether (three times) and the combined extracts were washed with water (twice), dried over magnesium sulphate and evaporated under reduced pressure to give the required product as a pale brown oil, 27.4 g.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.O.N([O-])=O.[Na+].[ClH:18]>>[Cl:18][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: Nc1cccc2c1CCC(=O)N2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2c(Cl)cccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
45 g of 5-amino-3,4-dihydrocarbostyril was suspended in 250 ml of a 15% hydrochloric acid and 250 ml of water having dissolved therein 20 g of sodium nitrite was added dropwise to the mixture followed by stirring at room temperature for 1 hour. The resulting solution was added dropwise to a solution prepared by dissolving 41.2 g of cuprous chloride in 120 ml of concentrated hydrochloric acid at room temperature while stirring. After completion of the addition, the mixture was heated on a water bath at 50° to 60° C. for 1 hour while stirring. After allowing the mixture to cool to precipitate crystals, they were collected by filtration and washed with water. The wet crystals were dissolved in chloroform and insoluble materials were removed by filtration. The residue was dried over anhydrous sodium sulfate. After removal of the solvent the residue was dissolved with heating and the solution was treated with activated carbon while hot. The ethanolic solution thus-treated was concentrated under reduced pressure. Recrystallization of the concentrate from ethanol gave 31.5 g of 5-chloro-3,4-dihydrocarbostyril having a melting point of 193° to 194° C.