Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:16][F:17])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11](/[CH:13]=[N:14]/[OH:15])=[CH:12][C:4]1=2.C1C(=O)N(Cl)C(=O)C1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[C:28]=1[Cl:40].Cl>CN(C=O)C.O>[F:17][CH2:16][C:3]1([CH2:2][F:1])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([C:13]3[CH2:34][C:33]([C:31]4[CH:30]=[C:29]([Cl:39])[C:28]([Cl:40])=[C:27]([Cl:26])[CH:32]=4)([C:35]([F:38])([F:37])[F:36])[O:15][N:14]=3)=[CH:12][C:4]1=2
Reactant: O/N=C/c1ccc2c(c1)C(CF)(CF)OB2O
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: OB1OC(CF)(CF)c2cc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
To a solution of (E)-3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (440 mg, 1.83 mmol) in DMF (10 mL) at rt was added NCS (294 mg, 2.19 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (577 mg, 2.10 mmol) and TEA (403 mg, 4.0 mmol) in DMF (10 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, then stirred at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2, then poured into water and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, 16%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.74 (s, 1H), 7.96-7.80 (m, 5H), 4.89-4.80 (m, 2 H), 4.73-4.64 (m, 2H), 4.46 (d, J=17.4 Hz, 1H), 4.35 (d, J=17.4 Hz, 1H) ppm; HPLC purity: 95.3% at 214 nm; MS: m/z=516 (M+1, ESI+).
Reaction SMILES: [CH2:1]([P:4](=[O:10])([CH2:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>CCOCC>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:6][CH2:5][P:4]([CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH3:3])=[O:10])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCCP(=O)(CO)CCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCP(=O)(CCC)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To dipropyl hydroxymethylphosphine-oxide (Ref. U.S. Pat. No. 5,272,128) (16.4 g, 0.1 mol) in anhydrous ether (200 mL) at 0° C., was added p-toluenesulfonyl chloride (19.1 g, 0.1 mol), triethyl amine (27.8 mL, 0.2 mol). The reaction was stirred at room temperature over night. The ether solution was decanted, and the precipitate was washed in a filter funnel with ˜1 L ether until HPLC found no product. Combined ether layer were concentrated. The crude product was purified on silica gel chromatography with 8% MeOH/DCM.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:15]1([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:24][CH2:23][C:22]([NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:25])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C=CC(=O)Nc1ccccc1
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CC1=C2CCN(CCC(=O)Nc3ccccc3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-phenyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 4 hours. M.P. of the hydrochloride of the title compound 207°-209° from 95% ethanol.
Reaction SMILES: CO.[OH-].[K+].[Br:5][C:6]1[C:11]2[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[O:14][C:10]=2[C:9]([C:19]([O:21]C)=[O:20])=[CH:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[Br:5][C:6]1[C:11]2[CH:12]=[C:13]([C:15]([CH3:17])([CH3:18])[CH3:16])[O:14][C:10]=2[C:9]([C:19]([OH:21])=[O:20])=[CH:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(Br)c2cc(C(C)(C)C)oc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc2c(Br)c(-c3ccccc3)cc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.4 %

Procedure:
A methanol (12 ml) solution of potassium hydroxide (1.26 g, 22.5 mol) was put into a tetrahydrofuran (50 ml) solution of methyl 4-bromo-2-tert-butyl-5-phenyl-1-benzofuran-7-carboxylate (I-255) (2.90 g, 7.49 mmol), followed by stirring at room temperature for 3.5 hours. The reaction liquid was concentrated under reduced pressure, then 1 N hydrochloric acid (100 ml) and water (100 ml) were added, the product was extracted with ethyl acetate (200 ml×2). The organic layer was washed with saturated brine (50 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain the entitled compound (2.64 g, 95%) as a yellow white solid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4].[OH-].[Na+].[S:10](=O)([OH:12])[O-:11].[Na+]>>[CH3:7][CH:6]1[CH:2]([CH3:1])[C:3](=[O:5])[O:4][S:10]1(=[O:12])=[O:11]
Reactant: C/C=C(\C)C(=O)O
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CC1C(=O)OS(=O)(=O)C1C

Procedure:
100 g. of α-methyl-crotonic acid is reacted with sodium hydroxide to neutralize the carboxyl group. Sodium bisulfite (104 g.) in aqueous solution is added and the reaction continued as described in earlier examples to obtain 3,4-dimethyl-1,2-oxathiolane-5-one-2,2-dioxide.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:4]=[N:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2cncnc2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncnc4)c32)c1CCCN1CCN(C)CC1

Procedure:
4-Pyrimidin-5-yl-1,3-dihydroindol-2-one (53 mg, 0.25 mmol) was condensed with 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (88 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17]>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>[CH3:17][O:16][N:15]([CH3:14])[C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)COc1ccc(F)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CON(C)C(=O)COc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
2-(4-Fluorophenoxy)ethanoic acid chloride was added slowly to a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (55.80 g, 572 mmol) in saturated K2CO3 and ethyl acetate (375 mL). A moderately exothermic reaction occurred (larger scale reactions are cooled with an ice bath), and after 20 minutes, the reaction mixture was partitioned between water and ether. The ether layer was washed with 1 M HCl and saturated NaCl, and dried over MgSO4. The dried solution was filtered and concentrated under vacuum to give N-methoxy-N-methyl-2-(4-fluorophenoxy)ethanamide, a compound of formula (Z), as a yellow oil which solidified to an off-white crystalline solid, 113.05 g (73% yield from starting acid); 1H NMR (CDCl3,400 mHz) δ 3.21 (s, 3H), 3.73 (s, 3H), 4.75 (s, 2H), 6.87 (m, 2H), 6.95 (m, 2H) ppm.
Reaction SMILES: CO[C:3](=[O:25])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10](=[O:24])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14](OC)=[CH:13][C:12]=1[N+:21]([O-])=O.C(Cl)(Cl)Cl.C[CH2:31][OH:32]>[Pd].Cl>[CH3:31][O:32][C:16]1[C:11]2[C:10](=[O:24])[N:5]3[CH2:6][C@H:7]([OH:9])[CH2:8][C@H:4]3[C:3](=[O:25])[NH:21][C:12]=2[CH:13]=[CH:14][C:15]=1[O:17][CH3:18]
Reactant: CCO
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2

Procedure:
10% Pd/C catalyst (3.3 g) was added to a solution of 169 (33.0 g, 93.1 mmol) in absolute EtOH (250 mL). The reaction mixture was hydrogenated under pressure using a Parr hydrogenator at 55 psi H2 for 18 h. The reaction mixture was filtered through celite, and the celite washed with hot MeOH, taking care not to allow the filter cake to dry out. Removal of excess solvent afforded the crude product (20.14 g). The crude product was allowed to stir in 1 N HCl (200 mL) and CHCl3 (200 mL) for 30 minutes. The organic layer was washed with 1 N HCl (100 mL) and the aqueous layers were combined and neutralised with saturated aqueous NaHCO3. On leaving the aqueous extract overnight, a fine white precipitate formed (170) which was collected by filtration and dried (7.81 g, 26.72 mol, 29%). 1H NMR (270 MHz, CDCl3) d 10.06 (s, 1H, NH), 7.61 (s, 1H, ArH), 7.36 (s, 1H, ArH), 4.49-4.41 (m, 1H, 2), 4.22-4.17 (m, 1H, 11a), 3.88 (s, 6H), 3.82-3.55 (m, 2H., 3), 3.20 (br s, 1H, OH), 2.87-2.77 (m, 1H, 1), 2.10-2.05 (m, 1H, 1); 13C NMR (CDCl3) d 170.2, 165.9, 152.0, 145.7, 130.7, 118.2, 111.9, 104.2, 68.1, 56.0, 55.6, 54.2, 34.6, 18.8.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:30](O)(=[O:34])[C:31]([CH3:33])=[CH2:32]>>[C:30]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: C=C(C)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=C(C)C(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl methacrylate was prepared by stirring a mixture of 16.3 grams of 2,6-di tert.butyl hydroquinone, 18.5 grams of trifluoroacetic acid anhydride, and 8.2 grams of methacrylic acid for 3 hours at room temperature. The product, which has precipitated during the course of the reaction, was filtered off, washed first with dilute sodium carbonate solution, then with water, and then dried. After recrystallization from hexane, there was obtained 10 grams of product melting at 138° C. to 139° C.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[O:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[O:44][C:45]1[CH:46]=[C:47]([NH:48][C:13]([NH:12][C:11]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]([C:22]([F:23])([F:25])[F:24])[CH:10]=2)=[O:21])[CH:49]=[CH:50][CH:51]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 78 %

Procedure:
Using the procedure described in Example 162B, phenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 172B (0.145 g, 0.4 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.190 g, 78%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 7.55 (m, 2H), 7.36 (m, 6H), 7.19 (d, 1H), 6.95 (d, 1H), 6.84 (s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35 (s, 3H), 2.41 (s, 3H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH2:32][OH:33])[C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24])[CH3:29]
Reactant: CCNCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CCN(CCO)C(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Yield: 74 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-(ethylamino)ethanol. And then, the product was recrystallized with isopropanol and hexane to give a desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[CH:8]OCC)[C:6]#[N:7])[CH3:2].[NH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[NH2:14]>C(O)C>[NH2:7][C:6]1[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:14]=[CH:8][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:12]
Reactant: NNc1ccccn1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccn2)c1N

Procedure:
Ethyl(ethoxymethylene)cyanoacetate, 19.5 g, was added in one portion into a solution of 2-hydrazinopyridine, 12.5 g, in 100 mL of absolute ethanol. The reaction was then heated at reflux for 21/2 hours and cooled. The solid which formed was collected by filtration and washed with absolute ethanol. After air-drying, the product weighed 22.6 g and melted at 92°-93° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:12]([C:13](OC)=O)=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3].O.[C:18](OCC)(=[O:20])[CH3:19]>C1COCC1>[CH2:1]([C:4]1[NH:5][C:6]2[C:12]([CH2:13][CH:18]([OH:20])[CH3:19])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCOC(C)=O
Reactant: CCCc1nc2cccc(C(=O)OC)c2[nH]1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cccc(CC(C)O)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
[step 1] To a mixture of methyl 2-amino-5-bromobenzoate (2.3 g, 10.0 mmol) and propionic anhydride (14 mL) was added dropwise fuming nitric acid (2.1 mL, 50.0 mmol) under ice-cooling. After stirring at 70° C. for 15 min, water and ethyl acetate were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give methyl 3-amino-5-bromo-2-butylamidobenzoate (1.23 g, 36%). [step 2] Methyl 3-amino-5-bromo-2-butylamidobenzoate (1.22 g, 3.53 mmol) obtained in step 1 was dissolved in methanol (20 mL) and the mixture was stirred in the presence of 10% palladium carbon (240 mg) under a hydrogen atmosphere at room temperature for 7 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid (1 mL), and the mixture was stirred at 100° C. for 1 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give methyl 2-propylbenzimidazole-4-carboxylate (0.299 g, 39%). [step 3] Methyl 2-propylbenzimidazole-4-carboxylate (0.295 g, 1.35 mmol) obtained in step 2 was dissolved in THF (10 mL), 3 mol/L methylmagnesium chloride THF solution (4.5 mL, 13 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the mixture were added water and ethyl acetate, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give the title compound (0.201 g, 68%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([F:30])([F:29])C(C1C=CC=CC=1)=O>O.C(#N)C>[F:29][CH:20]([F:30])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: COC(=O)c1ccc(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(OC(F)F)cn1
Temperature: 75 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A mixture of methyl 5-hydroxypicolinate hydrochloride from step K1 (1.12 g, 5.91 mmol), potassium carbonate (8.16 g, 59.1 mmol) and α-chloro-α,α-difluoroacetophenone (3.92 mL, 26.6 mmol) in water (20 mL) and acetonitrile (20 mL) was stirred at 75° C. for 5 h. The solid was filtered out and washed with diethyl ether. The filtrate was washed with water and concentrated. The residue was purified using silica gel column chromatography (hexanes-50% EtOAc) to give methyl 5-(difluoromethoxy)picolinate (730 mg, 3.59 mmol, 61% yield). 1H NMR (500 HMz, chloroform-d) δ 8.60 (d, J=2.4 Hz, 1H), 8.20 (dd, J=8.6, 0.5 Hz, 1H), 7.62 (dd, J=8.7, 2.7 Hz, 1H), 6.81-6.49 (m, 1H), 4.03 (s, 3H).
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)(O)=O.Cl.[O:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[CH:11]1[CH:4]=[CH:5][C:6](/[CH:7]=[C:17]2/[C:18]([C:14]3[C:15]([O:16]/2)=[CH:10][CH:11]=[CH:4][CH:5]=3)=[O:13])=[CH:9][CH:10]=1
Reactant: C1COCCO1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Product: O=C1/C(=C/c2ccccc2)Oc2ccccc21

Procedure:
This product was immediately dissolved in dioxane (50 ml.), 3-carboxybenzaldehyde (4.5 g., 0.03 mole) added, followed by concentrated hydrochloric acid (10 ml) and the solution heated on a steam bath for 15 minutes. Work up was as Example 49 with recrystallisation from dimethylformamide to give the desired aurone, m.p. 280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10](O)=[O:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=CO
Product: O=CNc1ccc(F)c(Cl)c1
Temperature: 106 °C

Procedure:
A mixture of 100 g of 3-chloro-4-fluoroaniline and 400 ml of 97% formic acid was refluxed (106° C.) for three hours. The mixture then was poured into ice water and the resulting mixture was filtered. The solid was washed with water and dried to give N-(3-chloro-4-fluorophenyl)formamide (J. Org. Chem., 26, 2563 (1961)) (1A), as a colorless crystalline solid, mp: 94°-97° C.
Reaction SMILES: O[C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].CC[OH:19]>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[O:6][C:2]([CH3:16])([CH3:15])[C:3](=[O:19])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)C#CC(C)(C)O)cc1
Reactant: CCO
Product: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a stirred solution of 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (6 g, 0.027 mol) in ethanol (100 mL) diethyl amine (2.86 g, 0.027 mol) in EtOH (15 mL) was added dropwise at RT and the reaction mixture was stirred for additional 4 h. The EtOH was then removed and the mixture diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (5.5 g, 92%).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][C:4](=[O:8])[CH:5]=[CH:6][CH3:7].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]([C:4](=[O:8])/[CH:5]=[CH:6]/[CH3:7])[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]=1
Reactant: CC=CC(=O)C=C(C)CCC=C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 10 g. of 6,10-dimethyl-4-oxo-2,5,9-undecatriene prepared according to the method of paragraph c) herebelow, 100 ml. of benzene and 1 g. of boron trifluoride etherate was heated to the reflux until the vapour phase chromatographic analysis of a sample showed that practically all the starting material had disappeared. The solution was cooled and stirred with ice-water. The organic layer was removed and treated as usual. Distillation of the residue of evaporation gave a 50 % yield of trans-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene of about 60 % purity as shown by the vapour phase chromatographic analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.P(OCC)(OCC)([S-])=[S:11].O1CCCC1.C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[S:11])[NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: CCOP(=S)([S-])OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)c1ccnc(N)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 2-aminopyridine-4-carbonitrile (6.0 g, 50 mmol), O,O′-diethyl dithiophosphate (11 mL, 60 mmol), tetrahydrofuran (25 mL) and water (25 mL) was stirred at 60° C. for 4 hr. To the reaction mixture was added O,O′-diethyl dithiophosphate (2.8 mL, 15 mmol) and the mixture was stirred at 60° C. for 1 day. To the reaction mixture was added aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give the title compound (6.2 g, 81%) as a yellow solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[NH2:17][C:18]1[C:27]2[N:26]=[CH:25][C:24]([CH2:28][CH2:29][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=3[CH3:38])=[CH:23][C:22]=2[C:21]2[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:20]=2[N:19]=1>C1COCC1>[NH2:17][C:18]1[C:27]2[N:26]=[CH:25][C:24]([CH2:28][CH2:29][C:30]3[CH:37]=[CH:36][C:33](/[CH:34]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:32][C:31]=3[CH3:38])=[CH:23][C:22]=2[C:21]2[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:20]=2[N:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 0 °C

Procedure:
To a suspension of NaH (3 eq) in THF (0.2 M) stirred at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (commercially available) (3 eq). After stirring for 30 minutes, a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzaldehyde (from the previous step) in THF (0.2 M) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with sat. NH4Cl solution, and was extracted with EtOAc. Combined organic extracts were dried and concentrated to give a crude residue which was purified by chromatography (silica gel, 50-100% EtOAc in hexanes) to afford (E)-ethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate as a white solid. 1H NMR: (CDCl3): δ 8.54 (d, 1H), 8.29 (d, 1H), 7.99 (d, 1H), 7.57 (d, 1H), 7.44 (s, 1H), 7.23 (dd, 1H), 7.11 (dd, 1H), 7.05 (d, 1H), 6.33 (d, 1H), 5.93 (s, 2H), 4.19 (q, 2H), 3.10-2.95 (m, 4H), 2.44 (s, 3H), 2.23 (s, 3H), 1.26 (t, 3H). LRMS [M+H]=426.2