Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[OH:14])=[CH:5][N:6]=1.CS([C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:7]2[C:8]([O:14][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2c(O)cccc2F)o1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(F)c2-c2cnc(C)o2)n1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
4 ml DMF solution containing 0.12 g 2-(2-methyloxazole-5-yl)-3-fluorophenol, 0.12 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.18 g pottasium carbonate was stirred for 14 hours at 50° C. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduced pressure, and the residue obtained was treated with petroleum ether, affording the objective substance in an amount of 0.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]1[C:22]([O:24]CC)=O.O.[NH2:31][NH2:32]>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[CH:8]=[C:7]1[C:22]([NH:31][NH2:32])=[O:24]
Reactant: NN
Reactant: CCOC(=O)c1cc2c(ccc(=O)n2-c2ccccc2)n1Cc1cccc(Cl)c1
Solvent: O
Solvent: CCOCCO
Product: NNC(=O)c1cc2c(ccc(=O)n2-c2ccccc2)n1Cc1cccc(Cl)c1
Temperature: 115 °C
Yield: 31.2 %

Procedure:
A solution of Example 26 (200 mg, 0.49 mmol) in 2-ethoxyethanol (3 ml) was treated with hydrazine hydrate (0.10 ml, 2.04 mmol) and heated at 115° C. overnight. The reaction mixture was concentrated in vacuo. Purification by chromatography (10%-50% EtOAc in DCM, silica) gave the title compound (60 mg, 31%). δH (d3-MeOD) 7.81 (1H, d, J 9.6 Hz), 7.55-7.41 (3H, m), 7.34-7.31 (2H, m), 7.21-7.13 (2H, m), 7.06 (1H, s), 6.99-6.95 (1H, m), 6.42 (1H, d, J 9.6 Hz), 6.17 (1H, s), 5.76 (2H, s). LCMS (ES+) RT 2.78 minutes, 393 [35Cl]:395 [37Cl] 3:1 (M+H+).
Reaction SMILES: C([N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:16]=1)[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=O)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[N:21]1([C:17]2[CH:16]=[C:15]([NH:4][C:5]3[CH:10]=[CH:9][C:8]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[CH:7][C:6]=3[N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: OB(O)c1ccco1
Reactant: CC(=O)N(c1cccc(-n2ccnc2)c1)c1ccc(I)cc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cc(-c2ccco2)ccc1Nc1cccc(-n2ccnc2)c1
Yield: 77 %

Procedure:
N-(3-(1-Imidazolyl)phenyl)-4-(2-furanyl)-2-nitroaniline (7o) was prepared analogously from 6c (Example 8) and 2-furanylboronic acid. Yield: 77%. Mp 147-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14](OC)=[O:15])=[C:4]([O:20][CH2:21][C:22]([NH:24][CH3:25])=O)[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH2:14][OH:15])=[C:4]([O:20][CH2:21][CH2:22][NH:24][CH3:25])[CH:3]=1
Reactant: CNC(=O)COc1cc(Cl)ccc1Oc1ccccc1CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNCCOc1cc(Cl)ccc1Oc1ccccc1CCO
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
27.2 g of methyl 2-[4-chloro-2-[[(methylamino) carbonyl]methoxy]phenoxy]benzeneacetate was dissolved in 800 ml of dry tetrahydrofuran and slowly added to a suspension of 8.7 g lithium aluminum hydride in 800 ml of dry tetrahydrofuran. The reaction mixture was stirred overnight at 40° C. and after addition of 35 ml of water stirred for another 1 h. The salts were removed by filtration with suction and the filtrate was evaporated in vacuo, to give 20.1 g (84%) of 2-[4-chloro-2-[2- (methylamino)ethoxy]phenoxy]benzene ethanol.
Reaction SMILES: [OH-].[K+].Br[CH:4]1[O:8][C:7]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]1[Br:14].C(O)(=O)C>C(O)C>[Br:14][C:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:7]=2[O:8][CH:4]=1
Reactant: Fc1cccc2c1OC(Br)C2Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1cccc2c(Br)coc12
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of potassium hydroxide (12.7 g) in ethanol (180 ml) was slowly added the product obtained in Step 1 (34 g) and stirred for 3 hours. The resulting solution was neutralized by acetic acid, then extracted with ether. The organic layer was washed with successive water and saturated aqueous NaCl solution. After drying over anhydrous sodium sulfate, ether was removed in vacuo to give 24.1 g of the objective compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)OC(C)(C)C)cs2)cn1
Product: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)cs2)cn1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and 3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionic acid tert.-butyl ester (Example H20) (154 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (225 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[O:35][CH3:36]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[C:28]([O:35][CH3:36])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: COc1cc([Mg]Br)ccc1Cl
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)ccc1Cl

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 92 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 2.01 mL 0.25M 4-chloro-3-methoxyphenylmagnesium bromide. Yield: 40 mg of a white solid. LC-MSD, m/z for C23H16BrClN2O3 [M+H]+=483.0, 485.0; HPLC retention time: 2.5 min.
Reaction SMILES: COC1C=CC(C[N:8]([C:31]2[S:35][N:34]=[CH:33][N:32]=2)[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:17][NH:16][C:15]3=[O:30])(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[C:19]2[C:14](=[CH:13][C:12]([S:9]([NH:8][C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[C:15](=[O:30])[NH:16][N:17]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)n[nH]c(=O)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 24 h
Yield: 21.9 %

Procedure:
N-(4-methoxybenzyl)-1-(2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (65.0 mg, 0.121 mmol) was dissolved in DCM (1.21 mL) and then TFA (46.7 μl, 0.607 mmol) was added. After 1 d at rt, LCMS showed mainly product. The reaction was quenched with 1 mL of saturated aqueous NaHCO3 and was concentrated. Chromatography was performed using reverse phase Isolera through a pre-packed C18 column (12 g), eluting with a gradient of 0% to 60% MeCN with 1% TFA in water with 1% TFA. Fractions containing the product were combined and concentrated. White solid precipitated out of the water. The solid was filtered off with an aid of water and dried to afford 1-(2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (11 mg, 21.8% yield). m/z (ESI) 416.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([F:15])[C:9]([OH:14])=[C:10]([F:13])[CH:11]=2)[O:6][C:5](=[O:16])[CH:4]=1.S(=O)(=O)(O)[OH:18]>[OH-].[Na+]>[F:13][C:10]1[C:9]([OH:14])=[C:8]([F:15])[C:7]2[O:6][CH:2]=[C:3]([CH2:4][C:5]([OH:16])=[O:18])[C:12]=2[CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: O=c1cc(CCl)c2cc(F)c(O)c(F)c2o1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1coc2c(F)c(O)c(F)cc12

Procedure:
4-Chloromethyl-6,8-difluoro-7-hydroxy-2-chromenone (0.2 g, 0.81 mmol) obtained in Step A was dissolved in 1N NaOH aqueous solution (8 mL), and the mixture was stirred under reflux for 2 hours. The reactant was acidified by the addition of sulfuric acid, and then extracted with EtOAc. The organic layer was dried with MgSO4, and distilled under reduced pressure to obtain the title compound (0.16 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH2:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29](OC=O)(=[O:31])C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:19])[CH3:20])=[C:13]([NH:21][CH:29]=[O:31])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC=O
Reactant: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester (0.97 g, 3.25 mmol) and pyridine (0.43 mL, 5.25 mmol) in CH2Cl2 (7.5 mL) was cooled to 0° C., and a solution of formic-acetic anhydride (3.5 mmol, prepared by mixing formic acid (158 μL, 4.2 mmol, 1.3 equiv) and acetic anhydride (0.32 mL, 3.5 mmol, 1.1 eq.) neat and aging for 1 hour) in CH2Cl2 (2.5 mL) was added dropwise over 2 min. After the addition was complete, the mixture was allowed to warm to room temperature, whereupon it deposited a precipitate, and the resulting slurry was stirred overnight. The mixture was washed with 1 M citric acid (2×20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na2SO4), and filtered. The cloudy mixture deposited a thin bed of solid above the drying agent, HPLC analysis showed this to be the desired formamide. The filtrate was concentrated to approximately 5 mL, and diluted with hexane (15 mL) to precipitate further formamide. The drying agent (Na2SO4) was slurried with methanol (50 mL), filtered, and the filtrate combined with material from the CH2Cl2/hexane recrystallisation. The resultant mixture was concentrated to afford (4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester as an off-white solid (650 mg, 50% over 2 steps). 1H and 13C NMR (CD3OD) show the product as a rotameric mixture. 1H NMR (400 MHz, CD3OD, rotameric) δ 8.27 (s, 1H-a), 8.17 (s, 1H-b), 7.42-7.26 (m, 8H), 5.17 (s, 1H-a), 5.15 (s, 1H-b), 4.86 (s, 2H), 1.37 (s, 9H-a), 1.36 (s, 9H-b); 13C NMR (100 MHz, CD3OD, rotameric) δ 1636.9, 163.5, 155.8, 141.40, 141.32, 139.37, 138.88, 138.22, 138.14, 136.4, 135.3, 129.68, 129.65, 129.31, 129.24, 129.19, 129.13, 128.94, 128.50, 121.4 (br), 118.7 (br), 67.80, 67.67, 35.78, 35.52, 31.65, 31.34; ESI-MS 327.5 m/z (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1.[Na].C([C:21]([O:23][CH2:24][CH3:25])=[O:22])#N>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1
Reactant: CCOC(=O)C#N
Reactant: CN1C(=O)CS(=O)(=O)c2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)N(C)c2ccc(Cl)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a suspension of sodium hydride (5.13 g, 60% oil dispersion, washed with dry petroleum ether) in dimethylformamide (110 ml) was added 7-chloro-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide (30 g) at 5° to 10° C. The mixture was allowed to warm to room temperature and stirred for 15 minutes for the preparation of the sodium salt. The reaction mixture was then cooled in an ice bath and a solution of ethyl cyanoformate (16.29 g) in dimethylformamide (15 ml) was added dropwise over 30 minutes. After being stirred for one hour, the mixture was quenched with acetic acid (14 ml), poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The oily residue was crystallized from ethanol to afford 31 g of 7-chloro-2-ethoxycarbonyl-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide, mp 86° to 91° C. (melt).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[C:19]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(F)cc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1cc(-n2ccnc2)ccc1C(=O)O
Temperature: 110 °C
Yield: 25.5 %

Procedure:
To a mixture of methyl 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoate (Example 246, 50 mg, 0.13 mmol), imidazole (17.8 mg, 0.26 mmol), and potassium carbonate (90.6 mg, 0.66 mmol) was added DMF (1 mL). The mixture was then heated to 110° C. for 16 h. The reaction mixture was allowed to cool to rt. The solvent was removed under reduced pressure, and the crude was purified by HPLC purification using gradient elution from 10 to 80% acetonitrile in water to afford 13.8 mg (25%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 9.48 (t, 1H), 8.15 (d, 1H), 8.07 (t, 1H), 7.76 (t, 1H), 7.52 (d, 1H), 7.28-7.42 (m, 4H), 7.10 (dd, 1H), 6.48 (s, 1H), 2.06 (s, 3H), 1.35 (s, 9H). ES-MS m/z 416.2 (MH+); HPLC RT (min) 2.21.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)nc1CBr

Procedure:
50 g (0.23 mol) of methyl 2-methyl-6-trifluoromethylnicotinate and 49 g (0.28 mol) of N-bromosuccinimide are heated for 90 minutes at 50° C. in 500 ml of carbon tetrachloride in the presence of a catalytic amount of α,α-azaisobutyronitrile with illumination by a 150 watt lamp. Precipitated succinimide is filtered off, and the product methyl 2-bromomethyl-6-trifluoromethylnicotinate is then isolated as main component by means of column chromatography (mobile phase ethyl acetate/hexane 1:15), 1H-NMR (CDCl3): 4.01, s, 3H; 5.03, s, 2H; 7.72, d (J 8.2 Hz), 1H; 8.43 ppm, d, (J 8.2 Hz), 1H. 25.6 g (35 mmol) of the above product are taken up in toluene and treated with 10.6 g (40 mmol) of triphenylphosphine. After the mixture has been heated for 2 hours at boiling point, pure (3-methoxycarbonyl-6-trifluoromethylpyridine-2-ylmethyl)triphenylphosphonium bromide of melting point 215-217° C. crystallizes out upon cooling.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C.CO.C1C[O:29][CH2:28]C1>>[CH3:28][O:29][C:9]1[C:8]([C:6]([OH:5])=[O:7])=[C:17]([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:14][CH:15]=2)[N:10]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 70 °C
Yield: 66 %

Procedure:
A 2M aq. LiOH sol. (12 ml) was added to a solution of 1.3 g (4.0 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (synthesis see Example 3 Section a)) in a MeOH/THF mixture (in each case 10 ml) and the solution was subsequently heated to 70° C. for 16 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with EtOAc, adjusted to pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 754 mg (2.6 mmol, 66%) 2-methoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]([CH2:9][C:10]([NH2:12])=[O:11])=[C:2]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: NC1CCCCC1
Reactant: NC(=O)Cc1cnc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)Cc1cnc(Cl)cc1NC1CCCCC1
Yield: 93 %

Procedure:
200 mg of 4,6-dichloropyridine-3-carboxyamide synthesized according to the method described in US2006/0217417 was dissolved in 2 mL of ethanol, to which 156 mg of cyclohexylamine and 203 mg of N,N-diisopropylethylamine were added, and heated at reflux for 8 hours. After cooling, the solvent was evaporated, and 10 mL of water was added to the residue, neutralized by adding 2 mol/L hydrochloric acid in water under ice cooling, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from chloroform-hexane to obtain 243 mg (92%) of the title compound as colorless needle crystals.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[O:29]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cnc(Oc2ccccc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
In a flask, 64 g of 2,3-dichloro-5-trifluoromethyl pyridine, 250 ml of dimethyl sulfoxide, 81.8 g of anhydrous potassium carbonate and 33.4 g of phenol were charged. The flask was heated in an oil bath at 100° C. to react them with stirring for 4 hours. The reaction mixture was poured into suitable amount of water and the reaction product was extracted with methylene chloride. The extracted phase was washed with water, with 5% sodium hydroxide aqueous solution and then, with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure and the residue was distilled to obtain 49 g of 2-phenoxy-3-chloro-5-trifluoromethyl pyridine. The product was mixed with 100 ml of 98% sulfuric acid and the mixture was cooled with ice water. A mixture of 11.3 g of 60% nitric acid and 30 ml of 98% sulfuric acid was added dropwise to the sulfuric acid solution of the reaction product at a temperature of 0° to 10° C. A mild exothermic reaction was performed. After the reaction, the reaction mixture was poured into suitable amount of ice water and neutralized with 10% sodium hydroxide aqueous solution. The reaction product was extracted with methylene chloride. The extracted phase was dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure to obtain 38.5 g of the object compound having a melting point of 90° to 91° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139°-142° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.98 (t, 2 H), 5.19 (s, 2 H), 6.68 (s, 1 H), 7.26 (m, 7 H), 7.43 (m, 5 H), 7.76 (d, 2 H).
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.Cl>C(OCC)C>[C:9]1([CH2:15][CH2:16][CH2:17][PH:4](=[O:3])[OH:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: CCOP(Cl)OCC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=[PH](O)CCCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
Diethychlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenylpropylmagnesium bromide (100 mL, 0.1 mol, 1.0 M solution of in Et2O) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and was stirred an additional 30 minutes. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. To the liquid was added 20 mL of water followed by 0.5 ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 20 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. To the clear liquid was added sodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for 1 hour and then washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give 3-phenylpropylphosphinic acid (1,R=CH2CH2CH2Ph,R1=H) (9.8 g, 53%) as a clear and colorless oil.