Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Br:8])=[CH:6][CH:7]=1.[OH-].[Na+].[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>C(OCC)(=O)C>[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1)=[O:21])([O-:17])=[O:16]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Br)c(C(F)(F)F)c1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-6-bromobenzotrifluoride (Fluka, Buchs, Switzerland; 24.0 g, 100 mmol) in ethyl acetate (240 mL) is added to a stirred aqueous solution of sodium hydroxide (110 mL of 1 M) at room temperature. This stirred solution is then treated dropwise over 30 minutes with a solution of 2-nitrobenzoyl chloride (Fluka, Buchs, Switzerland; 14.5 mL, 110 mmol) in ethyl acetate (150 mL). The resulting mixture is then stirred for 30 min at ambient temperature. The mixture is extracted with ethyl acetate (3×100 mL) and the combined extracts are sequentially washed with hydrochloric acid (2×100 mL of 2M), water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution (2×100 mL) and saturated aqueous sodium chloride (1×100 mL), dried (MgSO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give the title compound as a beige crystalline solid, m.p. 157–158° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]([F:14])[F:13]
Reactant: FC(F)CBr
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: FC(F)COc1ccc(Cl)cc1Br
Yield: 84 %

Procedure:
A stirred suspension of 2-bromo-4-chlorophenol (2.07 g, 10 mmol), 2-bromo-1,1-difluoroethane (1.74 g, 12 mmol) and potassium carbonate (1.65 g, 12 mmol) in 2-butanone (10 mL) was heated at reflux temperature for 16 hours. The suspension was allowed to cool and then filtered. The filtrate was concentrated and distilled in vacuo to afford the title compound as a colorless oil (2.28 g, 84%): bp 78-80° C. @ 0.1 torr
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1.[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH:15]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCON=C(C(=O)O)c1csc(N)n1
Solvent: O=CO
Product: CCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 87.7 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 100 g.), formic acid (85.5 g.) and acetic anhydride (190.1 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 99.1 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=O)=[C:7]([C:11]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:25][NH2:26]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([NH:26][CH3:25])=[O:23])=[C:7]([C:11]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Agent: Cl
Product: CNC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid (Example 31) and methylamine hydrochloride.
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.[CH2:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24][NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[CH3:14]>>[Cl:8][C:7]1[C:2]([N:25]([CH2:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([CH2:13][CH3:14])[N:16]=[CH:17]3)[S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)(=[O:28])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCn1ncc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21
Product: CCn1ncc2cc(CN(c3ncc(C(F)(F)F)cc3Cl)S(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-ethyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 15).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2OS(C(F)(F)F)(=O)=O.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:28]1([C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:27])([F:26])[F:1])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 95.3 %

Procedure:
Ethyl 8-(trifluoromethyl)-4-{[(trifluoromethyl)sulfonyl]oxy}quinoline-3-carboxylate (45.6 g, 109.3 mmol) was taken into dioxane (500 mL). Then phenylboronic acid (26.7 g, 218.6 mmol), K3PO4 (69.6 g, 327.9 mmol) and Pd(PPh3)4 (6.3 g, 5.5 mmol) was added and the reaction was brought to reflux for 1 hour. The reaction was filtered through Celite was still warm and concentrated. The resulting material was passed through a short silica gel plug and concentrated to yield the desired product as a brown viscous liquid (35.96 g). MS (ESI) m/z 346 ([M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:15](=[O:17])[N:13]([CH3:14])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1.[C-:20]#[N:21].[K+]>CN(C)C=O>[C:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:15](=[O:17])[N:13]([CH3:14])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1)#[N:21]
Reactant: [C-]#N
Reactant: Cn1c(=O)c2c(ncn2CCCCCCl)n(C)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CCCCCC#N)n(C)c1=O
Yield: 76.5 %

Procedure:
10.0 g. of 1-chloro-5-(theophyllin-7-yl)-pentane, 2.44 g. of potassium cyanide and 40 cm3 of dimethylformamide are reacted according to Example 13c and 7.92 g. (76.5% yield) of 7-(5-cyano-pentan-1-yl)-theophylline are obtained, m.p.: 86°-88° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9]([CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@@H:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:16](O)=[O:17])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[NH2:68][CH2:69][CH:70]1[CH2:75][CH2:74][CH:73]([C:76]#[N:77])[CH2:72][CH2:71]1>CN(C)C=O>[CH2:1]([N:8]([CH3:34])[C:9](=[O:10])[CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@H:15]([C:16](=[O:17])[NH:77][CH2:76][CH:73]1[CH2:74][CH2:75][CH:70]([C:69]#[N:68])[CH2:71][CH2:72]1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: N#CC1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)NCC1CCC(C#N)CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-cyano-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid (910 mg, 1.97 mmol) in dimethylformamide (150 ml) were added HATU (825 mg, 2.17 mmol) and collidine (263 mg, 2.17 mmol) at 0° C. After 30 minutes at 0° C. 4-aminomethyl-cyclohexanecarbonitrile (272 mg, 1.97 mmol) was added. The mixture was stirred for 1 hour, then allowed to warm to room temperature, and stand at room temperature for 72 hours. After evaporation the residue was stirred with Na2CO3 solution and the precipitate was sucked off to yield 1.18 g of the desired product which was used for further reactions without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C>C1(C)C=CC=CC=1.Cl>[CH3:12][C:8]1([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([B:23]([OH:24])[OH:22])[CH:11]=[CH:10][C:9]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1(C)CCCc2cc(B(O)O)ccc21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (-78° C.) solution of 2.02 g (8.4 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene in 11.0 mL of toluene, was added 4.6 g (6.8 mL, 10.9 mmol, 1.6M in hexane) of n-BuLi. The resulting solution was stirred at -78° C. for 45 min. and then 2.40 g (3.0 mL, 12.7 mmol) of triisopropylborate was dropwise added and the reaction stirred at room temperature for 12 h. The reaction was then diluted with 10% HCl, and extracted with ether (2×). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give an oil. Recrystallization from hexane afforded the title compound as a white solid. 1H NMR (CDCl3, 300 MHz): δ-- 1.34 (s, 6 H), 1.71 (m, 2 H), 87 (m, 2H), 1.89(t, J=6.3 Hz, 2H), 7.47 (d, J=7.8 Hz, 1H),7.89 (s, 1 H), 7.99 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:1]1([CH:7]2[CH2:8][C:9](=[O:14])[CH:10]([C:25](=[O:26])[NH:24][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:27])=[CH:16][CH:17]=3)(=[O:22])=[O:23])[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(c3ccccc3)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of 5-phenyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-PHENYL-2-[N-p-TOLUENESULFONYLCARBAMOYL]-1,3-CYCLOHEXANEDIONE, m.p. 163.5°-166° C. (corr.).
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][NH:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1)=[O:9])C.[NH3:23]>>[C:16]1([C:13]2[N:14]=[CH:15][C:10]([C:8]([NH:7][NH:6][CH2:5][C:4]([NH2:23])=[O:22])=[O:9])=[CH:11][N:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N
Reactant: CCOC(=O)CNNC(=O)c1cnc(-c2ccccc2)nc1
Product: NC(=O)CNNC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 46 %

Procedure:
A mixture of [N′-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid ethyl ester (0.37 mmol) in 25% ammonia solution (25 mL) is stirred at rt over night. The solid is collected by filtration and dried to afford 2-[N′-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetamide (46%). MS: 272 (M+H); 1H NMR (300 MHz, CD3OD): δ 4.45 (s, 2H), 7.45-7.56 (m, 3H), 8.40-8.50 (m, 2H), 9.18 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:24])[CH2:22][CH3:23])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)cc1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml once, saturated sodium bicarbonate solution 50 ml, and a saturated salt solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 4 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 251.6 mg.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:35])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)(=O)[NH2:6]>C(#N)C>[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:35])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)#[N:6]
Reactant: NC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: N#CC1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Yield: 85.4 %

Procedure:
75 ml of thionyl chloride and 150 ml of acetonitrile were added to 3.8 g (0.0086 mol) of 2-(4-carbamoylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The mixture thus obtained was heated under reflux for one hour. The reaction mixture was distilled under a reduced pressure to remove the solvent. A saturated aqueous solution of sodium hydrogencarbonate and triethylamine were added to the residue and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by a silica gel column chromatography (ethyl acetate-n-hexane) and recrystallized from chloroform-n-hexane to give 3.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:24]([CH3:23])[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Solvent: CCO
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1C

Procedure:
2.98 g (10 mmol) of 2-(4-fluorophenyl)-5-methyl1-phenyl-hexane-1,4-dione (Example 2) are heated at 80° C. in 10 ml of 40% strength aqueous methylamine solution, and about 14 ml of ethanol are added so that a clear solution forms. The solution is heated under reflux for a further 30 minutes and, after cooling, the precipitate is filtered off with suction. This is washed with a little ethanol and dried over phosphorus pentoxide in a vacuum desiccator.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:38][O:37][C:35]([C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[C:29]([F:28])[CH:34]=1)=[O:36]
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 2-fluoro-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 603122-84-5]. MS (m/e)=538.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:9][C:10]=2[CH3:26])=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Yield: 44 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethyl ester, 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (7.06 g, 31.5 mmol) and Cs2CO3 (13.3 g, 41.0 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (250 mL) and H2O (250 mL), and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, hexanes to 10% ethyl acetate/hexanes) to provide 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (6.81 g, 44%) as a off-white solid. Rf=0.39 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.11 (t, J=1.6 Hz, 1H), 7.89-7.86 (m, 1H), 7.49 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 6.80-6.72 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.15 (t, J=6.6 Hz, 2H), 2.92 (t, J=6.6 Hz, 2H), 2.34 (s, 3H), 1.49 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 510.1 (M+Na)+, 488.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:7]=2C(=O)O[C:4]1=O)[CH3:2].[CH2:19]([O:21][C:22](=[O:26])/[CH:23]=[CH:24]\[O-:25])[CH3:20].[Na]>CN(C)C=O>[CH2:1]([N:3]1[C:8]2[C:7](=[C:12]([O:13][CH3:14])[C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[C:24](=[O:25])[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1c(=O)oc(=O)c2c(OC)c(OC)ccc21
Reactant: CCOC(=O)/C=C\[O-]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2ccc(OC)c(OC)c2c1=O
Yield: 33.9 %

Procedure:
Under N2, 1-ethyl-5,6-dimethoxy-1H-benzo[d][1,3]oxazine-2,4-dione (12 g, 43.5 mmol) in N,N-Dimethylformamide (DMF) (250 mL) was added to a solution of (Z)-3-ethoxy-3-oxoprop-1-en-1-olate, Sodium salt (18.01 g, 130 mmol) in N,N-Dimethylformamide (DMF) (150 mL) with stirring. The resulting solution was stirred at 110° C. for 3 h. After cooling down, the mixture was concentrated in vacuo and the orange residue was taken up in water. The aqueous solution was washed with ethyl ether (3×), acidified to pH˜2 with 6 N HCl, and extracted with DCM (4×). The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by normal phase silica gel chromatography (CombiFlash), eluting with MeOH/DCM (0-15%) to afford ethyl 1-ethyl-5,6-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (4.5 g, 14.74 mmol, 33.9% yield) as a brown oil that turned into a brown solid after overnight. LCMS: (M+H)+: 306.4.
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+]>C1COCC1>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(C(=O)O)cc(Br)c2ccccc12
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 1-amino-4-bromo-2-naphthoate hydrobromide (2.00 g, 5.54 mmol) in 20 mL of THF was added sodium hydroxide (11.1 mL, 20% aqueous, 55.4 mmol). The mixture was stirred at 50° C. for 20 h, then heated at 90° C. for 2 h. The solvent was removed in vacuo and hydrochloric acid (1 N aqueous) was added until pH˜2. The beige solid was collected via filtration, washed twice with water, and dried to provide 1-amino-4-bromo-2-naphthoic acid that gave a mass ion (ES+) of 266.0 (79Br) for [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[C:10]([O:17][CH3:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([OH:22])=[O:21])[C:3]=1[Cl:23].[CH3:24][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[C:10]([O:17][CH3:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:24])=[O:21])[C:3]=1[Cl:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1c(C#N)cc(F)c(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc(-c2c(F)cc(C#N)c(OC)c2F)cc(N)c1Cl

Procedure:
A slurry of 4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxlic acid in tetrahydrofuran (10 mL) and methanol (3 mL) was treated with trimethylsilyldiazomethane (0.64 g, 0.28 mL of a 2M solution in hexanes) at ambient temperature. After 1 hour the reaction mixture was quenched with acetic acid (2 mL) and water (10 mL). The mixture was extracted with ethyl acetate (2×20 mL) and the combined extracts dried (Na2SO4), and concentrated. The residue was purified by chromatography (30-100% ethyl acetate in hexanes) to give 4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, methyl ester (0.083 g, 0.24 mmol): 1H NMR (CDCl3) δ 7.15 (dd, 1H), 6.85 (s, 1H), 4.98 (bs, 2H), 4.08 (d, 3h), 3.98 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[H-].[Na+].Cl[CH2:22][C:23](=O)[CH3:24]>CN(C=O)C>[CH3:24][C:23]1[C:12]2[C:13](=[O:15])[CH2:14][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:17])([F:18])[F:1])[CH2:10][C:11]=2[O:16][CH:22]=1
Reactant: O=C1CC(=O)CC(c2ccccc2C(F)(F)F)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccccc1C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-trifluoromethylphenyl)cyclohexane-1,3-dione (mp198-199° C.; 1.28 g) in DMF (20 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (14 hours). The reaction solution was cooled, and to the mixture was added ice-water. The mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 3-methyl-6-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g).