Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:15][CH:14]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: CSc1ccc(C=O)s1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1ccc(C=C2C(=O)Nc3ccccc32)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 189.9 mg of the 5-methylmercaptothiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 246.6 mg (90%) of the title compound as a orange solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[C:43]4=[CH:44][CH:45]=[CH:46][CH2:47][CH:42]4[NH:41][CH2:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[C:43]4=[CH:44][CH:45]=[CH:46][CH2:47][CH:42]4[NH:41][CH2:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[3-(tetrahydrobenzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:31]=[C:32]=[O:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:32]([NH:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:33])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[NH2:20])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(N)=O)c2)n1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(N)=O)c2)n1
Yield: 68.3 %

Procedure:
A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH2Cl2 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield 1-{3-tert-butyl-1-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)urea as a white solid (0.22 g). mp: 230 (dec.); 1H NMR (200 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.92 (s, 1H), 8.32-8.08 (m, 3H), 7.94-7.44 (m, 8H), 6.44 (s, 1H), 3.51 (s, 2H), 1.31 (s, 9H); MS:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:13])([F:14])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)S2
Temperature: 25 °C
Reaction time: 88 h
Yield: 28.4 %

Procedure:
The ester from Step 2 (0.55 g 1.8 mmol) was dissolved in THF (1.5 mL) and ethanol (1.5 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8 mmol), and stirred at room temperature for 88 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, filtered, and recrystallized from diethyl ether/petroleum ether to yield the title compound as a yellow solid (0.14 g, 28%): mp 180.8-184.2° C. 1H NMR (acetone-d6/300 MHz) 7.95 (s, 1H), 7.42 (s, 1H), 7.31 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=8.1 Hz), 4.94 (q, 1H, J=8.7 Hz), 2.34 (s, 3H). FABLRMS m/z 281 (M+Li). EIHRMS m/z 274.0250 (M+, Calc'd 274.0275). Anal. Calc'd for C12H9F3O2S: C, 52.55; H, 3.31. Found: C, 52.54; H, 3.35.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[C@:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH:20]1C=CC2N(O)N=NC=2C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH2:40])[C:34](=[CH:38][CH:39]=1)[C:35](O)=[O:36].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C.C(N)=N>CN1C(=O)CCC1.O>[Cl:30][C:31]1[CH:32]=[C:33]2[C:34]([C:35](=[O:36])[N:1]([C@H:2]([CH3:19])[C@:3]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])([OH:10])[CH2:4][N:5]3[CH:9]=[N:8][CH:7]=[N:6]3)[CH:20]=[N:40]2)=[CH:38][CH:39]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=CN
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: C[C@@H](n1cnc2cc(Cl)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
To a solution of (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (250 mg, 0.93 mmol) (obtained as described in Bartroli et al J. Org. Chem, 1995, 60, 3000-3012) in NMP (5 mL) was added HOBT (132 mg, 0.98 mmol, 1.05 eq). Next, 4-chloroanthranilic acid (160 mg, 0.93 mmol, 1 eq) and DCC (202 mg, 0.98 mmol, 1.05 eq) was added and the mixture was stirred at room temperature for 18 h. Then, formamidine acetate (437 mg, 4.19 mmol, 4.5 eq) was added and the mixture was heated at 130° C. for 24 h. Water (75 mL) was added and the solid formed was collected by filtration and was then partitioned between aqueous 1N NaOH solution and EtOAc. The aqueous phase was discarded and the organic phase was washed with brine, dried over Na2SO4, filtered, concentrated and the residue purified by flash chromatography (hex: EtOAc 1:5) and recrystallized from a EtOAc: hexane: ether mixture to give the title product (268 mg, 67%) as a white solid: mp 116°-122° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 8.57 (s, 1H, N=CH--N), 8.26 (d, J=8.5Hz, 1H, arom), 7.74 (s, 2H, triazole), 7.7-7.3 (m, 3H, arom), 6.9-6.7 (m, 2H, arom), 5.91 (dq, Jd =2, Jq =7, 1H, MeCH), 5.53 (d, J=2, 1H, OH), 5.14 (d, J=14, 1H, CH(H)), 4.00 (d, J=14, 1H, CH(H)), 1.29 (d, J=7, 3H, CHMe); GC/MS 224 (Tr--CH2COHAr, C10H8F2N3O), 207 (N-ethylheterocycle, C10H9ClN2O); [a]D =-7.9° (c 1, CHCl3). Analysis calculated for C20H16ClF2N5O2 : C 55.63; H 3.73; N 16.22. Found: C 55.23; H 4.09; N 16.13.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11](O)[CH:10]=[CH:9][N:8]=2)[CH2:3]1.O=P(Cl)(Cl)[Cl:16]>CN(C=O)C>[Cl:16][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)[N:12]=1
Reactant: Oc1ccnc(N2CCC(O)C2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: OC1CCN(c2nccc(Cl)n2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-hydroxypyrrolidin-1-yl)pyrimidin-4-ol (4.0 g, 23 mol) in DMF (50 mL) was added POCl3 (4.2 g, 27 mmol). The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into 200 mL ice-water. The resulting solution was concentrated at 60° C. under vacuum. The residue was purified by acidic reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to afford the title compound.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([Cl:19])=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:13]([Cl:19])=[N:14][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 9.7 %

Procedure:
A solution of benzenesulfonyl chloride (1.23 mL, 9.62 mmol, 2 eq) in DCM (50 mL) is added dropwise over 15 min to a solution of 3-amino-5-bromo-2-chloropyridine [Jouve, K.; Bergman, J., Journal of Heterocyclic Chemistry, (2003), 40(2), 261-268] (1 g, 4.81 mmol) and pyridine (1.94 ml, 24 mmol, 5 eq) in DCM (20 mL), under an argon atmosphere. The resulting mixture is stirred for 20 h at rt, concentrated, diluted with H2O and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM) to afford 163 mg of the title compound as a white solid: ESI-MS: 346.9 [M−H]−; tR=4.33 min (System 1); TLC: Rf=0.23 (DCM).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2nc(N3CCOCC3)sc2c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 2-chloro-6-methoxy-benzothiazole (9.96 g, 0.05 mol), morpholine (10.86 mL, 0.12 mol) and triethylamine (13.9 mL, 0.10 mol) in ethanol (75 mL) was refluxed for twenty-one hours before it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a light yellow solid (12.23 g): MS: (+) m/z 251 (M+1)
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18]([C:20]1[S:21][C:22]([C:25](O)=[O:26])=[CH:23][CH:24]=1)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[S:21][C:22]([C:25](=[O:26])[NH:15][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[CH3:14])=[CH:23][CH:24]=1)=[O:19]
Reactant: CC(N)c1ccc(N2CCOCC2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)s1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(N3CCOCC3)cc2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 1 from 1-(4-Morpholin-4-yl-phenyl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (261 mg, 0.83 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (214 mg, 0.83 mmol), EDC(hydrochloride) (239 mg, 1.25 mmol), HOBt (168 mg, 1.24 mmol), and DMAP (20 mg, 0.16 mmol) in DMF (8 mL) was stirred at room temp for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 470 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]amino]-1-propoxy]benzoate as a pale yellow amorphous solid.
Reaction SMILES: C([Li])CCC.O1CCCC1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C)[C:28](=[O:39])[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[O:37][CH3:38]>Cl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:28]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=2[O:37][CH3:38])=[O:39])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(OC)c(C(=O)N(C)C)c1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(=O)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyllithium (2.0M in hexanes, 6.6 ml, 13.2 mmol) was added dropwise under nitrogen, at -78° C. to a stirred tetrahydrofuran (20 ml) solution of 4-benzyloxy-bromobenzene (3.15 g, 11.97 mmol) to give a yellow coloured suspension, which was stirred for 10 minutes. A tetrahydrofuran (10 ml) solution of N,N-dimethyl 2,5-dimethoxybenzamide (2.09 g, 9.99 mmol) was then added slowly, and the resulting mixture warmed to room temperature over 20 h. The mixture was diluted with 50ml of 1M hydrochloric acid and the product extracted into dichloromethane (4×50 ml). The combined extracts were washed with brine, dried over sodium sulfate and evaporated to a yellow coloured solid. This crude product was purified by column chromatography on silica gel 60, using 4:1 petrol/ethyl acetate as the eluent. This gave the product as a colourless solid, which was recrystallised from hot ethanol (25 ml) to give the product as colourless platelets which were vacuum dried.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)CC(C)OB([C:17]([C:19]([F:22])([F:21])[F:20])=[CH2:18])O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Cl:8][C:7]1[C:2]([C:17]([C:19]([F:22])([F:21])[F:20])=[CH2:18])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Br
Reactant: C=C(B1OC(C)CC(C)(C)O1)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=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=C(c1ncccc1Cl)C(F)(F)F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 2-bromo-3-chloropyridine (Matrix, 1.651 g, 8.58 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (Frontier, 2.0 g, 9.01 mmol), and potassium carbonate (4.74 g, 34.3 mmol) in degassed 1,2-dimethoxyethane (50 mL) and water (25 mL) was added tetrakis(triphenylphosphine)palladium (496 mg, 0.429 mmol). The reaction mixture was refluxed for 8 hours, cooled to ambient temperature, diluted with water (200 mL), extracted twice with diethyl ether (200 mL), washed with brine, dried (Na2SO4) and concentrated to a yellow liquid. The residue was purified by silica gel chromatography (AnaLogix® SF25-40G; 50 micron silica; elution with 0-20% ethyl acetate in hexane at 30 mL/min) to provide the title compound (1.530 g, 7.37 mmol, 86% yield) as a colorless liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.61 (dd, J=4.6, 1.4, 1H), 8.10 (dd, J=8.2, 1.4, 1H), 7.53 (dd, J=8.3, 4.6, 1H), 6.51-6.46 (m, 1H), 6.13-6.10 (m, 1H); MS (EI) m/e 207 (M)+.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:26]=[CH:25][C:12]([O:13][CH:14]4[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]4)=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[NH:16]1[CH2:17][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([CH2:8][N:6]3[CH2:5][C:4]4([CH2:1][O:2][CH2:3]4)[CH2:7]3)=[CH:10][CH:11]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(OC2CNC2)ccc1CN1CC2(COC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
3A (0.19 g, 0.52 mmol) was dissolved in dichloromethane (20 mL) and TFA (1.95 mL, 26 mmol) was added. The reaction mixture was stirred at room temperature for two hours. K2CO3 (5 g) was added in portions and the mixture was stirred for 20 min. A saturated solution of K2CO3 (aq) was added and the mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was further extracted several times with dichloromethane. The combined organic solutions were dried (phase separator) and evaporated. There was obtained 128 mg (94%) of 3B as an oil. 1H NMR (500 MHz, CDCl3): δ 3.34 (s, 4H), 3.45 (s, 2H), 3.80 (m, 2H), 3.92 (m, 2H), 4.72 (s, 4H), 4.98 (m, 1H), 6.69 (d, 2H), 7.13 (d, 2H), MS (APCI+) m/z 261 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].Cl.[S:15]([O:20][CH3:21])([O:18][CH3:19])(=[O:17])=[O:16].[OH-].[Na+].[C:24]1(C)C(C)=CC=CC=1>>[S:15]([O:20][CH3:21])([O:18][CH3:19])(=[O:17])=[O:16].[CH3:24][O:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([O:20][CH3:21])=[O:6]
Reactant: Cc1ccccc1C
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(F)c(F)c(OC)c1F

Procedure:
The reaction proceeds according to the following reaction scheme: ##STR5##299 g of an aqueous solution which contains 15.6 g (81 mmol) of 3-hydroxy-2,4,5-trifluorobenzoic acid (B) are initially introduced into a glass flask with stirring and are treated with 10 g of xylene instead of the water-insoluble trialkylamine or amine mixture. A 30% strength by weight aqueous hydrochloric acid is added up to a pH of 7 and the pH is checked by means of a calibrated pH electrode which dips into the aqueous phase. A total of 156.8 g (1.41 mol) of dimethyl sulfate are then added dropwise at a temperature of 40° C. over a period of 3.5 hours and the pH is kept constant at 7 by addition of a total of 46.6 g of a 10% strength by weight aqueous sodium hydroxide solution. Despite a considerable excess of dimethyl sulfate, the dimethylated product, namely methyl 3-methoxy-2,4,5-trifluorobenzoate, is only formed in small amounts.3-Hydroxy-2,4,5-trifluorobenzoic acid (B) corresponding to a yield of 8.6%,methyl 3-hydroxy-2,4,5-trifluorobenzoate corresponding to a yield of 67% and methyl 3-methoxy-2,4,5-trifluorobenzoate (C) corresponding to a yield of only 8.7% are found, in each case based on 3-hydroxy-2,4,5-trifluorobenzoic acid employed.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[C:12]([B:13]([C:25]2[C:30]([F:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=2[F:35])[C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=2[F:24])=[C:11]([F:36])[C:10]([F:37])=[C:9]([F:38])[C:8]=1[F:39].[CH2:40]([N:58]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH3:59])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>C1(C)C=CC=CC=1>[F:31][C:30]1[C:25]([B:13]([C:12]2[C:7]([F:6])=[C:8]([F:39])[C:9]([F:38])=[C:10]([F:37])[C:11]=2[F:36])[C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])=[C:26]([F:35])[C:27]([F:34])=[C:28]([F:33])[C:29]=1[F:32].[F:31][C:30]1[C:25]([B:13]([C:12]2[C:7]([F:6])=[C:8]([F:39])[C:9]([F:38])=[C:10]([F:37])[C:11]=2[F:36])[C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])=[C:26]([F:35])[C:27]([F:34])=[C:28]([F:33])[C:29]=1[F:32].[CH2:60]([NH+:58]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH3:59])[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77].[NH:1]1[CH:5]=[N:4][C-:3]=[N:2]1
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCCCCCCCCCCCCCCCCC
Reactant: c1nc[nH]n1
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[NH+](C)CCCCCCCCCCCCCCCCCC
Product: [c-]1nc[nH]n1

Procedure:
1,2,4-triazole (0.1349 g, 1.953 mmol), tris(pentafluorophenyl)borane (2.0000 g, 3.9063 mmol) and dioctadecylmethylamine (1.0469 g, 1.9531 mmol) were placed in a 50 mL flask, taken up in 21 mL of toluene and refluxed under argon for 5 hours. The volatiles were then stripped under vacuum. Yield, 2.702 g, 84.92 percent.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[F:14][C:15]([F:35])([F:34])[C:16]1[C:25]([C:26](Cl)=[O:27])=[C:24]([OH:29])[C:23]2[C:18](=[CH:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][CH:22]=2)[N:17]=1>C(OCC)(=O)C>[F:34][C:15]([F:14])([F:35])[C:16]1[C:25]([C:26]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:27])=[C:24]([OH:29])[C:23]2[C:18](=[CH:19][C:20]([C:30]([F:33])([F:31])[F:32])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Nc1nccs1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Yield: 37.6 %

Procedure:
A solution of 5.37 g of 2-amino-thiazole, 16.27 g of triethylamine and 214 ml of ethyl acetate were added with stirring over 25 minutes at 7° C. to a solution of 18.62 g of the product of Step F in 320 ml of ethyl acetate, and after the temperature returned to room temperature, the mixture was refluxed for one hour and cooled. The mixture was vacuum filtered and the filtrate was washed with water, dried and evaporated to dryness under reduced pressure at 40° C. The 19.22 gm of residue which was the triethylamine salt of the acid was taken up in 180 ml of 2 N sodium hydroxide solution and the mixture was refluxed for 3-4 minutes and was cooled. The mixture was vacuum filtered and the pH of the filtrate was adjusted to 1 by addition of 20% hydrochloric acid. The mixture was vacuum filtered and the recovered product was crystallized from acetic acid to obtain 8.22 g of 2,7-bis-(trifluoromethyl)-4-hydroxy-N-(2-thiazolyl)-3-quinolinecarboxamide melting at 270° C.
Reaction SMILES: C[O-].[Na+].C(O)C.[OH:7][C:8]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=1[CH:10]=O.Br[CH2:18][C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O.O>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=2[CH:10]=1)#[N:26]
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1ccc(O)c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
A 500 mL 3-neck round bottom flask equipped with a magnetic stirrer, dropping funnel, thermometer and nitrogen bubbler was charged with 10.7 g (108 mmol) of sodium methoxide and 75 mL of absolute ethanol. A solution of 24.9 g (183 mmol) of 2-hydroxy-5-methylbenzaldehyde in 75 mL of dry dimethylformamide was added dropwise over 15 minutes. The mixture was stirred for 20 minutes then treated dropwise over 20 minutes with a solution of 34.8 g (177 mmol) of α-bromo-o-tolunitrile in 75 mL of dry dimethylformamide. The mixture was heated at 75° C. for 30 minutes, then allowed to cool for one hour. A suspension of 10.7 g (188 mmol) of sodium methoxide in 20 mL of dry dimethylformamide was added and the resulting mixture heated at 90° C. for 1.5 hours. The reaction mixture was concentrated under vacuum at 50° C. to give a brown solid that was slurried in 100-200 mL of cold water and filtered. The solids were triturated with 200 mL of methanol, filtered, washed with additional methanol, then air dried. After drying in a dessicator under high vacuum, 26.1 g (112 mmol,63%) of the product was isolated as a beige solid. 1H NMR (200 MHz,CDCl3): 2.45 (s,3H), 7.17 (d,8 Hz,1H), 7.4 (m,3H), 7.6-7.8 (m,3H), 8.10 (d,8 Hz,1H).