Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH2:6][CH3:7])[CH3:4].[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=[O:15]>>[CH2:3]([CH:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)[CH2:6][CH3:7])[CH3:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCC(CC)N1CCNCC1
Agent: Cl
Product: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from the product of Example 7 and 4-formylbenzoic acid.
Reaction SMILES: [CH2:1]=[O:2].C1CCN2C(=NCCC2)CC1.[N+:14]([C:17]1[CH:36]=[CH:35][CH:34]=[CH:33][C:18]=1[CH2:19][CH2:20][O:21]CCC1C=CC=CC=1[N+]([O-])=O)([O-:16])=[O:15]>CS(C)=O.CC(O)=O.C(Cl)Cl>[CH3:1][O:2][CH:19]([C:18]1[CH:33]=[CH:34][CH:35]=[CH:36][C:17]=1[N+:14]([O-:16])=[O:15])[CH2:20][OH:21]
Reactant: C=O
Reactant: O=[N+]([O-])c1ccccc1CCOCCc1ccccc1[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(CO)c1ccccc1[N+](=O)[O-]

Procedure:
Paraformaldehyde (750 mg, 25 mmol) and DBU (1.85 ml, 12.4 mmol) were added to a solution of 2-nitrobenzylmethylether (4.18 g, 25 mmol) in DMSO (3.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) and allowed to react at room temperature for 4 h. The pH value was adjusted from pH 9 to about pH 3.5 by means of a few drops of conc. AcOH. The mixture was diluted with CH2Cl2 (120 ml) and washed with H2O (80 ml). The aqueous phase was post-extracted with CH2 Cl2 (2×80 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (5.56 g) was purified by column chromatography (140 g SiO2, 21×4.2 cm, solvent: toluene 300 ml, toluene/EtOAc 20:1 210 ml, 15:1 160 ml, 10:1 220 ml, 15:2 170 ml, 6:1 210 ml, 5:1 180 ml, 4:1 400 ml, 3:1 240 ml, 2:1 240 ml). First 2-nitrobenzylmethylether (2.442 g, 58%) was eluted then 2-methoxy-2-(2-nitrophenyl)ethanol (1.696 g, 34% and 82% respectively, in relation to the consumed starting material).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].[NH4+].[Cl-]>CN(C=O)C>[CH2:16]([O:15][C:14]([N:13]([C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)[CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Nc1ccnc2ccc(C(F)(F)F)cc12)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)OCc1ccccc1)c1ccnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzyl (6-(trifluoromethyl)quinolin-4-yl)carbamate (440 mg, 1.27 mmol, prepared in Step D) in dry DMF (20 mL) is treated with cesium carbonate (870 mg, 2.67 mmol) and stirred at room temperature for 1 hour. Ethylbromoacetate (0.15 mL, 1.36 mmol) is added dropwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture was then poured into saturated NH4Cl solution and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/DCM) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][C@@:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][C@@:11]3([CH:17]4[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Solvent: CO
Product: Nc1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Yield: 91.6 %

Procedure:
The enantiomer (S)-(+)-5'nitrospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (6.85 g, 26.2 mmol) treated in the same way as described in example 8A in ammoniated methanol provided the title compound (5.55 g, 24 mmol, 92%): electrospray MS (m/z, relative intensity) 232 ([MH]+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=3[Br:16])[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)c(Br)c1
Reactant: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Product: Cc1ccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c(Br)c1
Temperature: 195 °C
Yield: 4 %

Procedure:
To a solution of 4-(4-hydroxyanilino)-6-chloropyrimidine (Reference Example 5, 5 g) was added 2-bromo-4-methylaniline (7.5 ml) and the reaction mixture was heated at 195° C. for 24 hours. The residue was absorbed onto silica and purified by column chromatography eluting with DCM:MeOH (19:1) to give the title compound (336 mg, 4%). NMR: 2.28 (3H, s), 5.72 (1H, s), 6.68 (2H, d), 7.17 (3H, m), 7.39 (1H, d), 7.48 (1H, s), 8.05 (1H, s), 8.38 (1H, s), 8.65 (1H, s), 9.08 (1H, s); m/z 371 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.C([Mg]Cl)(C)C.[Cl:24][CH2:25][C:26](N(OC)C)=[O:27]>CCOCC.C1COCC1>[Cl:24][CH2:25][C:26]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12)=[O:27]
Reactant: CON(C)C(=O)CCl
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1ccc2c(C(=O)CCl)ccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
To a solution of 4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (2.05 g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0° C. was added dropwise a solution of isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2-chloro-N-methoxy-N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). After 30 minutes reaction time, the solution was quenched by the addition of saturated ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2-chloro-1-(1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone (711 mg, 35%). 1H NMR (400 MHz, CDCl3): δ 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98 (dd, 2H), 0.01 (s, 9H); MS(ES): 325 (M+1).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([C:11]1[C:12]([F:22])=[C:13]([C:18]([F:21])=[CH:19][CH:20]=1)[C:14]([O:16]C)=[O:15])[S:6](=[O:10])(=[O:9])[NH:7][CH3:8])[CH3:4]>C1COCC1.CO>[CH2:3]([N:5]([C:11]1[C:12]([F:22])=[C:13]([C:18]([F:21])=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15])[S:6](=[O:9])(=[O:10])[NH:7][CH3:8])[CH3:4]
Reactant: CCN(c1ccc(F)c(C(=O)OC)c1F)S(=O)(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)NC
Temperature: 60 °C
Yield: 83.1 %

Procedure:
NaOH (0.908 mL, 1.82 mmol) was added to methyl 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoate (0.280 g, 0.908 mmol) in THF:MeOH (3:2; 5 mL). The mixture was warmed to 60° C. for 16 hours. The cooled mixture was concentrated under reduced pressure, and the residue was taken up in 1M NaOH (4 mL) and washed with EtOAc. The aqueous pH was lowered to below 3, and the mixture was extracted with EtOAc (3×6 mL) to provide crude 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoic acid (222 mg, 83% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][CH:17]([O:27][CH3:28])[C:18]1[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=1)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:23]([C:22]1[CH:25]=[C:18]([CH:17]([O:16][CH3:15])[O:27][CH3:28])[CH:19]=[CH:20][C:21]=1[F:26])[OH:24]
Reactant: c1ccc2scnc2c1
Reactant: COC(OC)c1ccc(F)c(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1ccc(F)c(C(O)c2nc3ccccc3s2)c1
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
A total of 1.08 g of benzothiazole was dissolved in 15 ml of dry tetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogen gas, 6.4 ml of 1.56 M solution of n-butyllithium in hexane was added. After stirring for 5 minutes, 8 ml of a solution of 1.35 g of 5-(dimethoxymethyl)-2-fluorobenzaldehyde in dry tetrahydrofuran was added, followed by stirring for 10 minutes. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 1.8 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 95 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 2.50 (s, 3H), 3.18-3.29 (m, 4H), 3.73-3.80 (m, 4H), 4.12 (s, 3H), 6.58 (s, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.55 (s, 1H), 7.72 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:31]=[CH:30][C:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[N:10]=1.C(N(CC)CC)C.[F:39][C:40]([F:47])([F:46])[CH2:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[Cl:15][C:14]1[C:9]([NH:8][C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH:1][S:42]([CH2:41][C:40]([F:47])([F:46])[F:39])(=[O:44])=[O:43])=[N:10][C:11]([NH:16][C:17]2[CH:31]=[CH:30][C:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25][C:19]=3[CH:18]=2)=[N:12][CH:13]=1
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N)n3)cc2CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(=O)(=O)CC(F)(F)F)n3)cc2CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
N*4*-((1R,2R)-2-Amino-cyclohexyl)-5-chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine was dissolved in Methylene chloride (5 mL) and Triethylamine (0.15 mL, 1.1 mmol) was added, followed by 2,2,2-Trifluoroethanesulfonyl chloride (0.025 mL, 0.23 mmol). Stir under an atmosphere of Nitrogen at room temperature for 45 min, then partition between 10 mL satd. sodium bicarbonate and 10 mL DCM. Separate and extract the aqueous layer, 3×10 mL DCM. Dry the combined organics over sodium sulfate, filter and concentrate in vacuo. The resultant oil was purified on a sulfonic acid resin cartridge, washing with methanol, eluting with ammonia/methanol. Conc. in vacuo reconcentrating from DCM afforded an oil. Subsequent purification on silica gel (0-10% MeOH:DCM, 12 g SiO2) gave 2,2,2-Trifluoro-ethanesulfonic acid ((1R,2R)-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-amide (55 mg, 53%) as a colorless film. LCMS (m/e) 591 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.21 (d, 1H, J=7.9 Hz), 7.18 (s, 1H), 7.01 (d, 1H, J=7.9 Hz), 6.97 (s, 1H), 5.36 (d, 1H, J=7.5 Hz), 5.31 (s, 1H), 3.84 (m, 1H), 3.61 (q, 2H, J=9.0 Hz), 3.55 (t, 2H, J=5.4 Hz), 3.36 (s, 3H), 3.29 (m, 1H), 2.9 (m, 4H), 2.72 (m, 6H), 2.17 (m, 2H), 1.82 (m, 2H), 1.34 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[CH:6][C:3]=1[CH2:4][OH:5].C1N=CN([C:22](N2C=NC=C2)=[S:23])C=1>CC(C)=O>[CH3:10][C:9]1[C:2]2[NH:1][C:22](=[S:23])[O:5][CH2:4][C:3]=2[CH:6]=[C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)[CH:8]=1
Reactant: Cc1cn(-c2cc(C)c(N)c(CO)c2)cn1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC(C)=O
Product: Cc1cn(-c2cc(C)c3c(c2)COC(=S)N3)cn1
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixed solution of 2-amino-3-methyl-5-(4-methylimidazol-1-yl)benzylalcohol (135 mg), N,N'-thiocarbonyldiimidazole (116 mg) and acetone (3.1 ml) was heated under stirring under nitrogen atmosphere for 2 hours. The mixture was distilled under reduced pressure to give a residue. The residue was column chromatographed(chloroform: methanol=30:1) to give 95 mg (59.0%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C(OC(=O)[C:33](Cl)([F:35])[F:34])C.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:33]([F:35])[F:34])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 70 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.00 g, 2.13 mmol), chlorodifluoroacetic acid ethyl ester (2.700 mL, 21.29 mmol), K2CO3 (882.7 mg, 6.387 mmol) and DMF (40 mL, 500 mmol) was heated to 70° C. for 6 h in a sealed tube. The material was extracted with EtOAc, and washed with water (3×). The organic layer was purified via column chromatography, eluting with 3-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.67-1.69 (m, 9H), 1.80 (d, J=7.1 Hz, 3H), 4.94-5.03 (m, 1H), 6.63 (s, 1H), 7.15 (dd, J=9.1, 4.5 Hz, 1H), 7.22-7.28 (m, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H). MS (ES+): m/z=519.03/521.03 (75/100) [MH+]. HPLC: tR=1.93 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl.O>[Br:12][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][C:1]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)CCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CC(Br)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 100 g (0.667 mol) of hydrocinnamic acid, 120 g (0.674 mol) of N-bromosuccinimide, and 1.8 g of benzoyl peroxide (BPO) in 900 ml of CCl4 was heated at reflux for 20 hr under nitrogen. After cooling to room temperature the reaction mixture was filtered. The filtrate when stripped to dryness yielded only a small amount of additional material which was combined with the original solid and the whole was slurried for 2 hr with warm water to dissolve the succinimide. The slurry was filtered and rinsed with water again and oven dried at 50° C. overnight to 120.8 g (79%) of material which is pure enough for the next step. Material recrystallized from toluene melts 138.5°-140.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[C:20]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[N:25]=1)O)#[N:21]>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH:22]([C:20]#[N:21])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[N:25]=1)=[O:15]
Reactant: N#CC(O)c1cccc(Oc2cccc(F)c2)n1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Solvent: CCOCC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OC(C#N)c1cccc(Oc2cccc(F)c2)n1

Procedure:
The acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with cyano[6-(3-fluorophenoxy)-2-pyridyl]methanol in ether as in Example 2 to give cyano[6-(3-fluorophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([S:15]CC2C=CC(OC)=CC=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([SH:15])[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)c1c(SCc2ccc(OC)cc2)nc2c(F)c(F)c(F)cc2c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(S)nc2c(F)c(F)c(F)cc2c1O
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Ethyl 4-hydroxy-6,7,8-trifluoro-2-(p-methoxybenzylthio)quinoline-3-carboxylate (59.9 g) was added to a mixture of trifluoroacetic acid (500 g), trifluoromethanesulfonic acid (100 g) and anisole (92.5 g) at -23° to -20° C. with stirring over a period of 15 minutes. The mixture was stirred at -20° to -15° C. for 30 minutes and then at room temperature for 1.5 hour. After the reaction mixture was concentrated under reduced pressure, a piece of ice was added to the concentrate and the mixture was made alkaline with 10% aqueous sodium hydroxide. After insoluble materials were removed by filtration, the filtrate was washed with ether and made strongly acidic with concd. hydrochloric acid. The resulting powder was filtered to give the title compound (33 g), which was recrystallized from ethanol to give yellow crystals, m.p. 190° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:25][C:26]([C:27]([OH:29])=[O:28])([CH3:31])[CH3:30])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Temperature: 120 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (388 mg, 1 mmol), 2-amino-2-methyl-propionic acid (516 mg, 5 mmol), copper(I) iodide (114 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120° C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (410 mg, 100%) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C24H30N2O4 (M+H)+: 411.52, observed: 411.1.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[CH:8]=1)N.[CH:15]([C:18]([CH3:20])=O)([CH3:17])[CH3:16]>C(O)(=O)C>[CH3:20][C:18]1[C:15]([CH3:17])([CH3:16])[C:4]2[C:3](=[CH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][C:5]=2[C:12]([OH:14])=[O:13])[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1cc(C(=O)O)cc(C(=O)O)c1
Solvent: CC(=O)O
Product: CC1=Nc2cc(C(=O)O)cc(C(=O)O)c2C1(C)C
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 5-hydrazinylbenzene-1,3-dicarboxylic acid (30.0 g, 129 mmol), isopropylmethylketone (22.0 mL, 205 mmol) in acetic acid (300 mL) and was heated under reflux in an oil bath for 18 h. After cooling to ambient temperature the solvent was evaporated off under reduced pressure to a small volume of ˜100 mL. To the crude mixture was added iPrOH (200 mL) and the solid was collected with a filter funnel, washed with EtOAc (3×200 mL) and ethyl ether (2×200 mL) and dried. Further drying of the solid in an oven at 50° C. under high vacuum for 18 h provided 30.44 g (95.5%) of the product.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].CO>O>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:23]1[N:24]=[C:20]([CH:17]([CH3:19])[CH3:18])[S:21][CH:22]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Reactant: CC(C)c1nc(C=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Br
Temperature: 50 °C
Yield: 94.9 %

Procedure:
A mixture of 12G (2 g, 7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (2.2 g, 14.6 mmol), NaOH (1.5 g) and MeOH (20 mL) was heated to 50° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15A (2.8 g, 94.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.[NH2-].[Na+].Cl[CH:20](Cl)[C:21]([O-:23])=[O:22].[K+].[K]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CN(C)P(N(C)C)(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH:20]([C:21]([OH:23])=[O:22])[O:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: O=C([O-])C(Cl)Cl
Reactant: Oc1ccc(Cl)cc1C(O)c1ccccc1
Agent: [K+]
Agent: [K]
Agent: [NH2-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)C1Oc2ccc(Cl)cc2C(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
A solution of 30.1 g of 5-chloro-2-hydroxy-α-phenyl-benzene-methanol in 200 ml of anhydrous toluene was added dropwise with stirring at room temperature to a mixture of 10.35 g of sodium amide and 100 ml of toluene and the mixture was stirred for 2 hours at room temperature and was then refluxed for 6 hours. After cooling the mixture to room temperature, 22.3 g of potassium dichloroacetate were added thereto in small portions and 20 ml of hexamethylphosphoramide were added. The mixture was stirred for 20 hours at room temperature and was then refluxed for 4 hours and then returned to room temperature. 20 ml of ethyl acetate were added thereto followed by show addition of 250 ml of water and the aqueous phase containing the potassium salt of the desired acid was extracted 3 times with 100 ml of ether and acidified by bubbling sulfur dioxide therethrough. The mixture was then extracted 3 times with 100 ml of ether and the combined ether extracts were washed 3 times with 100 ml of water, dried over magnesium sulfate, treated with activated carbon and evaporated to dryness under reduced pressure. The 24 g of residue were effloresced in cyclohexane to obtain crystals which were crystallized from 520 ml of a 7-3 benzene-cyclohexane mixture to obtain 5.3 g of 6-chloro-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid melting at 194° C.