Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:15][CH2:16][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:18][CH2:19]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reaction time: 2 h

Procedure:
tert-Butyl 3-(3-((4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate (Example 277, step a) was dissolved in DCM (10 mL) and TFA (2 mL) was added. The resulting mixture was stirred for 2 h then evaporated. The residue was azeotroped with toluene and redissolved in MeCN (10 mL). This was applied to a SCX cartridge (50 g, Varian) which had been pre-wetted with MeCN. The cartridge was washed with MeCN (100 mL) and eluted with 880 aqueous ammonia in MeCN (1:4, 100 mL). The eluent was evaporated to afford the subtitled compound. Material used directly in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2cccc(F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(C[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.7 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert butyl (R)-3-(3-fluorobenzyl)-pyrrolidine-1-carboxylate (Intermediate 99, 0.515 g) in DCM (10 mL) and the mixture was stirred for 1 hour at room temperature. The mixture was evaporated to dryness and the residue was partitioned between DCM and saturated aqueous NaHCO3. The organic extract was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-(R)-(3-fluoro-benzyl)pyrrolidine (0.402 g) as an oil.
Reaction SMILES: C(O[CH2:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([Br:19])[N:13]=2)C1C=CC=CC=1.B(Br)(Br)[Br:21]>C([O-])(O)=O.[Na+]>[Br:19][C:14]1[N:13]=[C:12]2[S:11][C:10]([CH2:9][Br:21])=[N:18][C:17]2=[CH:16][CH:15]=1
Reactant: BrB(Br)Br
Reactant: Brc1ccc2nc(COCc3ccccc3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: BrCc1nc2ccc(Br)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.1 %

Procedure:
A solution of 2-Benzyloxymethyl-5-bromo-thiazolo[5,4-b]pyridine (1.60 g, 4.77 mmol) DCM (15 mL) was cooled to −78° C. followed by addition of BBr3 (2.27 ml, 23.86 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (2.0 g, Crude yield).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Cl[CH2:14][C:15]([NH2:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH2:14][C:15]([NH2:17])=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CON1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2-hydroxyisoindoline-1,3-dione (2.4 g, 14.71 mmol), 2-chloroacetamide (1.65 g, 17.65 mmol) and K2CO3 (2.44 g, 17.65 mmol) in 40 mL of DMF was stirred at 90° C. overnight. The solid was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, 1H), 7.68-7.64 (m, 2H), 7.45-7.43 (m, 2H), 7.35 (s, 1H), 4.23 (s, 2H). LCMS (method A): [MH]+=221, tR=2.665 min.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[O:19][CH3:20]>C1COCC1.[OH-].[Na+]>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzyl chloride (24.6 ml, 209 mmol, 1.1 eq.) in THF (100 ml) was added dropwise at 0° C. over 15 min, to a mechanically stirred solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid, 1) (30 g, 179 mmol) in THF (90 ml) and 2.0 M aq. NaOH (225 ml). The mixture was allowed to warm to room temperature and then heated under reflux for 48 hours. After cooling, the mixture was washed with hexane (2×100 ml) and the THF was removed in vacuo. The remaining aqueous phase was acidified to pH 1 with conc. HCl. The resulting precipitate was collected by filtration, washed with water and dried to afford 4-benzyloxy-3-methoxybenzoic acid (2) as a pale amorphous solid.
Reaction SMILES: C([Mg]Br)C.[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH2:15]([O:22][C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@@H:26]1[C:27](O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH2:15]([O:22][C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@@H:26]1[C:27]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([Br:5])[CH:7]=2)[NH:11][CH:10]=1)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a separate flask a solution of ethylmagnesium bromide (1.4 ml of a 3M solution in diethyl ether) was added dropwise over 5 minutes to a stirred solution of 5-bromoindole (0.75 g) in dry diethyl ether (18 ml). The mixture was stirred at room temperature for 10 minutes, heated under reflux for 2 hours, then cooled to -30° C. A solution of the above acid chloride of N-benzyloxycarbonyI-D-proline in dry diethyl ether (4 ml) was then added dropwise with stirring and stirring was continued for a further 1 hour. Diethyl ether (12.5 ml) and saturated aqueous sodium bicarbonate (6.5 ml) were added and the reaction was allowed to warm to room temperature. Stirring was continued for a further 10 minutes and the mixture was filtered. The solid was washed with ethyl acetate and the combined filtrate and washings were washed with water then brine and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with ethyl acetate gave, after combination and evaporation of the appropriate fractions, the title compound as a foam, (0.82 g). Found: C,58.85; H,4.51; N,6.38; C21H19BrN2O3 requires: C,59.02; H,4.48; N,6.56%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:16])/[CH:11]=[CH:12]/OCC.C1C(=O)N(Br)C(=O)C1.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH:33][C:34]([NH2:36])=[S:35])[CH:27]=1>C1COCC1.O>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH:33][C:34]2[S:35][C:11]([C:10]([NH:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:16])=[CH:12][N:36]=2)[CH:27]=1
Reactant: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Reactant: Cc1nc(Cl)cc(NC(N)=S)n1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 21 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a slurry of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide 5B (120 mg, 0.50 mmol) in THF (0.75 ml) and water (0.5 mL) was added NBS (98 mg, 0.55 mmol) at 0° C. The mixture was warmed and stirred at 20-22° C. for 3 h. To this was added 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea 5A (100 mg, 0.49 mmol), and the slurry heated and stirred at reflux for 2 h. The slurry was cooled to 20-22° C. and the solid collected by vacuum filtration giving 140 mg (71% yield) of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:29]([F:30])=[CH:28][C:8]2[N:9]([CH3:27])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>>[F:30][C:29]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[N:11]=[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)[N:9]([CH3:27])[C:8]=2[CH:28]=1
Reactant: COC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Yield: 89.3 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (121 mg) was prepared by following General Procedure E starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (140 mg) and lithium hydroxide (53 mg). LC/MS: m/z 427.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.01 (d, 1H), 7.95 (s, 1H), 7.61 (d, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 3.65 (s, 3H), —COOH and —NH proton signal was not observed.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27]C1C=CC=CC=1C1CCC2C(=CC=C(O)C=2)O1>>[Cl:27][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:12]=2)[O:17]1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1Cl)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2Cl)O3)nc1

Procedure:
2-[2-(2-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 485 mg of 2-(2-chlorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9, 0.5 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.62 (dd, 1H, J 7.5, 1.8 Hz), 7.51 (dd, 1H, J 7.6, 1.7 Hz), 7.45-7.40 (m, 2H), 7.21 (dd, 1H, J 9.1, 0.5 Hz), 7.04 (d, 1H, J 2.7 Hz), 6.99 (dd, 1H, J 8.8, 2.7 Hz), 6.94 (d, 1H, 8.8 Hz), 5.40 (dd, 1H, J 10.4, 2.1 Hz), 3.04 (m, 1H), 2.80 (m, 1H), 2.24 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.C[O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[N:24]1([C:4]2[N:3]=[C:2]([C:38]3[CH:37]=[C:36]([CH2:35][CH2:34][C:32]([OH:33])=[O:31])[CH:41]=[CH:40][CH:39]=3)[CH:7]=[C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)[N:5]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: COC(=O)CCc1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cccnc1N1CCN(c2cc(Cl)nc(N3CCOCC3)n2)CC1
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: O=C(O)CCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Temperature: 80 °C

Procedure:
Purge a solution of 4-{4-chloro-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-morpholine (142 mg, 0.33 mmol), (3-(2-methoxycarbonylethyl)phenyl)boronic acid (Combi-Blocks, Inc., San Diego, Calif.; 104 mg, 0.5 mmol) and K3PO4 (2M, 331 μL) in dioxane with nitrogen for 10 minutes. Add Pd(PPh3)4 (19 mg, 0.017 mmol) and purge for an additional 5 minutes. Seal the contents in a reaction vial and heat at 80° C. for 16 hours. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Filter the residue through a small pad of silica gel eluting with 50% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:21]=[C:20]([C:31]([OH:33])=O)[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:35]([NH2:37])[CH3:36]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:21]=[C:20]([C:31]([NH:37][O:35][CH3:36])=[O:33])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCN(C)CC4)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCN(C)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid (Example 196) and methoxylamine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=4)[CH2:26][CH2:27]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.24 mmol, 1.00 equiv) in methanol (20 mL) and a solution of sodium hydroxide (47.2 mg, 1.18 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred for 3 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 30 mL of water. The pH value of the aqueous solution was adjusted to 3 with 1N hydrochloric acid. The resulting solids were collected by filtration and washed with 10 mL×1 of water. The solid was dried in an oven under reduced pressure. The solid was purified by re-crystallization from methanol. This resulted in 60 mg (51%) of 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:31][CH:32]=2)[O:3]1.[OH-].[Na+]>CO.O>[OH:3][CH:4]([C:28]1[N:29]=[C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[S:31][CH:32]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2csc(-c3ccccc3)n2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of tert-butyl (4RS,5RS)-2-oxo-5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (3.17 g, 5.74 mmol) in methanol (60 ml) was added 1N sodium hydroxide (6.9 ml, 6.9 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give tert-butyl (1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate (1.72 g, 57%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.Br[CH:18]([CH3:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].[Br-].C(=O)([O-])[O-].C1(O)C=CC=CC=1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:18]([CH3:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2F)cc1
Reactant: CCOC(=O)CCC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CCOC(=O)CCC(C)Oc1ccc(Oc2ccc(Cl)cc2F)cc1
Temperature: 130 °C

Procedure:
A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33.
Reaction SMILES: Cl.C1(C)C=CC=CC=1.C=[N:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH2:10])=[CH:17][N:16]=1
Reactant: C=NCc1ccc(Cl)nc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NCc1ccc(Cl)nc1
Yield: 90 %

Procedure:
On the other hand, 7 g of concentrated hydrochloric acid was added to the toluene layer, and the resulting water layer containing the hydrochloride salt of an N-methylidene-(2-chloro-pyridin-5-yl)methylamine oligomer (II-5) or a mixture of two or more such salts was separated. 3.2 g of methanol was added to the separated water layer, and the resulting mixture was treated for 3 hours at 60° C., yielding an aqueous solution of the hydrochloride salt of (2-chloropyridin-5-yl)methylamine. Analysis by HPLC revealed an amount of the (2-chloropyridin-5-yl)methylamine of 1.28 g (yield: 90%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23](=[O:26])[CH2:24][CH3:25]>>[CH2:22]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCC(=O)CBr
Product: CCC(=O)Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 49 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-bromo-2-butanone were reacted by the same way with the example 1 to obtain the titled compound (179 mg, yield: 49%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[CH2:15](I)C.[OH-].[Na+]>CN1CCCC1=O>[CH3:15][O:12][C:3]1[C:2]([NH2:1])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Nc1cc2ccccc2cc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1cc2ccccc2cc1N
Yield: 52.3 %

Procedure:
3-Amino-2-naphthol (7.96 g, 50.0 mmol) was dissolved in N-methylpyrrolidone (190 ml), and the mixture was stirred under ice-cooling. Then, 60% sodium hydride (2.08 g, 52 mmol) was added, and the mixture was stirred at the same temperature for 40 min. Then, ethyl iodide (3.3 ml, 53 mmol) was added, and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture was added diluted aqueous sodium hydroxide solution, and the mixture was extracted with an ethyl acetate-hexane=1:1 mixed solvent. The organic layer was washed with diluted aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane), and the obtained solid was washed with hexane and dried under reduced pressure to give the title compound (4.53 g, yield 52%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[NH:5][CH:6]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][N:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])=[O:8])[NH:5][CH:6]=1
Reactant: O=C(O)c1cc(Cl)c[nH]1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1cc(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-chloro-1H-pyrrole-2-carboxylic acid (1 eq), N-hydroxysuccinimide (1 eq) and DCC (1.05 eq) in dry THF was stirred at RT for 12 h. The solid urea was filtered off and washed with THF. The filtrate was evaporated under reduced pressure and the resulting crude was purified by on silica gel eluting with petrol ether/EtOAc to obtain the title compound as a white-off powder. 1H NMR (400 MHz, DMSO-d6) δ: 12.87 (1H, br. S), 7.50-7.45 (1H, m), 7.16-7.12 (1H, m), 2.87 (4H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[C:12](=O)([O-:14])[O-:13].[K+].[K+].C.[C]=O.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]([OH:14])=[O:13])=[C:3]([CH3:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(Br)c(C)c1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
63.9 g (300 mmol) of 4′-bromo-3′-methylacetophenone, 256 g of toluene, 32 g of water, 45.5 g (330 mmol) of potassium carbonate, 9.66 g (30 mmol) of tetra(n-butyl) ammonium bromide, 1.45 g (water content 55.95% by weight) of activated charcoal supported 5% palladium and 0.372 g (0.90 mmol) of 1,3-bis(diphenylphosphino)propane were fed into a pressure-tight reactor, and reaction was performed at 120° for 7 hours by pressurizing with carbon monoxide at 0.8 MPa. After cooling the reaction solution to room temperature, inside of the reactor was purged with nitrogen, and then the pressure was reduced to atmosphere pressure. 224 g of water was added, and stirred for 30 minutes. Catalyst was filtered with Celite and the organic phase was separated. 43.8 g (420 mmol) of 35% hydrochloric acid was added to the water phase. The obtained slurry was filtered, and then dried under reduced pressure to obtain 48.1 g of 4-acetyl-2-methylbenzoic acid as white crystal (yield 90%).