Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: O=C(O)c1cccc2nc3ccc4cccnc4c3nc12
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4cccnc4c3nc12

Procedure:
Pyrido[2,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrido[2,3-α]phenazine-11-carboxylic acid (II.1) and N,N-dimethylethylenediamine
Reaction SMILES: Cl.Cl.[N:3]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[K+].Br[C:16]1[S:17][C:18]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35]CC)=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=2[N:20]=1.[OH-].[Na+]>CCO.C1COCC1.CN(C)C(=O)C.O.C(Cl)Cl>[C:39]([O:38][C@@H:32]([C:23]1[C:22]([CH3:43])=[CH:21][C:19]2[N:20]=[C:16]([N:9]3[CH2:10][CH2:11][C:12]4[N:3]=[CH:4][CH:5]=[CH:6][C:7]=4[CH2:8]3)[S:17][C:18]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:33]([OH:35])=[O:34])([CH3:42])([CH3:40])[CH3:41]
Reactant: c1cnc2c(c1)CNCC2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc2nc(N3CCc4ncccc4C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with 5,6,7,8-tetrahydro-1,6-naphthyridine, dihydrochloride, hydrate (125 mg), DCM (1.5 mL), and 50% w/v aq KOH (200 μL). The vial was shaken. Then H2O (1.3 mL) was added. The organic phase was collected, dried with a small amount of Na2SO4, decanted, and concentrated to give the free base. N,N-dimethylacetamide (500 μL), and (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (25 mg, 50 μmol) were added. The vessel was sealed and heated to 100° C. for 30 min. Then THF (1 mL), EtOH (absolute, 500 μL), and 5 M aq NaOH (500 μL) were added. The reaction was heated to 100° C. for 30 min. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C28H28ClN3O3S: 522.2, 524.2 (M+H+); Found: 522.3, 524.2 (M+H+). NMR (400 MHz, CD3OD): δ 8.62 (d, J=5.6 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.78 (dd, J=7.9, 5.6 Hz, 1H), 7.63 (dd, J=8.5, 1.9 Hz, 1H), 7.58-7.52 (m, 2H), 7.52-7.44 (m, 1H), 7.38 (app. s, 1H), 5.15 (s, 1H), 4.96 (s, broad, 2H), 4.03 (t, J=5.9 Hz, 2H), 3.31-3.23 (m, 2H), 2.51 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30]I.[H-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25]3[N:29]([CH3:30])[CH:28]=[CH:27][N:26]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCc3ncc[nH]3)CC[C@H]2c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCc3nccn3C)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=428.2 (M+H+) and [α]D20=−69.7° (c=0.2770 in chloroform), was prepared by methylation of (2R,5S)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole in accordance with the general method of example 8 (methyl iodide, sodium hydride).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reaction time: 5 h
Yield: 31.8 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (231) (2.0 g, 4.14 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (2.7 g, 12.41 mmol) in pyridine (25 ml), was added POCl3 (1.16 ml, 12.41 ml) at −10° C. The reaction mixture was stirred at this temperature for 5 h. After completion of the reaction, the reaction mixture was quenched with water and the mixture was extracted with ethyl acetate. The organic part was washed with water, separated and dried over Na2SO4. After evaporation, the crude product was purified by 100-200 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (232) (0.9 g, 32%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[OH:12])[N:7]([CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([O:27][CH3:28])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:12][CH2:23][CH2:22][CH2:21][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Yield: 31.6 %

Procedure:
A solution of methyl 4-chloro-2-[(2,4-dichlorophenyl)(hydroxy)methyl]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 215, 703 mg, 1.58 mmol) and cyanomethylenetributylphophorane (763 mg, 3.16 mmol) in toluene (32 mL) was stirred for 12 h at 110° C. The reaction mixture was concentrated in vacuo and purified by column chromatography on NH silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to afford the desired product as pale yellow oil (212 mg, 0.499 mmol, 32%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[C:13]([F:21])[CH:12]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=3)=[O:20])=[C:13]([F:21])[CH:12]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cccc(C(F)(F)F)c2)c(F)c1
Yield: 11.6 %

Procedure:
A solution of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (80 mg, 0.275 mmol), 3-(trifluoromethyl)aniline (44.3 mg, 0.275 mmol), HATU (125 mg, 0.330 mmol) and DIEA (0.048 mL, 0.275 mmol) in DMF (10 mL) was stirred at rt for 5 h. After LCMS analysis showed the starting material had disappeared, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness to give crude product which was purified by preparative HPLC to give pure product 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide (14.56 mg, 0.032 mmol, 12% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.03 (br. s., 1H), 7.77 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.46-7.36 (m, 2H), 7.31-7.24 (m, 2H), 6.28 (s, 1H), 4.24-4.19 (m, 2H), 3.84 (s, 2H), 1.41 (t, J=6.8 Hz, 3H); ES-LCMS: m/z 435.1 (M+H).
Reaction SMILES: [C:1]([NH:5][CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C1C=CC=CC=1>[C:1]([N:5]([CH3:6])[C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(C)(C)C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)C(C)(C)C
Yield: 72.6 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were N-tert-butyl-N-methyl amine (3.36 g, 0.0386 mole) and 4-nitrobenzoyl chloride (3.58 g, 0.0193 mole), the reaction was carried out in benzene, the product was crystallized from cold ethanol, and the desired product was 3.31 g of crystals (28% yield), mp 119°-121° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 8.252 ppm (d, 8.8 Hz, 2H; 3,5-aryl H); 7.569 ppm (d, 8.8 Hz, 2H; 2,6-aryl H); 2.838 ppm (s, 3H; N-CH3); 1.526 ppm (s, 9H; tert-butyl H) .
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1NN=[N:27][N:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])=[N:26][N:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccccc1-c1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccccc2Cl)o1
Yield: 78.9 %

Procedure:
The title compound (1.65 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.35 g), 5-(2-chlorophenyl)tetrazole (1.0 g) and dicyclohexylcarbodiimide (0.16 g) according to the method of description 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])([O:26][Si](C)(C)C)[CH2:8][CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])([OH:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3(O[Si](C)(C)C)C(F)(F)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)C(F)(F)F)CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
To 6,7-Dichloro-1-(perfluoroethyl)-9-tosyl-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.25 g, 0.47 mmol) in THF (5 mL) was added 6N KOH (6 mL). The reaction mixture was stirred at room temperature for 10 min. and then refluxed for 36 h, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography [EtOAc-hexane (3:22) as eluant] to give the title compound as a white solid (0.06 g, 34%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.21 (bs, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 2.82-2.80 (m, 1H), 2.68-2.62 (m, 1H), 2.45 (s, 1H), 2.28-2.23 (m, 1H), 2.18-2.15 (m, 1H), 2.12-2.06 (m 1H), 2.03-2.0 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:11]1[C:20]2[C:15](=[CH:16][C:17](I)=[CH:18][CH:19]=2)[C:14](=[O:22])[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:28]([NH:30][C:31]([NH:33][C:34]1[CH:39]=[C:38]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1)=[O:32])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:28]([NH:30][C:31](=[O:32])[NH:33][C:34]1[N:35]=[CH:36][C:37]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:11]([C@@H:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][OH:1])[CH:12]=[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]3=[O:22])=[C:38]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:39]=1)[CH3:29]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn([C@H](CO)Cc2ccccc2)c2ccc(I)cc2c1=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)Cc2ccccc2)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of palladium (II) acetate (23.52 mg, 0.10 mmol, 0.1 equiv.) and 1,1′-bis(di-t-butylphosphino)ferrocene (49.7 mg, 0.10 mmol, 0.1 equiv.) in acetonitrile (3 mL) was added (S)-ethyl 1-(1-hydroxy-3-phenylpropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 51, 500 mg, 1.05 mmol), followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (Intermediate 17, 381 mg, 1.06 mmol) and a solution of potassium carbonate (217 mg, 1.57 mmol) in water (1 mL). The reaction mixture was stirred at 60° C. for 2 h, cooled to room temperature, and diluted with water (2 mL). The reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organics were dried over sodium sulfate and concentrated to provide (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3-phenylpropan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a grey solid (619 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:13]S[C:11](=[O:14])[N:10]=1.[Cl:15][C:16]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([Cl:27])=[CH:19][C:17]=1[NH2:18].C(P(CCCC)CCCC)CCC>ClCCl>[Cl:15][C:16]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][C:20]([Cl:27])=[CH:19][C:17]=1[NH:18][C:11]([NH:10][C:9](=[S:13])[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:14]
Reactant: O=c1nc(-c2c(F)cccc2F)ss1
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: O=C(NC(=S)c1c(F)cccc1F)Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-1,2,4-dithiazole-3-one (0.9 g) in 20 ml of dichloromethane was added dropwise a solution of 2,5-dichloro-3-trifluoromethylaniline (0.9 g) and tributylphosphine (0.8 g) in 10 ml of dichloromethane under ice-cooling and the solution was stirred for 30 minutes at room temperature. The dichloromethane was then distilled off under reduced pressure and to the residue was added ligroin. The precipitated crystal was filtered and the crystal was washed with ligroin to obtain the desired product 1.3 g. (d.p. 176°-177° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(N)cccc2[nH]1
Yield: 69.8 %

Procedure:
Ethyl 4-nitroindole-2-carboxylate (2.3 g) and 10% palladium on carbon (0.5 g) in ethanol (400 ml) were stirred under a hydrogen atmosphere for 3 hours. The reaction was then filtered through Celite and concentrated to give the end product as a pale brown solid (1.4 g, 70%); NMR δ(CD3SOCD3) 1.3 (t, 3H), 4.3 (q, 2H), 5.4 (s, 2H), 6.1 (d, 1H), 6.6 (d, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 11.4 (bs, 1H); M/z (+) 205 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])C1C=CC=CC=1.[CH:18]([O-])=O.[NH4+]>CO.[Pd]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1
Reactant: O=C(O)C1CC(O)CCN1Cc1ccccc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C1CC(O)CCN1
Temperature: 25 °C
Yield: 123 %

Procedure:
To a stirred solution of the product of step B (600 mg, 2.4 mmol) in methanol (15 mL) was added 10% palladium on carbon (60 mg) and ammonium formate (1.26 g, 20.0 mmol). The reaction mixture was heated to reflux for 2 h, cooled to ambient temperature then filtered through Celite. The filtrate was concentrated in vacuo to afford methyl 4-hydroxypiperidine-2-carboxylate (470 mg, 95%) as a colorless oil which was carried forward without purification: 1H NMR (CDCl3, 400 MHz) δ 3.76-3.74 (m, 4H), 3.44-3.41 (m, 1H), 3.26-3.21 (m, 1H), 2.70-2.63 (m, 1H), 2.33-2.28 (m 1H), 1.91-1.90 (m, 1H), 1.50-1.40 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:15][OH:16]
Reactant: OCCBr
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
To a solution of 3-(trifluoromethoxy)phenol (3 g, 16.8 mmol) in DMF (30 mL) was added 2-bromoethanol (3.16 g, 25.3 mmol), potassium carbonate (4.65 g, 33.7 mmol). The mixture was heated at 80° C. overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by a column chromatography eluting with petroleum ether and ethyl acetate (10:1) to give 2-(3-(trifluoromethoxy)phenoxy)ethanol (3.5 g, 94.5% yield) as a yellow oil. 1H-NMR (DMSO-d6) δ 7.28-7.30 (t, 1H), 6.81-6.86 (m, 2H), 6.78 (s, 1H), 4.07-4.09 (t, 2H), 3.95-3.99 (m, 2H), 2.58 (t, 1H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[C:14]1([C:20]2[C:28]3[C:27]([N:29]4[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]4)=[N:26][CH:25]=[N:24][C:23]=3[S:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:35][CH:32]1[CH2:33][CH2:34][N:29]([C:27]2[C:28]3[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:21][S:22][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:30][CH2:31]1
Reactant: OCc1cccc(OCC2CO2)c1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Product: OCc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c1
Yield: 64 %

Procedure:
Synthesis followed SP6 (4 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 64% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:32]=[CH:31][C:23]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>CO>[N:28]1[CH:29]=[CH:30][C:25]([O:24][C:23]2[CH:22]=[CH:21][C:20]([C:17]3[N:16]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[O:19][N:18]=3)=[CH:32][CH:31]=2)=[CH:26][CH:27]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5ccncc5)cc4)no3)cc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(-c2nc(-c3ccc(Oc4ccncc4)cc3)no2)cc1
Temperature: 55 °C
Reaction time: 14 h
Yield: 4 %

Procedure:
In a single neck round bottom flask fitted with a condenser, 4-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenoxy)pyridine (97 mg, 229 μmol) was suspended in methanol (3.0 mL) and THF (3.0 mL) 10% Pd/C (1 mg, 16 μmol) was added The reaction vessel was sealed and the solution was stirred under H2 at 55° C. for 14 hours. The hot solution was filtered through Celite and the pad was washed with methanol (20 mL). The hot solution was filtered through Celite and the pad was washed with methanol (20 mL). The solvent was removed under reduced pressure the solid residue was purified by silica gel column chromatography (EtOAc/Hex 1:2) to give the product as a white solid (3 mg, 4%). 1H NMR (500 MHz, DMSO-d6) δ(ppm): 6.57 (2H, d, J=7.8 Hz), 6.84 (1H, d, J=9.0 Hz), 7.50 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz), 8.08 (2H, d, J=7.8 Hz).
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH:21]3[NH:24][C:25]3[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=3)[O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH:21]3[NH:24][C:25]3[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=3)[O:28][CH2:29][C:30]([O:32][CH3:3])=[O:31])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A 2 M solution of (diazomethyl)trimethylsilane in THF (0.20 mL, 0.40 mmol) was added to a solution of 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetic acid (159 mg, 0.421 mmol) in THF (5 mL) at 0° C. in a 50 mL round bottom flask. The mixture was allowed to stir for 2 hours at room temperature. The resulting mixture was concentrated in vacuo and the resulting crude residue was purified on a Teledyne-Isco combiflash machine (12 g column, hexanes→100% ethyl acetate/hexanes, gradient), to afford 135 mg (82%) of methyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate.
Reaction SMILES: CC1C=CC=C2C=1CC(=O)N2.[C:12]([O:19]CC)(=[O:18])[C:13](OCC)=O.[O-]CC.[K+].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31](C)[C:30]=1[CH3:36])([O-:28])=[O:27]>CCOCC>[CH3:36][C:30]1([CH2:13][C:12]([OH:19])=[O:18])[C:29]([N+:26]([O-:28])=[O:27])=[CH:34][CH:33]=[CH:32][CH2:31]1
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cc1cccc2c1CC(=O)N2
Agent: [K+]
Solvent: CCOCC
Product: CC1(CC(=O)O)CC=CC=C1[N+](=O)[O-]
Yield: 45 %

Procedure:
Preparation of 4-Methyl-2-oxindole. Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternatively with 10% sodium hydroxide and 30% hydrogen peroxide until the dark color was no longer present. The solid was filtered off and the filtrate acidified with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 1-methyl-6-nitrophenylacetic acid as an off-white solid. The sold was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid.