Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=3)[CH2:5]1.Br[C:47]1[NH:51][C:50]([C@@H:52]2[CH2:56][C@H:55]([CH3:57])[CH2:54][N:53]2[C:58](=[O:69])[C@@H:59]([NH:64][C:65](=[O:68])[O:66][CH3:67])[C@@H:60]([CH3:63])[CH2:61][CH3:62])=[N:49][CH:48]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:67][O:66][C:65]([NH:64][C@H:59]([C:58]([N:53]1[CH2:54][C@@H:55]([CH3:57])[CH2:56][C@H:52]1[C:50]1[NH:51][C:47]([C:32]2[CH:33]=[C:34]3[CH2:35][O:36][C:23]4[CH:22]=[C:21]5[C:26]([CH:27]=[CH:28][C:18]6[N:17]=[C:16]([C@@H:6]7[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]7[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[NH:20][C:19]=65)=[CH:25][C:24]=4[C:29]3=[CH:30][CH:31]=2)=[CH:48][N:49]=1)=[O:69])[C@@H:60]([CH2:61][CH3:62])[CH3:63])=[O:68]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(Br)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Temperature: 95 °C
Yield: 62.1 %

Procedure:
(2S,4S)-Tert-butyl 4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (856 mg, 1.4 mmol), methyl (2S,3S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate (932 mg, 2.1 mmol), Pd(PPh3)4 (162 mg, 0.14 mmol), PdCl2(dppf)2 (102 mg, 0.14 mmol), and K2CO3 (2M in H2O, 2.31 mL, 4.62 mmol) were combined in DMSO (8 mL) and dioxanes (8 mL). The mixture was degassed with bubbling Argon for 10 min then heated to 95° C. for 1 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (1% to 20% MeOH/EtOAc) to afford tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (701 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[CH:6]([CH3:12])[C:7](=[N:10]O)[CH2:8][CH3:9])[CH3:2].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[O:13][N:10]=[C:7]([CH2:8][CH3:9])[C:6]=1[CH3:12])=[O:14])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C)C(CC)=NO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(CC)c1C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
4-Hydroxyimino-3-methyl-2-oxo-hexanoic acid ethyl ester (3.7 g, 18.4 mmol) and concentrated sulfuric acid (3 mL) were added to 50 mL of absolute ethanol and the mixture was refluxed for 16 hours. After the mixture cooled to room temperature, saturated sodium bicarbonate solution was added to neutralize the mixture. The product was extracted with CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated to give 3.3 g of the title compound. MS: (+) m/z 184.26 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH2:18][OH:19])[CH:7]=[C:8]([CH:15]3[CH2:17][CH2:16]3)[C:9]=2[O:10][C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:7]=[C:8]([CH:15]3[CH2:17][CH2:16]3)[C:9]=2[O:10][C:11]([F:12])([F:13])[F:14])[CH:18]=[O:19])[CH2:2][CH2:3]1
Reactant: OCc1cc(C2CC2)c(OC(F)(F)F)c(C2CC2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cc(C2CC2)c(OC(F)(F)F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
[3,5-Dicyclopropyl-4-(trifluoromethoxy)phenyl]methanol (190 mg, 0.698 mmol) was dissolved in DCM (6 mL) and Dess-Martin periodinane (444 mg, 1.05 mmol) was added. The mixture was stirred for 1 hour at room temperature. The mixture was evaporated in vacuo and the residue was purified by silica gel chromatography (0-10% EtOAc/hexanes) to yield the title compound as a clear oil (174 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.ClC(OCC)=O.[NH3:29]>C(Cl)(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH2:29])=[O:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reaction time: 0.5 h

Procedure:
18 g of trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxylic acid were dissolved in 600 ml of chloroform while gassing with argon and the solution was treated dropwise at 0° C. while stirring within 3 minutes with a solution of 7.2 ml of ethyl chloroformate in 40 ml of chloroform. The reaction solution was stirred for a further 30 minutes. Ammonia gas was then conducted into the solution during 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes and then extracted twice with 300 ml of water each time. The aqueous phases were back-extracted with in each case 100 ml of chloroform. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. Recrystallization of the brown crystalline crude product obtained (19 g) from 800 ml of methylene chloride gave 13 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxamide as pale brown crystals.
Reaction SMILES: [C:1]([NH:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([NH:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)Oc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 99.5 %

Procedure:
1 g (2.27 mmole) 5-(4-[2-(4-tert-butylaminocarbonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated on Pd/C (5%) in ethyl acetate at atmospheric pressure over night. The catalyst was filtered off and the solvent was evaporated in vacuo to give 1 g (yield 99%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:18][C@@H:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C@H:16]([OH:24])[CH2:15]1.CN(C=O)C.CCO>[Fe].O>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][N:14]2[CH2:18][C@@H:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C@H:16]([OH:24])[CH2:15]2)=[C:2]([F:1])[CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccncc2C#CCN2C[C@@H](O)[C@H](N3CCCC3)C2)c(F)c1
Agent: [Fe]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(Oc2ccncc2C#CCN2C[C@@H](O)[C@H](N3CCCC3)C2)c(F)c1
Temperature: 100 °C
Yield: 49.2 %

Procedure:
A mixture of (3R,4R)-1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol (35 mg, 0.082 mmol), DMF (1 mL), EtOH (1 mL) and H2O (1 mL) was treated with Fe powder (67 mg, 1.2 mmol, 2.4 mmol) and heated at 100° C. for 45 min. The mixture was filtered through Celite®, made basic with NaHCO3 and concentrate in vacuo. The residue was partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was dried (MgSO4) and concentrated in vacuo to give the crude aniline (16 mg, 50%) which was used directly in the next step without further purification. MS(ESI+): m/z 397.28 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:8][C:7]1=[CH:6][C:5](=O)[CH2:4][CH2:3]2.[CH:17](Cl)(Cl)Cl>>[CH3:17][C:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[CH2:11][CH2:10][C@@H:9]3[CH2:8][C@:7]2([O:15][C:12]3([CH3:14])[CH3:13])[CH:6]=1
Reactant: CC12CCC(=O)C=C1C[C@H](C(C)(C)O)CC2
Reactant: ClC(Cl)Cl
Product: CC1=C[C@@]23C[C@@H](CC[C@]2(C)CC1)C(C)(C)O3

Procedure:
White solid,: mp 38-39° C., [α]D1045.8° (c=0.47, chloroform). MS: 220 (M+, 15), 205 (50), 187 (14), 162 (31), 147 (50), 31 (100); 1H NMR (CDCl3, δ): 0.90 (s, 3 H, 6-CH3), 1.21 (s, 3 H, 10-CH3), 1.33 (s, 3 H, 10-CH3), 1.37 (s, 3 H, 3-CH3), 5.16 (s, 1 H, 2-H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([C:20]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([CH3:46])[CH:40]=1)([C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([CH3:38])[CH:24]=1)[CH2:21][CH3:22])[CH3:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]([C:5]1[S:6][C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:20]([CH2:21][CH3:22])([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([CH3:46])[CH:40]=3)[CH2:18][CH3:19])=[CH:24][C:25]=2[CH3:38])=[C:3]([CH3:11])[CH:4]=1)=[O:8]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)c1cc(C)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2sc(C(=O)OC)cc2C)c(C)c1
Temperature: 85 °C
Reaction time: 17 h
Yield: 46.9 %

Procedure:
Methyl 5-bromo-4-methyl-2-thiophenecarboxylate (178.85 mg, 0.761 mmol), tetrakistriphenylphosphine palladium (14.7 mg, 0.013 mmol) and a 2 M sodium carbonate aqueous solution (0.3 mL, 0.6 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 15-(2); 100 mg, 0.254 mmol) in toluene (0.5 mL) at room temperature, and the mixture was stirred at 85° C. for 17 hours. Ethyl acetate was added to the reaction solution. The organic layer was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (50.3 mg, 46.9%).
Reaction SMILES: ClC1C(Cl)=C(C2C=CC(Cl)=CC=2)N=C(C(Cl)=O)C=1.[F-].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([C:34](F)=[O:35])[CH:31]=[C:30]([F:37])[C:29]=2[F:38])=[CH:24][CH:23]=1.C(N(CC)CC)C.[CH:46]([OH:49])([CH3:48])[CH3:47]>S1(CCCC1)(=O)=O.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([C:34]([O:49][CH:46]([CH3:48])[CH3:47])=[O:35])[CH:31]=[C:30]([F:37])[C:29]=2[F:38])=[CH:24][CH:23]=1
Reactant: CC(C)O
Reactant: O=C(F)c1cc(F)c(F)c(-c2ccc(Cl)cc2)n1
Agent: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)OC(=O)c1cc(F)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of 4,5-dichloro-6-(4-chlorophenyl)picolinoyl chloride (2.0 g, 6.23 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, 100 ppm H2O) was added potassium fluoride (2.2 g, 37.4 mmol). The reaction mixture was heated at 130° C. for 24 h. Reaction mixture was analyzed by GC-MS and 19F NMR. (Data for 6-(4-chlorophenyl)-4,5-difluoropicolinoyl fluoride, GC-MS: m/z=271, 223; 19F NMR (376 MHz, Toluene-d8) δ 17.05 (s), −123.81 (d, J=19.1 Hz), −140.17 (d, J=19.1 Hz). Reaction was allowed to cool to room temperature and triethylamine (1.1 mL, 7.8 mmol) and isopropanol (0.7 mL, 9.4 mmol) were added. After stirring for 1.5 h, the reaction mixture was diluted with water (100 mL) and transferred to a separatory funnel. The reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×50 mL). The combined organic extracts were washed with water (3×50 mL) and saturated aqueous NaCl solution (50 mL) and concentrated under reduced pressure to provide a brown oil. The crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) to provide 0.93 g (48% yield) of isopropyl 6-(4-chlorophenyl)-4,5-difluoropicolinate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04-7.98 (m, 2H), 7.90 (dd, J=9.4, 5.3 Hz, 1H), 7.51-7.45 (m, 2H), 5.31 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.72 (d, J=3.5 Hz), 158.12 (d, J=12.6 Hz), 155.49 (d, J=12.4 Hz), 149.41 (d, J=11.0 Hz), 147.16 (dd, J=7.9, 1.0 Hz), 146.73 (d, J=10.9 Hz), 136.51 (d, J=0.9 Hz), 130.34 (d, J=6.6 Hz) 128.93 (s), 113.80 (d, J=16.1 Hz), 70.25 (s), 21.85 (s). 19F NMR (376 MHz, CDCl3) δ−124.73 (dd, J=17.7, 9.5 Hz), −144.38 (dd, J=17.7, 5.4 Hz). LRMS. Calcd. C16H15F2NO3: 307.10. Found: m/z=307 (M+), 221, 206. MP. 73-74° C.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([O-])=O>C(O)C>[C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([NH2:8])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Add 474 g (2.10 mol) tin chloride dihydrate to a refluxing solution of 125 g (0.420 mol) 4-(4-nitrophenyl)-1-(phenylmethyl)piperazine in ethanol. Reflux the solution for about 15 h then cool to room temperature and remove the solvent. Dissolve the residue in water and adjust to pH 12 withsodium hydroxide. Extract the aqueous solution with methylene chloride and dry the organic layer with anhydrous sodium sulfate. Concentration at reduced pressure gives the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])C>[OH-].[K+].O>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:15]2[OH:16]
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A suspension of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (102.59 g, 337.7 mmol) in 10% potassium hydroxide in water (689 mL) was heated to reflux for 5 h to afford a light brown solution. After cooling to room temperature, the undissolved solid particles were removed by filtration and the filtrate was extracted with dichloromethane to remove any neutral impurities. The aqueous layer was neutralized with 3.0N hydrochloric acid to afford a white precipitate. Then, the solids were collected by filtration and washed with water. After drying in air, 91 g (98% yield) of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid was isolated as a white solid: EI-HRMS m/e calcd for C10H6BrNO3 (M+) 266.9531, found 266.9521.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[N:18]([CH3:28])[N:19]=[N:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:13][CH:14]=1)=[O:8])C>O.C1COCC1.CO>[CH3:28][N:18]1[C:17]([CH2:16][O:15][C:12]2[N:11]=[N:10][C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=2)=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:20]=[N:19]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of lithium hydroxide monohydrate (130 mg, 3.06 mmol) in water (5 mL) was added dropwise to a suspension of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (521 mg, 1.53 mmol) in THF (5 mL) and MeOH (0.5 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (320 mg, 67%) as a white solid. MS: m/e=311.2 [M−H]−.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[H][H].[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[C:19]#[CH:20])[CH3:14]>CCO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[CH:19]=[CH2:20])[CH3:14]
Reactant: C#CC(N)CC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: C=CC(N)CC(=O)OCC
Reaction time: 2.5 h

Procedure:
A mixture of 5% Pd/BaSO4 (0.025 g) and quinoline (0.30 mL) was stirred under a balloon of hydrogen for 30 minutes. 3-Amino-pent-4-ynoic acid ethyl ester (18-1 (for preparation, see J. A. Zablocki, et al., J. Med. Chem., 1995, 38, 2378-2394) (1.77 g, 10.0 mmol) in EtOH (15 mL) was added and the solution stirred for an additional 2.5 hours. The solution was filtered through a pad of celite and concentrated in vacuo to provide 2.65 g of crude product 18-2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:19][C:18]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[C:16]=2[CH3:25])(=[O:14])=[O:13])=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:6]=1)=O.O1CCOCC1.C(=O)([O-])O.[Na+].[C:41]([NH2:44])(=[S:43])[CH3:42]>C(O)C>[F:24][C:22]1[CH:21]=[CH:20][C:18]2[S:19][C:15]([S:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]4[N:44]=[C:41]([CH3:42])[S:43][CH:2]=4)=[CH:6][C:7]=3[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:13])=[O:14])=[C:16]([CH3:25])[C:17]=2[CH:23]=1
Reactant: CC(N)=S
Reactant: Cc1c(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2S(C)(=O)=O)sc2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)cs1
Reaction time: 2 h
Yield: 42.6 %

Procedure:
Into 4.0 mL of chloroform was dissolved 200 mg of Compound 19, and 194 mg of benzyltrimethylammonium tribromide was added, followed by 1 hour of stirring at room temperature. The reaction was terminated by adding water to the reaction solution and then the solvent was once removed by evaporation. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was washed with methanol to obtain 201 mg of N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide as a colorless solid. The thus obtained N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide (150 mg) was dissolved into a mixed solution of 1.5 mL of dioxane and 1.5 mL of ethanol, and 53 mg of sodium hydrogen carbonate and 26 mg of thioacetamide were successively added, followed by 2 hours of stirring under heating and refluxing. The reaction was terminated by adding water to the reaction solution and then the solvent was removed by evaporation under reduced pressure. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 61 mg of the title compound as light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)([N:16]=[C:17]=S)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:30]1([NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].CCN=C=NCCCN(C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:16][C:17]2[NH:37][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]=2)([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(N=C=S)c2ccc(Cl)cn2)c1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: CC(Cl)Cl
Product: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(Nc2nc3ccccc3[nH]2)c2ccc(Cl)cn2)c1
Temperature: 80 °C
Yield: 47.2 %

Procedure:
5-chloro-2-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-isothiocyanato-2-phenylethyl)pyridine (0.036 g, 0.083 mmol) in dichloroethane (1 mL) in a two drum vial was added phenylenediamine (12 mg, 0.108 mmol) and TEA (13 mL, 0.091 mmol). The reaction was heated at 80° C. for 2 hours. EDCI (24 mg, 0.124 mmol) was added and the reaction was continued to be heated at 80° C. overnight. The reaction was concentrated and the crude mixture was purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-40% over 25 min) to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-1H-benzo[d]imidazol-2-amine as a white solid (20 mg, 47% yield). LCMS: 3.2 min [M+1] 511.22 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CD3OD) d ppm 4.01-4.10 (m, 1H), 4.51 (d, J=13.21 Hz, 1H), 6.48 (d, J=7.34 Hz, 2H), 6.93-7.04 (m, 5H), 7.22 (dd, J=5.50, 3.06 Hz, 2H), 7.34 (d, J=8.31 Hz, 1H), 7.51-7.58 (m, 1H), 7.71-7.77 (m, 2H), 7.82 (dd, J=8.56, 2.45 Hz, 1H), 8.41 (d, J=2.45 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH3:15])[CH:9]=1)[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([CH2:27][C:28](O)=[O:29])=[CH:25][N:24]=[C:23]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:22]=2)[CH2:20][CH2:19]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:28](=[O:29])[CH2:27][C:26]2[C:21]([CH:18]3[CH2:19][CH2:20]3)=[N:22][C:23]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:24][CH:25]=2)[CH3:15])[CH:9]=1)([CH3:16])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC)c1
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cccc(N(C)C(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-phenoxy)-propionic acid ethyl ester (example 26 A]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [K].[O-:2][CH2:3][CH2:4]CC.Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C(O)C>[CH2:3]([O:2][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1)[CH3:4]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCCC[O-]
Agent: [K]
Solvent: CCO
Product: CCOc1ncccc1C(=O)O
Temperature: 170 °C
Yield: 86.3 %

Procedure:
A solution of potassium ten-butoxide (44.9 g, 0.40 mol) in absolute ethanol (300 ml) was added slowly to a solution of 2-chloronicotinic acid (30 g, 0.19 mol) in ethanol (100 ml), and the reaction heated in a sealed vessel at 170° C. for 20 hours. The solvent was removed under reduced pressure, the residue dissolved in water (200 ml) and acidified to pH 3 with aqueous hydrochloric acid. The aqueous solution was extracted with dichloromethane (4×200 ml), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid (27.4 g).