Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[Si:24]([C:28]#[CH:29])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:22]=[C:21]([C:29]#[C:28][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1
Reactant: O=C(NCCCO)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Yield: 94 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as an off-white solid (94%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 11.48 (br s, 1H), 10.50 (s, 1H), 8.49 (t, J=5.4 Hz, 1H), 7.93 (s, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.43 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.5 Hz, 1H), 5.66 (s, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.45 (q, J=5.9 Hz, 2H), 3.25 (q, J=6.5 Hz, 2H), 1.65 (pentet, J=6.7 Hz, 2H), 0.23 (s, 9H). HRMS (FAB+) calcd C20H25FN3O3Si (MH+) 402.1649, found 402.1649.
Reaction SMILES: COC1C=C(C=CC=1OCCCC)[CH2:6][N:7]([C@H:18]([CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10].[H-].[Na+].N1C(C)=CC=CC=1C.C(Cl)(Cl)=[O:50]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH2:19][C@H:18]([N:7]2[CH2:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[O:10][C:6]2=[O:50])[CH3:30])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CCCCOc1ccc(CN(CC(O)c2cccc(Cl)c2)[C@H](C)Cc2ccc(OC)c(OC)c2)cc1OC
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(C[C@@H](C)N2C[C@@H](c3cccc(Cl)c3)OC2=O)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5.0 g. of (R)-N-(3-methoxy-4-n-butoxybenzyl)-N-[2-(3-chlorophenyl)-2-hydroxyeth-1-yl]-1-(3,4-dimethoxyphenyl)-prop-2-ylamine (obtained in Example 2) in 45 mL of toluene is added to 406 mg. of sodium hydride at room temperature. The mixture is stirred for one hour, 1.29 mL of 2,6-lutidine are added, and stirring is continued for 30 minutes. The reaction mixture then is added with stirring to 5.74 mL of a 20% solution of phosgene in toluene which has been cooled to 0° C. Excess phosgene is destroyed with 3N sodium hydroxide and the reaction mixture diluted with toluene, washed sequentially with 3N sodium hydroxide and brine, dried over magnesium sulfate, and evaporated to yield (R,R)-3-[1-(3,4-dimethoxyphenyl)prop-2-yl]-5-(3-chlorophenyl)oxazolidin-2-one. This is further purified by stirring in heptane at 55° C. for 15 minutes, filtering, washing with additional heptane, and recrystallization from 5:4 ethyl acetate:heptane to yield white crystals. Gas chromatography indicates the chemical purity is 99.3% and HPLC indicates the de is 99.6%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:23]([Si:27]([CH3:47])([CH3:46])[O:28][CH2:29][CH:30]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31]OS(C)(=O)=O)([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.O>[C:23]([Si:27]([CH3:46])([CH3:47])[O:28][CH2:29][CH:30]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:25])([CH3:26])[CH3:24]
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Ex-64A: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (10.0 g, 42.7 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (11.8 g, 85.4 mmol) and the resulting yellow slurry was heated to 80° C. Once at 80° C., methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propyl ester (Ex-50A, 19.5 g, 46.9 mmol) was added dropwise and the reaction was stirred for an additional 24 h at 80° C. and cooled to room temperature. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers was sequentially washed with a saturated sodium bicarbonate solution (1×150 mL), water (1×150 mL), and brine (1×150 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (100% ethyl acetate to 10% ethyl acetate/hexanes) gave 19.0 g (81%) of 2-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-4-methoxy-5-thiophen-2-yl-benzaldehyde as an off-white solid, mp 91–92° C. 1H-NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.6, 1.2 Hz), 7.29 (d, 1H, J=5.1 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.19 (d, 2H, J=6.0 Hz), 3.99 (s, 3H), 3.72–3.82 (m, 4H), 2.28 (pentet, 1H, J=6.0 Hz), 0.88 (s, 18H), 0.048 (s, 12H). MS (EI) m/z=550 ([M]+, 100%). Anal. Calcd. for C28H46O5SSi2: C, 61.05; H, 8.42; S, 5.82. Found: C, 61.20; H, 8.74; S, 5.69.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[F:16])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: Nc1ccccc1F
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1F
Yield: 33.9 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.1 mL, 29.1 mmol) in benzene (60 mL), followed by 2-fluoroaniline (2.3 mL, 23.4 mmol) and CHCl3 (60 mL). The product was chromatographed in CH2Cl2 to provide 1.05 g of a yellow solid (34%). 1H NMR (CDCl3) δ: 8.45 (t, J=8.0 Hz, 1H); 8.01 (br s, 1H); 7.02-7.22 (m, 4H); 6.78 (dd, J=0.5, 7.9 Hz, 1H); 6.64 (dd, J=0.8, 8.2 Hz, 1H); 4.73 (br s, 2H). MS (ES): m/z 265.0 (M+).
Reaction SMILES: O.Cl.[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14](=O)[CH3:15]>[Zn].Cl[Hg]Cl.C1(C)C=CC=CC=1>[CH2:14]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[OH:3])[CH3:15]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1c(O)ccc2ccccc12
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
A single neck round-bottom flask was charged with 2.3 g of zinc, 0.23 g of HgCl2 and 4 mL of water. Then 37% HCl (0.1 mL) was added and the mixture stirred for 5 minutes. After this, 3 mL of toluene and 3.4 mL of 37% HCl were added and finally 1 g (5.37 mmol) of 1-(2-hydroxynaphthalen-1-yl)ethanone was added portion wise. The resulting mixture was heated at 110° C. for 18 h. The phases were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 780 mg (84% yield) of 1-ethylnaphthalen-2-ol as brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.CC#N.N1C=CC=CC=1.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:9][O:8][C:4]1[N:3]=[C:2]([NH:1][C:26](=[O:27])[O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[N:6][CH:5]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cncc(N)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cncc(NC(=O)Oc2ccccc2)n1
Reaction time: 18 h

Procedure:
2-Amino-6-methoxy-pyrazine (1.00 g, 8 mmol) was dissolved in a mix of 1:2 THF:MeCN (30 mL), cooled to 0° C., and treated with pyridine (0.664 g, 8.3 mmol) followed by the dropwise addition of phenylchloroformate (1.3 g, 8.3 mmol) in THF (10 mL). After stirring for 18 h, the resulting white solid was collected by filtration (1.3 g, 68%) and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]1.CS(C)=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 95 °C
Reaction time: 26 h

Procedure:
A mixture of 5-chloro-2-fluoro-4-iodopyridine (517 mg, 2.008 mmol), tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (550 mg, 2.410 mmol), DMSO (2 ml) and TEA (0.336 ml, 2.410 mmol) reaction mixture was stirred at about 95° C. for about 26 hours. The crude reaction mixture was cooled to room temperature, mixed with 125 ml ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3×), saturated salt solution (1×), dried sodium sulfate, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography using a 40 g column, eluting from 0%-35% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 656 mg of titled compound as free base. LCMS (m/z): 466.1 (MH+), retention time=0.93 min.
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.OO.S([O-])([O-])=[O:22].[Na+].[Na+]>C(O)(=O)C>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1=[O:22]
Reactant: O=S([O-])[O-]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 30.0 gm (0.118 mol) of (E)-2-[(amino)-phenylmethylene]-benzo[b]thiophen-3(2H)-one, 200 ml of glacial acetic acid and 13.5 gm (0.119 mol) of an aqueous 30% hydrogen peroxide solution was heated at 50° C. for four hours while stirring, and was then allowed to stand overnight at room temperature. After the addition of 100 ml of a 10% sodium sulfite solution, the solvent was largely distilled off in vacuo, and the residue was mixed with 300 ml of water. The solid precipitated thereby was suction-filtered off and recrystallized from ethanol/ethyl acetate (1:1 v/v) using activated charcoal. 23.0 gm (72% of theory) of light yellow crystals were obtained, m.p. 246°-247° C. (decomposition).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)[CH:15]=3)[CH:10]=2)=O)[CH:2]=1.C(O)COCCOCCO.NN.[OH-].[K+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]4([CH3:24])[O:20][CH2:21][CH2:22][O:23]4)[CH:15]=3)[CH:10]=2)[CH:2]=1
Reactant: CC1(c2ccc3cc(C(=O)c4cccnc4)ccc3c2)OCCO1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CC1(c2ccc3cc(Cc4cccnc4)ccc3c2)OCCO1
Temperature: 160 °C
Yield: 62 %

Procedure:
A mixture of 270 mg of 2-(3-pyridylcarbonyl)-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene, 7 ml of triethylene glycol, 1 ml of anhydrous hydrazine and 500 mg of potassium hydroxide were heated at 160° C. for 30 minutes. The temperature was then raised to 210° C. for 1 hour. The mixture was cooled, poured into water and extracted with methylene chloride. The organic layer was dried over sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel to give 160 mg of 2-(3-pyridylmethyl)-6-(2-methyl-1,3dioxolan-2-yl)naphthalene as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[NH:16][C:15](=[S:18])[N:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>C(#N)C>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([S:18][CH3:23])[N:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OCCCn1c(=S)[nH]c2c(OCc3ccccc3)cccc21
Solvent: CC#N
Product: CSc1nc2c(OCc3ccccc3)cccc2n1CCCO
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 4-benzyloxy-1-(3-hydroxypropyl)-2-thioxo-2,3-dihydro-1H-benzimidazole (70 mg) in acetonitrile (2 ml) was added methyl iodide (37.9 mg), and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo. The residue was purified by preparative thin layer chromatography and pulverized with diisopropyl ether to give 4-benzyloxy-1-(3-hydroxypropyl)-2-methylthio-1H-benzimidazole (67 mg).
Reaction SMILES: C([C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[O:6])C(C)C.[CH3:11][C:12](=[C:14](C)C)C.ClC(Cl)C(Cl)=[O:20]>[Zn]>[CH3:11][C:12]1([CH3:14])[C:8]([CH3:9])([CH3:10])[CH:7]1[C:5]([OH:6])=[O:20]
Reactant: CC(C)CC(=O)CC(C)C
Reactant: CC(C)=C(C)C
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Zn]
Product: CC1(C)C(C(=O)O)C1(C)C

Procedure:
Experiments 4, 5, 6, 7 and 8 were conducted in the same way as experiments 2 and 3. The details are stated in the table; the zinc particles had a largest dimension below 0.01 mm, see column 5. The diisobutyl ketone used in experiments 6 and 7 had a purity of 89 and 90%, respectively. At the end of experiments 4, 5, 6 and 7 the reaction mixture was free from dispersed zinc, see column 10, indicating that the zinc had been fully converted. The conversions of 2,3-dimethyl-2-butene and dichloroacetyl chloride are stated in columns 11 and 12, respectively. The yields of 2,2,3,3-tetramethylcyclopropanecarboxylic acid, presented in column 13, are slightly higher than that obtained in experiment 2. In the experiments 6 and 7 less brownish tarry material was formed than in the experiments 4 and 5 and the yield and purity of the TMCA formed were higher. The mixture obtained at the end of experiment 8 contained dispersed zinc and the yield of 2,2,3,3-tetramethylcyclopropanecarboxylic acid was only 49%, the molar ratio of zinc to dichloroacetyl chloride being 1.5.
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]([CH3:22])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])N=[N+]=[N-])C1C=CC=CC=1.[C:24]([P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])#[CH:25].[N-:34]=[N+:35]=[N-:36]>C1(C)C=CC=CC=1>[C:18]([O:17][C:15]([NH:11][C@@H:10]([CH2:22][N:34]1[C:24]([P:26]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:33])=[CH:25][N:36]=[N:35]1)[C:9]([OH:8])=[O:23])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: C#CP(=O)(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](C(=O)OCc1ccccc1)N(N=[N+]=[N-])C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cnnn1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Boc-azidoalanine benzyl ester 11 (360 mg, 1.13 mmol) and diethyl ethynylphosphonate 9 (370 mg, 2.26 mmol) were dissolved in dry toluene (4 mL) in a round bottom flask and degassed by free-pump-thaw (3 cycles). In a separate round bottom flask equipped with a magnetic stir bar, Cp*Ru(COD)Cl wherein COD is η4-cyclooctadiene (65 mg, 0.15 mmol) and Cp* is η5-C5Me5 was dissolved in degassed toluene (3 mL) under argon atmosphere. To this, the solution of the azide and alkyne was added dropwise via a cannula over 1 min The resultant solution was stirred at room temperature under argon for 1.5 h while being monitored by TLC. The reaction mixture was directly loaded to a pad of silica gel (10 cm×3 cm diameter, packed with 10% ethyl acetate/hexane) and eluted with 60% ethyl acetate/hexane to remove the ruthenium catalyst. The cycloaddition product was not further purified but used directly in the subsequent deprotection step because the product and the unreacted alkyne have very similar mobility on silica gel (Rf=0.3, 50% ethyl acetate/hexane, a brown spot stained with p-anisaldehyde).
Reaction SMILES: [OH-].[Na+].[C:3](OC([O-])=O)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O1CCCC1.[CH2:19]([NH:22][CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21]>O>[CH2:19]([N:22]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C=CCNC[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(C[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A 2N aqueous NaOH solution (50 mL) and 6.1 g of tert-butyl dicarbonate were added to a tetrahydrofuran (100 mL) solution of 7 g of the compound obtained in Step 1, stirring at room temperature and reacted at room temperature for 6 hours. After the completion of reaction, 100 mL of water was added, followed by two extractions with 100 mL of ethyl acetate. The combined organic layer was washed with 100 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 8 g of the compound of interest as a yellow oil (86%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:13][C:14]1[C:15]([C:20](O)=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[SH:12][C:3]1[C:2]([NH:1][C:20]([C:15]2[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:21])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=1
Reactant: Nc1cc(C(F)(F)F)cnc1S
Reactant: O=C(O)c1ncccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)cnc1S)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.2 %

Procedure:
A mixture of 3-amino-5-trifluoromethylpyridin-2-thiol (0.45 g), 3-chloropyridin-2-carboxylic acid (0.39 g), WSC (0.67 g), HOBt (31 mg) and pyridine (4 ml) was stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was filtered to collect a solid. The resulting solid was washed with water, followed by n-hexane, and dried to give 3-chloropyridin-2-carboxylic acid (2-mercapto-5-trifluoromethylpyridin-3-yl)-amide (0.45 g), which is hereinafter referred to as “intermediate compound (M20-11)”.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.Cl.[C:37]([C:40]1[O:41][CH:42]=[CH:43][CH:44]=1)(=[NH:39])[NH2:38].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:39][C:37]([C:40]3[O:41][CH:42]=[CH:43][CH:44]=3)=[N:38]2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Reactant: N=C(N)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCCc1ccccc1)C1=C(COCCN2CCCCC2)NC(c2ccco2)=NC1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 11.2 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (3.22 g, 9.27 mmol), 3,4-dichlorobenzaldehyde (1.62 g, 9.27 mmol), 2-amidinofuran hydrochloride (1.36 g, 9.27 mmol) and sodium hydrogen carbonate (0.78 g, 9.27 mmol) was stirred in N,N-dimethylformamide (15 mL) for 3 days at room temperature and then heated to 60° C. for 6 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (617.1 mg) as an oil. Electrospray MS m/z 596/598 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:39][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:39][CH:40]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cs1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg) obtained in Step C of Example 35 in DMF (4 mL)/water (0.40 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (98.3 mg), tetrakis(triphenylphosphine)palladium(0) (28.2 mg) and potassium carbonate (67.5 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (44.9 mg).