Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O.O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCNCC2)nc1
Yield: 76.3 %

Procedure:
A solution of methyl 6-chloronicotinate (25.4 g) and piperazine (38.3 g) in dimethylsulfoxide (125 ml) was heated at 100° C. for 2 hours then cooled and diluted with water, followed by extraction with ethyl acetate (4×). The combined organic layers were washed with water then dried over magnesium sulfate, filtered and evaporated to give a crude product that was triturated with isopropyl ether-hexane to yield methyl 6-(1-piperazinyl)nicotinate (25 g) as a light yellow powder.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]([NH2:4])=[O:3].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]([NH2:4])=[O:3]
Reactant: NC(=O)NCCCCCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-ureidohexanoic acid (0.996 g, 5.72 mmol, 1.0 equiv) in methanol/benzene (2:7, 60 mL) was cooled to 0 degrees C., and a solution of trimethylsilyldiazomethane in hexanes (2.0 M, 3.43 mL, 6.86 mmol, 1.2 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 1 h prior to removing all volatile components in vacuo. The crude methyl ester (1.06 g, 5.61 mmol, 98%) was used without further purification in the Biginelli reaction.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].[PH2:12](=[O:14])[OH:13]>>[CH2:5]([O:4][CH2:1][CH2:2][CH2:3][PH:12](=[O:13])[OH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCOCc1ccccc1
Reactant: O=[PH2]O
Product: O=[PH](O)CCCOCc1ccccc1

Procedure:
The title compound was prepared from allylbenzyl ether and 50% aqueous phosphinic acid by an analogous procedure to that described in J. Inorg. Nucl. Chem., 1965, 27, 697.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1ccccc1Br
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Brc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-bromobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 380.2, 382.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.44 (br s, 1H); 8.02 (br s, 1H); 7.85 (m, 1H); 7.64 (d, J=5.6 Hz, 1H); 7.48 (d, J=7.3 Hz, 1H); 7.18 (m, 1H); 6.86 (d, J=5.5 Hz, 1H); 6.18 (br s, 1H); 4.83 (d, J=6.4 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15](I)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C([Si](CC)(CC)[C:23]([F:26])([F:25])[F:24])C.[F-].[K+]>CN(C)C=O.CN1CCCC1=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:23]([F:26])([F:25])[F:24])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cc(C)c(I)cn2)c1C
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cc(C)c(C(F)(F)F)cn2)c1C

Procedure:
1-(5-Iodo-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (395 mg), copper(I) iodide (1.13 g), triethyl(trifluoromethyl)silane (1.11 ml), and potassium fluoride (345 mg) were suspended in N,N-dimethylformamide (6.2 ml) and N-methylpyrrolidone (6.2 ml), and stirred at 70° C. for 9 hours. After completion of the reaction, the mixture was allowed to cool, extracted with ethyl acetate, the obtained organic layer was sequentially washed with 28% ammonia water, water, and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-methyl-1-[4-methyl-5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (271 mg) as a white solid.
Reaction SMILES: [C:1]([NH2:5])(=[NH:4])[CH2:2][CH3:3].[C:6]([CH:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10](OCC)=[O:11])(=O)[CH3:7]>>[CH2:2]([C:1]1[N:5]=[C:10]([OH:11])[C:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]([CH3:7])[N:4]=1)[CH3:3]
Reactant: CCC(=N)N
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Product: CCOC(=O)CCc1c(C)nc(CC)nc1O
Yield: 12819.8 %

Procedure:
The title compound (1.99 g) was prepared from 5.00 g of propioamidine and 15.0 mg of diethyl 2-acetylglutarate using the procedure in Example 1, 18% yield.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH:12][CH2:13][C:14]1[C:18]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]3=[O:35])[CH:21]=[CH:22][C:17]=2[S:16][N:15]=1.CN1C(C(F)(F)F)=CC(=[O:47])N(C2C=CC3SN=C(C=O)C=3C=2)C1=O>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH3:34][N:25]1[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:27][C:28](=[O:29])[N:23]([C:20]2[CH:21]=[CH:22][C:17]3[S:16][N:15]=[C:14]([C:13]([OH:47])=[O:12])[C:18]=3[CH:19]=2)[C:24]1=[O:35]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CO)c3c2)c1=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of potassium dichromate (10.0 g) in 1.5 M sulfuric acid (200 mL) is cooled to 0° C., treated dropwise with a solution of a 2:3 mixture of 3-[3-(hydroxymethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (12.0 g) in acetic acid, stirred at room temperature for 2 hours, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a white solid (8.50 g, mp 149-152° C.).
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23]C)=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:9]([O:8][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(N)Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(O)c1ccc(CC(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound 8 (410 mg, 1.02 mmol) in dioxane (10 mL) was treated with 1 N NaOH (5.1 mL, 5 eq.) and stirred at ambient temperature (0.5 h), yielding a solution of crude 4-[bis(tert-Butoxy)phosphorylhydroxymethyl]-D,L-phenylalanine (15), which was not isolated. The pH was adjusted to 8 by bubbling in CO2 gas, Fmoc-OBT (402 mg, 1.12 mmol) was added and the mixture stirred at ambient temperature (3.5 hours). Ice-cold 5% citric acid (25 mL) was added and the resultant solution was extracted with CHCl3 (3×30 mL). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to yield crude 16. Purification by silica gel chromatography afforded pure 16 as a colorless foam (277 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:18])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
6-bromo-2-naphthoic acid (72.3 g, 282 mmol, 1.0 equiv.) was suspended in dichloromethane (600 mL) and DMF (catalytic, 5 drops) was added. Oxalylchloride (71.6 g, 564 mmol, 2.0 equiv.) was added portion wise during 1 hour. The reaction mixture was stirred overnight with a CaCl2 drying tube mouthed on the flask. Complete dissolution occurred. The reaction mixture was concentrated, dichloromethane (100 mL) was added and the solvent was evaporated again, yielding 6-bromo-2-naphthoyl chloride (76.1 g, 100%) as an oil which was used as such in next step.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]([CH2:21][CH:22]=O)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][NH:25][CH2:22][CH2:21][N:13]([C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[O:3][CH2:4][C:5]=2[CH:10]=1)[CH3:31]
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccc2c(c1)COC2=O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNCCN(CCc1ccc2c(c1)COC2=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-Butyl [2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl](2-oxoethyl)carbamate (580 mg, 1.8 mmol) in MeOH (50 mL) was added ethyl aminoacetate hydrochloride (380 mg, 2.7 mmol), sodium cyanoborohydride (340 mg, 5.4 mmol) and a drop of acetic acid. The reaction was allowed to stir at RT for 16 hours. LC showed the desired product, which was purified by silica gel chromatography. LC-MS (IE, m/z): 407 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH3:14][NH2:15]>CC#N.O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:15][CH3:14])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CN
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(Cl)cc1NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (5 g, 22.8 mmol) in CH3CN (30 mL) was added dropwise aqueous methylamine (65%, 5.2 g, 45.6 mmol) at 0° C. The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure to give the crude product, which was suspended in H2O and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give ethyl 6-chloro-4-(methylamino)nicotinate (4 g, 82% yield), which was used in the next step without further purification. 1HNMR (300 MHz, DMSO-d6): δ 8.48 (s, 1 H), 8.04 (d, J=4.5 Hz, 1 H), 6.71 (s, 1 H), 4.27 (q, J=6.9 Hz, 2 H), 2.85 (d, J=5.1 Hz, 3 H), 1.29 (t, J=6.9 Hz, 3 H).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]=1[C:17]#[N:18])C.S(=O)(=O)(O)[OH:21]>>[NH2:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]=1[C:17]([NH2:18])=[O:21]
Reactant: CCCCCSc1nsc(NC(=O)OCC)c1C#N
Reactant: O=S(=O)(O)O
Product: CCCCCSc1nsc(N)c1C(N)=O
Temperature: 10 °C
Yield: 100 %

Procedure:
A mixture of (4-Cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester (2.7 g, 9.0 mmol) and concentrated sulfuric acid (5 mL) was heated to 10° C. for 6 hours. After cooling to ambient temperature, the mixture was diluted with ice water, extracted three times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, affording 2.2 g (100%) of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.26 (t, 2H, J=7.2 Hz), 1.71 (m, 2H), 1.43-1.19 (m, 4H), 0.86 (1, 3H, J=6.8 Hz) ppm.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.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.[Cu](I)I>[O:28]=[C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])=[CH:8][CH:9]=2)[O:14][CH:13]=[C:12]1[C:17]1[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:21][CH:22]=1
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Temperature: 85 °C

Procedure:
3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.5 g, 5.39 mmol), trimethylsilylacetylene (0.92 ml, 1.2 eq), PdCl2(PPh3)2 (175 mg, 0.05 eq), copper iodide (28.8 mg 0.03 eq), triphenylphosphine (40 mg 0.03 eq) and triethylamine (3.12 ml, 4.0 eq) were combined in dry tetrahydrofuran (10 ml) and heated in microwave for 30 minutes at 85° C. The reaction mixture was partitioned between ethyl acetate and water, the organic phase dried with magnesium sulfate, and solvent removed under reduced pressure. The crude product was heated in acetonitrile, cooled down and the solids were filtered off. This procedure was repeated twice in order to afford N-(4-(4-oxo-7-((trimethylsilyl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6].[C:14]1([CH2:24][CH2:25][OH:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[C:14]1([CH2:24][CH2:25][O:26][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: OCCc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of 3-fluoro-4-nitro-benzamide (1.0 g, 5.43 mmol) in tetrahydrofuran (55 mL) at room temperature was added 1-napthaleneethanol (1.02 g, 5.97 mmol) followed by potassium tert-butoxide (0.67 g, 5.97 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was then diluted with ethyl acetate and washed with 1N hydrochloric acid (50 mL), saturated sodium bicarbonate (50 mL), and saturated sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a pale yellow solid. The powder was collected and washed with ether, followed by drying under reduced pressure to yield 3-(2-naphthalen-1-yl-ethoxy)-4-nitro-benzamide 1.09 g (60%). 1HNMR(300 MHz, DMSO) 8.13 (d, 2H), 7.91 (t, 2H), 7.88 (dd, 1H), 7.72(s, 1H), 7.64 (s, 1H), 7.41 (m, 5H), 4.50 (t, 2H), 3.54 (t, 2H). MS(APCI) m/z 335.1 (M−H). Anal. Calcd. for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.35; H, 4.53; N, 8.06.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[C@H:54]([CH3:55])[CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:56])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[C@H:54]([CH3:55])[CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:56])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 0 °C
Yield: 99.8 %

Procedure:
Methane sulfonylchloride (11.0 μL, 0.13 mmol) was added to an ice cold solution of Intermediate 96e (89.0 mg, 0.13 mmol) and DIPEA (27.0 μL, 0.15 mmol) in DCM (1.5 mL). After 1 hour additional DIPEA (27.0 μL, 0.15 mmol) and methane sulfonylchloride (11.0 μL, 0.13 mmol) was added. After a further 1 hour additional DIPEA (27.0 μL, 0.15 mmol) and methane sulfonylchloride (11.0 μL, 0.13 mmol) was added. After 1 hour the reaction was partitioned between DCM and water. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound (100 mg, 99%). LCMS (Method 1): Rt 3.73 min, m/z 771 [MH+].
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Temperature: 25 °C

Procedure:
The 4-acetoxy-3,5-di-tert-butylanisole obtained in Example 13 and 1.37 kg (9.14 mol) of sodium iodide were dissolved in 5.0 L of acetonitrile; thereafter, 1.16 L (9.14 mol) of trimethylsilyl chloride was added dropwise and the mixture was refluxed for 8 hours. Thereafter, the reaction mixture was cooled to room temperature, water was added and the organic layer was separated. The organic layer was washed with an aqueous solution of sodium thiosulfate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic layer was recrystallized from an ethanol/water mixed solvent and the crystal was dried to give 1.55 kg of the title compound (92.4% in yield from the 2,6-di-tert-butyl-4-methoxyphenol of Example 13).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH:28]=[C:27]([NH:29][C:2]2[N:21]=[C:5]3[C:6]([O:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:26]=[N:25]1)[CH3:23]
Reactant: CCn1cc(N)cn1
Reactant: CS(=O)(=O)c1ccc(Oc2cccn3nc(Cl)nc23)cc1
Product: CCn1cc(Nc2nc3c(Oc4ccc(S(C)(=O)=O)cc4)cccn3n2)cn1

Procedure:
(1-Ethyl-1H-pyrazol-4-yl)-[8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (0.065 g, 0.20 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.029 g, 0.26 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (45 mg, 56%). MP=183-185° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.27 (s, 1H), 8.67 (d, J=6.51 Hz, 1H), 7.89 (d, J=7.72 Hz, 2H), 7.68 (s, 1H), 7.45 (d, J=7.74 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J=7.29 Hz, 2H), 7.00 (t, J=7.29 Hz, 1H), 4.055 (q, J=7.18 Hz, 2H), 3.20 (s, 3H), 1.32 (t, J=7.06 Hz, 3H). MS=399 (MH)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][CH:18]([O:26][C:27]1[C:35]2[CH:34]=[CH:33][S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)C)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[S:32]1[CH:33]=[CH:34][C:35]2[C:27]([O:26][CH:18]([CH2:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:17][CH2:16][NH:14][CH3:13])=[CH:28][CH:29]=[CH:30][C:31]1=2
Reactant: CN(CCC(CC1CCCCC1)Oc1cccc2sccc12)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCC(CC1CCCCC1)Oc1cccc2sccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
Add trifluoroacetic acid (5.5 ml, 71 mmol) to a stirred solution of [3-(benzo[b]thiophen-4-yloxy)-4-cyclohexyl-butyl]-methyl-carbamic acid tert-butyl ester (1.49 g, 3.6 mmol) and dichloromethane (80 ml) at 0° C. under N2. Stir for 5 minutes at 0° C. and allow the reaction to reach room temperature. Stir for 90 minutes, add sodium bicarbonate. Partition between sodium bicarbonate and dichloromethane, wash the combined dichloromethane layers with brine, dry over sodium sulfate. Filter and concentrate to give the crude compound. Purify the compound by flash chromatography, eluting with 3% ethanol/0.3% ammonium hydroxide/chloroform to yield 0.511 g (45%) of the title compound: mass spectrum (ion spray) m/z=318 (M+1); HPLC (90/5/5 to 0/95/5 water/acetonitrile/5% formic acid) Xterra MS C18 2.1 mm×50 mm×3.5micron: Retention time 3.08 minutes, Purity 100%.
Reaction SMILES: C([BH3-])#N.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH:17]2[CH2:20][NH:19][CH2:18]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[F:21][C:22]1[CH:32]=[CH:31][C:25]2[C:26]([CH:29]=O)=[CH:27][S:28][C:24]=2[CH:23]=1>CO.C(O)(=O)C>[F:21][C:22]1[CH:32]=[CH:31][C:25]2[C:26]([CH2:29][N:19]3[CH2:20][CH:17]([CH2:16][S:13]([C:10]4[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=4)(=[O:15])=[O:14])[CH2:18]3)=[CH:27][S:28][C:24]=2[CH:23]=1
Reactant: O=Cc1csc2cc(F)ccc12
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(CC1CN(Cc2csc3cc(F)ccc23)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (13 mg, 0.20 mmol) was added to a stirred solution of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4, 49 mg, 0.18 mmol) and 6-fluoro-1-benzothiophene-3-carbaldehyde (36 mg, 0.20 mmol) in methanol (3 mL) and acetic acid (50 μL). The reaction was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue partitioned between sodium carbonate and ethyl acetate. The aqueous layer was extracted with further ethyl acetate and the combined organic layers washed with water and brine, dried over MgSO4 and evaporated. The residue was purified by preparative TLC (40% ethyl acetate/isohexane) to give the title compound which was treated with ethereal HCl to give the hydrochloride salt (46 mg, 59%). 1H NMR (400 MHz, CD3OD) δ 8.00–7.96 (3H, m), 7.88 (1H, s), 7.74 (1H, dd, J=2.4, 8.8 Hz), 7.43–7.37 (2H, m), 7.31–7.27 (1H, m), 4.68 (2H, s), 4.24 (2H, s), 4.16 (2H, t, J=9.7 Hz), 3.67 (2H, d, J=7.6 Hz), 3.30–3.22 (1H, m); m/z (ES+) 394 (M+H)+.