Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C:19]3([C:24]([N:26]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH:27][C:28](=[O:54])[C@@H:29]([C@@H:34]([C:44](=[O:53])[NH:45][O:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][O:48]4)[CH2:35]/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.N1CCCCC1>[NH2:18][C:19]1([C:24]([N:26]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH:27][C:28](=[O:54])[C@@H:29]([C@@H:34]([C:44](=[O:53])[NH:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH2:35]/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(N)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of 0.69 g of (E)-2′-[(1-(9-fluorenylmethyloxycarbonylamino)-1-cyclopentyl)carbonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in a mixture of 6.4 ml of dichloromethane and 1.6 ml of piperidine was stirred at room temperature for 1 hour. The solution was evaporated and the residue was treated with diethyl ether. The ethereal solution was filtered and evaporated. Chromatography on silica gel using methanol/dichloromethane (1:33) for the elution followed by evaporation gave 0.36 g of (E)-2′-[(1-amino-1-cyclopentyl)carbonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29](CC5C=C(C=CC=5)C(OC)=O)[C:28](=O)[CH2:27]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.[C:44]1([CH3:54])[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51]>>[C:44]1([CH3:54])[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:17]([C:10]3[O:9][C:8]([N:4]4[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]4)=[N:12][C:11]=3[C:13]([F:15])([F:16])[F:14])=[O:18])=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:52])=[O:51]
Reactant: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)N1CCN(c2ccc(NC(=O)c3oc(N4CCCCC4)nc3C(F)(F)F)cn2)CC1

Procedure:
Compound 9 was prepared by the general procedure for compound 8, by using intermediate C-3 and o-tolylsulfonyl chloride as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.33 (d, 1H, J=2.6 Hz), 7.82 (m, 2H), 7.59 (m, 1H), 7.45 (m, 2H), 6.87 (d, 1H, J=9.2 Hz), 3.60 (br s, 4H), 3.55 (m, 4H), 3.12 (m, 4H), 2.59 (s, 3H), 1.60 (br s, 6H). LCMS (ESI) Rt=3.89 min, [M+1]+ 579.3.
Reaction SMILES: [CH3:1][N:2]([CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.I[CH:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH:35]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH:11]=[C:10]([NH:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)=[CH:19][CH:20]=4)=[O:14])[CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:30]1)([CH3:37])[CH3:36]
Reactant: CC(C)I
Reactant: CN(CC1CCNC1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1CCC(CN(C)c2nc3ccc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)cc3s2)C1
Yield: 90.9 %

Procedure:
Place 4′-fluoro-biphenyl-4-carboxylic acid [2-(methyl-pyrrolidin-3-ylmethyl-amino)-benzothiazol-6-yl]-amide (16 mg, 0.035 mmol), 2-iodopropane (0.007 mL, 0.070 mmol), and potassium carbonate (15 mg, 0.108 mmol) in DMF (2 mL) and stir at rt for 3 d. Dilute the reaction with ethyl acetate and wash the organic layer with water (5 times). Chromatograph (silica gel, eluting with 10% 2M NH3 in MeOH:DCM) to yield 16 mg (91%) of the title compound: mass spectrum (ion-spray): (m/z)=503.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:19][C:20](=[CH2:24])[C:21](Cl)=[O:22]>C(OCC)C>[F:19][C:20](=[CH2:24])[C:21]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)=[O:22]
Reactant: C=C(F)C(=O)Cl
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1ccc(C(F)(F)F)cc1
Yield: 83.3 %

Procedure:
16.2 g (0.1 mol) of 4-trifluoromethylphenol were dissolved in 80 ml of anhydrous diethyl ether, and 10.1 g (0.1 mol) of triethylamine were added in portions to the solution; 12 g (0.11 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were then added dropwise, at a temperature of 10° C., with stirring, and in the course of 20 minutes, and the reaction mixture was stirred for a further 60 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of diethyl ether. The mixture of filtrate and wash solution was distilled, after adding 0.005 g of hydroquinone monomethyl ether. 19.5 g (83% of theory) of 4-trifluoromethylphenyl α-fluoroacrylate were obtained, boiling point 69° to 70° C. (under 3 mbar).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[I:16])[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C.C=O.C([O-])(=O)C.[Na+]>O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[C:6]1[I:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(-c2ccccc2)nc1I
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCn1c(I)nc(-c2ccccc2)c1CO
Temperature: 115 °C
Reaction time: 10 h

Procedure:
To a 60 ml sealed flask is added 1-butyl-2-iodo-4-phenylimidazole (3.26 g, 10 mmol) followed by the addition of 5.5 ml of acetic acid, 16 ml of 37% formaldehyde and 7 g of sodium acetate. The resulting mixture is stirred at 115° C. for 10 h, cooled to room temperature and diluted 50 ml of water. The reaction mixture is adjusted to pH=9, extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 2:1) affords 3.24 of 1-butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.59 (2H, dd, J=1.6, 6.8 Hz), 7.39 (2H, m), 7.31 (1H, m), 4.78 (2H, s), 4.00 (2H, t, J=8.0 Hz), 1.78 (2H, m), 1.46 (2H, m), 1.00 (3H, t, J=7.2 Hz); MS (+VE) m/z 357(M+1).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:17])[CH2:3]1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:17])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2cc(C3=NNC(=O)CC3C)ccc21
Temperature: 25 °C

Procedure:
To a solution of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indoline in 100 ml of chloroform was added 5 ml of triethylamine with stirring. To the mixture was added dropwise 3 ml of acetic anhydride. After maintaining at room temperature for one hour, the reaction mixture was concentrated under reduced pressure. The residual crystals were filtered off, washed with water and recrystallized from ethanol to give 4.3 g of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-acetylindoline as white crystals, melting at 258°-261° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][Si:8]([CH2:13][CH2:14][CH2:15][I:16])([O:11][CH3:12])[O:9][CH3:10]>C(OCC)(=O)C>[I-:16].[CH3:6][O:7][Si:8]([CH2:13][CH2:14][CH2:15][CH:2]1[CH2:3][CH2:4][CH2:5][S:1]1)([O:11][CH3:12])[O:9][CH3:10]
Reactant: C1CCSC1
Reactant: CO[Si](CCCI)(OC)OC
Solvent: CCOC(C)=O
Product: CO[Si](CCCC1CCCS1)(OC)OC
Product: [I-]

Procedure:
2.0 g of tetrahydrothiophene and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 9.9 g of trimethoxysilylpropyl iodide was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, tetrahydrothiophene and trimethoxysilylpropyl iodide as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropyltetrahydrothiophene iodide.
Reaction SMILES: [I-].[CH3:2][S+:3]([CH3:5])[CH3:4].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].OO.C(Cl)(Cl)(Cl)Cl>O.C(O)C>[S:6]([O-:10])([OH:9])(=[O:8])=[O:7].[CH3:2][S+:3]([CH3:5])[CH3:4]
Reactant: O=S(=O)(O)O
Agent: C[S+](C)C
Agent: OO
Agent: [I-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])O
Reaction time: 6 h
Yield: 32 %

Procedure:
Trimethylsulphonium iodide (9.8g, 0.048 moles) was dissolved in water (50 ml). Sulphuric acid (4.8 g at 98%, 0.048 moles) and hydrogen peroxide (2.72 g at 30%, 0.024 moles) were each diluted to 10 ml with water and added to the stirred trimethylsulphonium iodide solution. Carbon tetrachloride (150 ml) was added to extract the iodine that was produced and the mixture was stirred for 6 hours. The layers were separated. To the aqueous layer was added carbon tetrachloride (150 ml) and this was stirred overnight. The layers were separated and the aqueous layer was extracted with aliquots of carbon tetrachloride (20 ml) until no further pink colouration was visible. Palladium on carbon (3%, 0.25 g) was added to the aqueous solution to destroy any unreacted peroxide. The solution was filtered after 60 minutes, and washed with ether (2×20 ml). The water was removed under reduced pressure to produce an oily residue which was dried under vacuum at 78° C. The oil was dissolved in hot ethanol and cooled in an acetone/solid carbon dioxide bath to produce a white solid. The solid was filtered maintaining the temperature below 0° C. and dried under reduced pressure at 78° C. to yield a very deliquescent residue (2.7 g, 32% yield of theory). This material was dissolved in hot ethanol and allowed to cool slowly in an acetone/solid carbon dioxide bath to produce a waxy solid. The solid was filtered maintaining the temperature below 0° C. and dried under reduced pressure at 80° C. to yield a very deliquescent solid. Melting point 20°-21° C.; C3H10S2O4 (174.2): calculated C 20.7, H 5.8, S 36.8; found C 20.7, H 5.9, S 36.6. 1H NMR (DMSO-d6 /TMS): δ 2.91(s, 9H, CH3 --S); 7.4-7.6(s, 1H, HSO4)- pH=1.8-1.9 (HSO4-).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)[N:17]=[C:16]([CH3:21])[N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)cc(OC2CCN(C(=O)OC(C)C)CC2)n1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(OC2CCN(C(=O)OC(C)C)CC2)cc(N2CCc3cc(S(C)(=O)=O)ccc32)n1
Temperature: 90 °C

Procedure:
14a (100 mg) was dissolved in DMF with 5-methanesulfonyl-2,3-dihydro-1H-indole (0.3 mmol) and NaH (0.3 mmol). The mixture was heated at 90° C. for 4 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The organic layer was washed with a saturated NaHCO3 solution, isolated, evaporated and purified by preparative HPLC to give 14-1, LCMS 475.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[CH2:22](O)[CH3:23]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1c(-c2ccc(O)cc2)[nH]c2nccnc12
Reactant: CCO
Product: CCOC(=O)CCc1c(-c2ccc(O)cc2)[nH]c2nccnc12

Procedure:
A solution of 3-{6-(4-hydroxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionic acid (0.02 g) [Example 30] in ethanol (2 mL) was treated with a catalytic amount of paratoluenesulfonic acid. The mixture was refluxed for 4 hours, the solvent removed by evaporation and the precipitate filtered. The solid was then taken in ethyl acetate, the organic layer washed with water, brine, dried over magnesium sulfate and evaporated to give a yellow solid which was subjected to flash chromatography on silica, eluting with ethyl acetate) to give the title compound. MS: 298 (MH+).HPLC (Method C): RT=2.58 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:11]CN=C=NCCCN(C)C.Cl.Cl.[CH3:24][N:25](C)[OH:26]>CN(C1C=CN=CC=1)C.CC(N(C)C)=O.C(Cl)Cl>[CH3:11][O:26][N:25]([CH3:24])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccccc1C(=O)O
Reactant: CN(C)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CON(C)C(=O)c1ccccc1C
Yield: 80 %

Procedure:
To a premixed solution of 2-methylbenzoic acid (7.5 mmol), EDCl (1.5 mmol) and DMAP (3.0 mmol) in DMA 40 mL and DCM 13 mL is added dimethylhydroxylamine hydrochloride (1.5 mmol). The reaction is stirred at room temperate over night. The reaction mixture is then filtered. The filtrate is diluted with EtOAc and washed with water, 10% NaHSO4 and brine. The solution is dried over Na2SO4 and the solvent is evaporated. A light yellow oil N-methoxy-N,2-dimethylbenzamide is obtained in 80% yield.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni].[Mo]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Agent: [Mo]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Temperature: 20 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate (Example 5), 8.2 kg (30.5 mol) in 100 L of methanol containing 15 kg of anhydrous ammonia was reacted with hydrogen gas under 50 pounds per square inch (psi) at 30° C. in the presence of a slurry of 8 kg of Raney nickel doped with 1% molybdenum. After 6 hours, uptake of hydrogen had ceased, the mixture was cooled to 20° C., the atmosphere was vented and exchanged for nitrogen, and the slurry was filtered, concentrated by distillation and distilled under vacuum to give 7.8 kg of 96% pure (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate as a clear oil; bp 125-135° C. at 0.5 mm Hg.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([CH:19]1[CH2:22][CH2:21][CH2:20]1)=O)(=O)OC.O.[NH2:24][NH2:25]>>[CH:19]1([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:25][N:24]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)C1CCC1)OC
Solvent: O
Product: c1c(C2CCC2)nnc2c1C1CCC2C1

Procedure:
light yellow solid. MS (ESI): 200.2 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, (2-Cyclobutyl-2-oxo-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([N:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:26]([OH:31])(=[O:30])[C@H:27]([CH3:29])[OH:28]>>[C:26]([O-:31])(=[O:30])[CH:27]([CH3:29])[OH:28].[CH2:18]([NH+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C[C@H](O)C(=O)O
Reactant: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Product: CC(O)C(=O)[O-]
Product: CCCCCCCC[NH+](CCCCCCCC)CCCCCCCC

Procedure:
In a mixing vessel, trioctylamine and L-lactic acid with an optical purity of 99% L-lactic acid was converted by heating to form trioctyl ammonium lactate. This was placed in a distillation vessel that was equipped with a reducing Liebig cooler and an Anschütz-Thiele distillation adaptor. Furthermore, 1 percent by mass (relative to lactic acid) dibutyltin oxide was placed as catalyst in the recipient vessel.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C[O:14][C:15](=O)[C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18].C(O)(=O)C>C1COCC1.O>[CH3:19][C:16]([CH3:20])([CH2:17][CH3:18])[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCC(C)(C)C(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Yield: 50 %

Procedure:
Dimethyl methylphosphonate (9.3 g, 0.075 mol) was dissolved in anhydrous THF (80 ml) under argon atmosphere. To the solution stirred at -78° C. was added dropwise n-butyl lithium (1.61N, 47 ml, 0.075 mol) over 30 minutes, and then a solution of 2,2-dimethylbutanoic acid methyl ester (3.9 g, 0.03 mol) in anhydrous THF (10 ml) was also added dropwise over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Under ice cooling, acetic acid (4.5 ml) and water (10 ml) were added to the mixture. After concentration, water (20 ml) was added to the residue, and the mixture was then extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxo-pentylphosphonate (3.36 g, 0.015 mol, yield: 50%, b.p.=115-117/0.5 mmHg). The structure was identified by the following data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:42][N:43]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNc1ccccc1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methylaniline (108 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-phenylamide. MS m/z: 548.2 (M+H), 526.0 (M+H-MeOH).
Reaction SMILES: C(OC([N:8]([C@@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Cl:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: CN[C@@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Product: Cl

Procedure:
Intermediate 25b can be used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[S:25][C:24]([CH2:26]O)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[S:25][C:24]([CH2:26][N:53]5[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CNC1
Reactant: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)s1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using (5-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.12 g, 0.29 mmol) that was obtained in Example 4 (4c), carbon tetrabromide (0.19 g, 0.58 mmol), triphenylphosphine (0.15 g, 0.58 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.13 ml, 0.73 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:5) as the developing solvent to afford the title compound (0.12 g) in a yield of 80% as a colourless oily product.