Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[S:3].[P:6]([O:11]C)([O:9][CH3:10])[O:7][CH3:8]>C1(C)C=CC=CC=1>[CH3:5][O:4][C:2]([P:6]([O:9][CH3:10])([O:7][CH3:8])=[O:11])=[S:3]
Reactant: COC(=S)Cl
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COC(=S)P(=O)(OC)OC
Reaction time: 2 h
Yield: 56.5 %

Procedure:
While cooled externally with cold water, 34 g of the crude oil described above was treated with 9 g of chlorine. The temperature should not exceed 30° C. to avoid over-chlorination. The mixture was heated slowly, then fractionated. The fraction boiling at 84-86° C./760 mm was collected, giving 12.7 g of O-methyl chlorothioformate, Y=72%. 1H NMR: δ(ppm) 4.16. [See, Dieter Martin and Wolfgang Mocke, Chemishe Berichte, 98 (7), 2059 (1965).4] A solution of 0.55 g (5 mmol) of O-methyl chlorothioformate in 8 mL of dry toluene was added over 10 min to a solution of 0.62 g (5 mmol) trimethyl phosphite in 15 mL of dry toluene under N2. The mixture was stirred and left for 2 hr at room temperature. The solvent was rotary-evaporated, and the residue distilled in vacuo, giving 0.52 g of a yellow oil, 80-81° C./100μ, Y=56.5%. 1H NMR: δ(ppm) 4.18 (d, 3H, 4JHP=2 Hz, COCH3), 3.87 (d, 6H, 3JHP=11 Hz POCH3); 13C NMR: δ1 (ppm)2.5 (d, 1JCP=223 Hz, PC), 59.1 (d, 2JCP=8 Hz, POCH3), 54.8 (d, 3JCP=6 Hz, COCH 3); 31P NMR {H}: δ(ppm) −1.14 (s); 31 P NMR: δ (ppm) −1.14 (m, 3JPH=11 Hz); HRMS: 185.0031 (MH+, Found); 185.0037 (MH+, Calcd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Nc1cc[nH]n1
Product: Cc1ccc(Cl)cc1NC(=S)Nc1cc[nH]n1
Yield: 66 %

Procedure:
Prepared using Method A from 5.5 g (30.1 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (30.1 mmol) of 3-amino-1H-pyrazole to give 5.3 g of tite compound as a white solid (66% yield, m.p. 221-222° C.).
Reaction SMILES: FC(F)(F)CC(=O)[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=1.CCO.Cl>O>[F:18][C:15]([F:16])([F:17])[CH2:14][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([SH:5])=[CH:7][CH:8]=1)=[O:19]
Reactant: O=C(CC(F)(F)F)Nc1ccc(SC(=O)CC(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Temperature: 50 °C
Yield: 44.8 %

Procedure:
S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) are charged to a flask. Concentrated HCl (22.5 mL) is slowly added to keep the temp below 30° C. The reaction is then heated to 50° C. for 17.5 h. The reaction mixture is reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) is added. The slurry is filtered and the filter cake is washed with H2O (3×35 mL). The solid is dried under vacuum to produce the desired compound (19.9 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCNC3)c2c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-fluoro-2-((S)-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (110 mg) in dichloromethane (3 ml) at 0° C. was added DIPEA (55 μl) followed by methanesulfonyl chloride (25 μl) and the reaction was allowed to warm to room temperature and stirred for 2 h.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[Cl:9][C:10]1[N:15]=[N:14][C:13]2[CH2:16][CH2:17][NH:18][CH2:19][C:12]=2[CH:11]=1.[C:20]1([CH3:29])[C:21]([C:26](Cl)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C(O)C.CCOCC>[Cl:9][C:10]1[N:15]=[N:14][C:13]2[CH2:16][CH2:17][N:18]([C:26]([C:21]3[C:20]([CH3:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[CH2:19][C:12]=2[CH:11]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccccc1C(=O)N1CCc2nnc(Cl)cc2C1

Procedure:
Produced in a manner analogous to that described in Example 8 (g), from 28.5 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 16.9 g of o-toluoyl chloride. Reaction time 24 hours. M.P. 123°-126° (decomp., from 95% ethanol/ether).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CC(C)(C)c1n[nH]c(SCc2ccco2)n1
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCc1ccco1

Procedure:
3-t-Butyl-5-(fur-2-yl-methylthio)-1H-1,2,4-triazole was reacted with dimethylcarbamoyl chloride by substantially the same procedure as described in Example 1 to yield 1-dimethylcarbamoyl-3-t-butyl-5-(fur-2-yl-methylthio)-1H-1,2,4-triazole, an oil.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].O>O1CCCC1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC(O)(CF)CF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
An amount (6.6 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and p-toluenesulfonyl chloride (9.5 g) were dissolved in tetrahydrofuran (100 ml); to the solution under cooling with ice, 60% oily sodium hydride (2.4 g) was added under a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 5 hours while its temperature was raised to room temperature. To the reaction mixture, water was added followed by extraction with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (11.1 g).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:26])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:27]([N:25]([CH3:26])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:35])=[O:5])[S:12][CH:13]=2)=[CH:24][CH:23]=1)(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(C(=O)c1ccccc1)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1)c1ccc(OCCc2csc(SC(C)(C)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
2-{[4-(2-{4-[Benzoyl(methyl)amino]phenoxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (290 mg) obtained in Example 55-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (170 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]=[CH:22][C:23](N(OC)C)=[O:24]>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]=[CH:22][C:23](=[O:24])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1]
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1ccc(F)cc1F
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccc(F)cc1F)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (79.0 mL, 66.0 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (44.0 mL, 66.0 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(2,4-difluoro-phenyl)-N-methoxy-N-methyl-acrylamide (5.0 g, 22.0 mmol, in diethyl ether 30.0 mL) prepared in Step 2 was slowly added thereto at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 6.2 g of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].[Br:14]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(O)=O>[Br:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([CH:12]=[O:13])=[C:2]([OH:1])[CH:11]=[CH:10]2
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1c(O)ccc2cc(Br)ccc12
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a solution of 2-hydroxy-1-naphthaldehyde (60.0 g) in AcOH (300 mL) was added dropwise a solution of bromine (66.8 g) in AcOH (30 mL) over 30 min. After being stirred for 1 h, the mixture was poured into aqueous Na2S2O3 solution, and the resulting mixture was extracted with AcOEt. The combined organic layers were washed with water, 1N-NaOH, and brine followed by drying over MgSO4. After removal of the solvent in vacuo, the residue was washed with EtOH to give a yellow powder. The powder was crystallized from iPrOH to afford the title compound (28.8 g) as pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=O)(=[O:10])=[O:9]>CN(C=O)C.P(Cl)(Cl)(Cl)=O>[CH:14]1([C:12]2[NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[S:8](=[O:10])(=[O:9])[N:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccncc1S(=O)(=O)NC(=O)C1CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(C2CCCC2)Nc2ccncc21

Procedure:
A solution of 1 g of 4-amino-3-cyclopentylcarbonylaminosulfonylpyridine (Preparation 17) in 1 cm3 of DMF and 10 cm3 of phosphorus oxychloride is stirred at ambient temperature for 3 hours. The solvents are removed under partial vacuum (rotary evaporator) and the residue is dissolved in 10 cm3 of water. The solution is adjusted to a pH of 4 (NaHCO3) and the crystalline precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:13][C:12]([C:15]#[C:16][Si](C)(C)C)([OH:14])[CH2:11][CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>>[C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:13][C:12]([C:15]#[CH:16])([OH:14])[CH2:11][CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(O)(C#C[Si](C)(C)C)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CC1(O)CCOC(C(C)(C)O[SiH2]C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trimethylsilanylethynyl-tetrahydro-pyran-4-ol (1.75 g, 5.1 mmol) and K2CO3 (1.4 g, 10.2 mmol) was stirred at room temperature for 30 minutes. After concentration, the residue was partitioned between EtOAc (50 mL) and water (30 mL) and the separated aqueous layer was extracted with EtOAc. The combined organic extract was dried over sodium sulfate and concentrated to give 1.33 g (96%) of light yellow oil: 1H NMR (CDCl3) δ 0.05 (s, 6H), 0.88 (s, 9H), 1.50 (m, 1H), 1.78 (m, 1H), 1.84 (d, 1H), 2.01 (m, 1H), 2.55 (s, 1H), 3.55-3.70 (m, 4H), 4.00 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].C([Li])CCC.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:17]([O:11][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: CCC1(O)CCCCCCC1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(=O)OC1(CC)CCCCCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a 500-mL 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 32.5 g (0.208 mol) of 1-ethyl-1-cyclooctanol and 100 mL of anhydrous tetrahydrofuran. The addition funnel was charged with 150 mL (0.239 mol, 15% excess) of n-butyllithium (1.6M in hexane) which was then added to the cooled alcohol over 2 hours. The addition funnel was then charged with a solution of 25 g (0.239 mol) of freshly distilled methacryloyl chloride in 50 mL of dry tetrahydrofuran which was then added slowly with cooling over 1.5 hours. The reaction mixture was allowed to warm to room temperature with stirring overnight after which 100 mL of saturated sodium bicarbonate was carefully added with stirring. The mixture was stirred for 1 hour at which time it was diluted with 500 mL of diethyl ether and the organics washed with water, brine and dried for 1 hour over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was distilled twice from Na2CO3 and phenothiazine through a based-washed 15-cm Vigreux to yield 24 g (51%) of the title compound (bp 84° C.@ 1 mmHg) as a clear, colorless oil.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC)=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:37]=[CH:38][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:40][CH:41]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2coc(C(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (180 mg), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (0.8 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The residue was recrystallized from ethyl acetate-hexane and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid (47 mg, yield 27%) as colorless crystals. melting point: 116-118° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C(=O)([O-])[O-:16].[Na+].[Na+].OO>CO>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH2:8])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: COC(Cc1ncccc1C#N)OC
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COC(Cc1ncccc1C(N)=O)OC
Reaction time: 4.5 h
Yield: 85 %

Procedure:
The product from Example 36b (1.46 g, 7.6 mmol) was dissolved in methanol (20 mL) to which was added at room temperature sodium carbonate as a 3N solution (35 mL) followed by hydrogen peroxide as a 15% solution (35 mL). The reaction was allowed to stir for 4.5 hours then partitioned by the addition of ethyl acetate and solid sodium chloride. The aqueous phase was extracted several times with ethyl acetate and the combined organics stirred with solid sodium bisulfite followed by drying over MgSO4, filtered and concentration under vacuum to give the title compound (1.36 g, 85%) sufficiently pure for use as isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[SH:20]>>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([S:20][C:16]1[N:15]([CH3:14])[CH:19]=[CH:18][N:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: Cn1ccnc1S
Product: CCCCCCC(Sc1nccn1C)C(=O)OCC

Procedure:
2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl-2-bromooctanoate (12.1 g, 48 mmol) and 1-methyl-2-mercapto imidazole (5 g, 43.8 mmol). Yield: 12 g (96%); clear oil; MS: 285 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1([CH:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC(c1ccncc1)N1CCOCC1
Product: Cc1ccccc1C(=O)NCC(c1ccncc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:37]1([C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of Boc-Gly-OH (80) (4.0 g, 22.83 mmol) in dry CH2Cl2 (50 mL) at 0° C. under N2 was added HATU (8.70 g, 22.9 mmol). After stirring for 15 min at r.t., 1,2,3,4-tetrahydroquinoline (2.9 mL, 23.0 mmol), and DIPEA (12 mL, 68.8 mmol) were added. The reaction was stirred for 36 h at room temperature. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated NaHCO3, 5% HCl, water, and saturated NaCl. Dried over MgSO4, and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-50% EtOAc in hexanes) to afford 81 as a solid (5.76 g, 87%).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:1](=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH2:13]
Reactant: NN
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)NN
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a round-bottom flask was added a solution of diethyl oxalate (10.0 g, 68.4 mmol, 1.00 equiv) in ethanol (100 mL). Hydrazine hydrate (2.75 g, 85.8 mmol, 1.00 equiv) was added and the resulting mixture was stirred for 3 h at 80° C. After cooling to ambient temperature, the solids were removed via filtration and the filtrate was concentrated in vacuo to yield 8.00 g (80%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([N:21]=[C:22]=[S:23])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=[S:23])[NH:10][S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: COc1nc(N=C=S)nc(OC)n1
Reactant: NS(=O)(=O)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(NC(=S)NS(=O)(=O)c2ccccn2)nc(OC)n1

Procedure:
A mixture of 1.58 g of 2-pyridinesulfonamide, 2.04 g of 4,6-dimethoxy-2-isothiocyanato-1,3,5-triazine and 1.5 g of anhydrous potassium carbonate is stirred in 75 ml of acetone for 60 hours at ambient temperature. The reaction mixture is then poured into 500 ml of cold water, acidified with hydrochloric acid and the precipitated product removed by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[CH2:25][CH2:26][CH2:27]4)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1ccc2c(c1)CCC2
Product: CC(NC(=O)c1coc(Oc2ccc3c(c2)CCC3)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 67.7 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with indan-5-ol (35 mg, 0.26 mmol) to give the title compound (42 mg, 67%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH:1]1([C:5](=[O:9])[CH2:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]=[C:12]=[O:13]>C(O)C>[CH:1]1([C:5](=[O:9])[CH:6]([C:12](=[O:13])[NH:11][CH3:10])[C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CCC1
Reactant: CN=C=O
Solvent: CCO
Product: CNC(=O)C(C#N)C(=O)C1CCC1
Yield: 77.9 %

Procedure:
β-Cyclobutyl-β-oxopropionitrile (2.25 g, 18.3 mmoles) [prepared in Step A]was reacted with methyl isocyanate (1.10 g, 19.2 mmoles) according to the general procedure of Example 1, Step B to yield 2.57 g of the title compound as a white solid afater recrysstallization from 50% aqueous ethanol, mp 81°-83° C.