Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[C:11]#[CH:12]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:13][CH2:10][C:11]#[CH:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: C#CCN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT overnight during which time solid precipitated out. 600 mL hexane was added and the mixture was vigorously stirred for a few hours. The solid was collected by filtration and washed with hexane to give 5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%) which was used directly without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0 (chlorine pattern).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>C(O)C>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][S:19][C:17]2[N:16]=[C:15]([S:20][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]4[C:12]=3[N:11]=[CH:10][CH:9]=[CH:8]4)[C:14]([CH3:21])([CH3:13])[N:18]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrCc1cccc2cccnc12
Reactant: CC1(C)NC(=S)NC1=S
Solvent: CCO
Product: CC1(C)N=C(SCc2cccc3cccnc23)N=C1SCc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Initially, 3 g of 8-bromomethylquinoline was added to a solution of 1 g of 5,5-dimethyl-2,4-dithiohydantoin in 50 mL of ethanol (EtOH). The reaction mixture was stirred at the room temperature for 1.5 hour, and concentrated in vacuo. To the residue, 100 mL of CHCl3 was added. The mixture was washed with an aqueous solution of K2CO3, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatograph (CHCl3). Recrystallization from diethyl ether gave the desired compound in the form of a needle-like crystal. The yield of this compound was 2.3 g with a yield ratio of 83.3%, and the melting point was 101°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[S:23][C:18]=2[C:17]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>O1CCCC1.O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[S:23][C:18]=3[C:17]=2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:2]([NH:1][C:45](=[O:46])[CH2:44][Cl:43])[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3N)c(C3CCCCC3)c2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3NC(=O)CCl)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
To a suspension of methyl 5-(2-amino-4-benzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (6.30 g, 13.8 mmol), sodium acetate (1.36 g, 16.6 mmol) and acetic acid (0.95 ml, 16.6 mmol) in tetrahydrofuran (100 ml) was added dropwise chloroacetyl chloride (1.32 ml, 16.6 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The obtained crude product of methyl 5-[4-benzyloxy-2-(2-chloroacetylamino)phenyl]-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (8.22 g) was used for Step 6 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]#[N:13])[C:6]=2[CH:14]=1.CN(C)[C:17]1[O:18][C:19](=[O:27])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1>C(O)(=O)C>[O:18]=[C:17]1[NH:22][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:20][C:19](=[O:27])[N:1]1[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]#[N:13])[C:6]=2[CH:14]=1
Reactant: N#CCOc1nsc2ccc(N)cc12
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Product: N#CCOc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of [(5-amino-1,2-benzisothiazol-3-yl)oxy]-acetonitrile (4.30 g, 21.0 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (4.37 g, 21.0 mmol) in acetic acid is refluxed for three hours, stirred overnight at room temperature, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried overnight in a vacuum oven at 55° C. to give the title product as a brown solid (2.63 g, mp 254-258° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[CH3:26]>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:15]=[C:14]([CH3:25])[C:13]=2[CH3:26])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-5-(3-fluorophenyl)-2,3-dimethyl-benzamide (160 mg, 0.4 mmol, 1.0 eq) in THF (15 mL) was added a solution of BH3 (1M in THF, 180 mg, 2.1 mmol, 5.0 eq). The solution was stirred for 30 min then heated at 60° C. overnight. The reaction was quenched by addition of 1M HCl and the aqueous layer extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (137 mg, 89%).
Reaction SMILES: C([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13](=[O:18])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>O.[Pd]>[CH3:17][N:14]1[C:15](=[O:16])[C:10]2[CH2:9][NH:8][CH2:20][CH2:19][C:11]=2[NH:12][C:13]1=[O:18]
Reactant: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Yield: 179.8 %

Procedure:
A solution of 96 g of 6-benzyl-3-methyl-5,6,7,8-tetra-hydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione from c) in 1.5 1 of glacial acetic acid was debenzylated by hydrogenolysis for 6 h on 14.6 g of 10% palladium/activated charcoal at 25° C. and 3.5 bar. After the catalyst had been filtered off, the filtrate was concentrated under reduced pressure. The above preparation was repeated. The two crude products were combined, dissolved in water and precipitated, with stirring, by the addition of 33% sodium hydroxide solution to pH 6.9. The precipitate was washed with water and dried at 60° C. under reduced pressure to give 115.3 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione.
Reaction SMILES: [P:1]([O-:29])([O:25][CH2:26][CH2:27]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:2].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[P:1]([O-:29])([O:25][CH2:26][CH2:27][N+:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:2]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Product: CCCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCC[n+]1ccccc1

Procedure:
In the same manner as above, 2-[2-(pentadecyloxy)ethoxy]ethyl 2-bromoethyl phosphate is reacted with pyridine to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:27][CH2:26][CH2:25][N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCCN1CCOCC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (2 g, 7.19 mmol) in 2-propanol (100 mL) was added 2-morpholinoethanamine (1.0 g, 7.9 mmol) followed by triethylamine (800 mg, 7.9 mmol). The reaction mixture was stirred with heating at reflux for 6 hours. The solvent was then removed under reduced pressure. The residue was washed with 2-propanol and water to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 2.1 g, 80%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([CH3:13])([CH3:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[C:28]([F:29])=[CH:27][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][C:24]=2[F:34])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[NH2:11][C:9](=[O:10])[C:8]([C:6]1[N:7]=[C:2]([NH:14][C:15]2[S:16][C:17]([C:23]3[C:24]([F:34])=[CH:25][C:26]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:27][C:28]=3[F:29])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[CH:3]=[CH:4][CH:5]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(C(N)=O)c1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(C)(C)C(N)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-2-methylpropanamide (117 mg, 0.48 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) as starting materials.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH3:14])[N:4]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:18][CH:17]=1>>[CH3:14][N:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:3]([CH2:2][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:20][CH:21]=2)=[N:4]1
Reactant: N#CCCCc1ccc(O)cc1
Reactant: Cn1nc(CCl)nc1-c1ccccc1
Product: Cn1nc(COc2ccc(CCCC#N)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 45, 3-chloromethyl-1-methyl-5-phenyl-1,2,4-triazole was allowed to react with 4-(4-hydroxyphenyl)butyronitrile to give 4-[4-(1-methyl-5-phenyl-1,2,4-triazol-3-ylmethoxy)phenyl]butyronitrile. Recrystallization from dichloromethane-isopropyl ether gave colorless prisms, m.p.106°-107° C.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=[CH:9]1)=O)(C)(C)C.C(N(CC)CC)C.[C:36]1([C:42](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>FC(F)(F)C(O)=O.ClCCl>[C:36]1([C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=[CH:9]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(Cc1cn(C(=O)OC(C)(C)C)cn1)c1ccc2c(c1)OCO2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
A solution of ethyl 3-(1-tert-butoxycarbonylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate (633 mg) in trifluoroacetic acid (5 ml) was stirred at ambient temperature for 10 minutes. Trifluoroacetic acid was removed by evaporation and the residue was diluted with ethyl acetate followed by washing successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of the solvents afforded a crude intermediate compound. To a solution of the above compound and triethylamine (214 mg) in dichloromethane (10 ml) was added portionwise triphenylmethyl chloride (545 mg) and the mixture was stirred at ambient temperature for 20 minutes. The resulting solution was washed successively with saturated ammonium chloride aqueous solution and saturated sodium bicarbonate aqueous solution. Drying, filtering and removal of the solvents afforded ethyl 3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionate (740 mg) as a slightly yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([NH2:31])[CH3:30].C(N(CC)CC)C>>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([NH:31][S:11]([C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:13])=[O:12])[CH3:30]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c(OC)c1
Yield: 69.2 %

Procedure:
The title compound was prepared from 2,4-dimethoxybenzenesulfonyl chloride (473 mg, 2.0 mmol), 1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethylamine (466 mg, 2.0 mmol), and triethylamine (334 μL, 2.2 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40Mi column of prepacked column of silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (600 mg, 69%) as a white solid;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:20]([O:22]CC)=[O:21])[C:14]=2[CH:31]=1)=[O:8])([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19][C:20]([OH:22])=[O:21])[C:14]=2[CH:31]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3)cc21
Agent: Cl
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3)cc21

Procedure:
A solution of ethyl 3-{6-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (40 mg, 87 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 96 hours. The solution was then evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.92 min, MH+ 431].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6].[I-].[Na+].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCCl)(c2ccccc2)S1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN=[N+]=[N-])(c2ccccc2)S1
Temperature: 90 °C
Reaction time: 4 h
Yield: 119.8 %

Procedure:
The optically active N-[5-(3-chloropropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.50 g, 2.90 mmol) obtained in Step 1 mentioned above, sodium iodide (8.69 g, 58.0 mmol) and sodium azide (1.89 g, 29.0 mmol) were suspended in DMF (20 mL), and the suspension was stirred at 90° C. for 4 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to give optically active N-[5-(3-azidopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.82 g).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:13]([Mg]Br)=[CH2:14]>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:13]=[CH2:14]
Reactant: CCCCC(C)=CCCC(C)=O
Reactant: C=C[Mg]Br
Product: C=CC(C)(O)CCC=C(C)CCCC

Procedure:
By the procedure described in Example 13, from 6-methyl-5-decen-2-one and vinyl-magnesium bromide there is obtained 3,7-dimethyl-1,6-undecadien-3-ol; nD26 = 1.4618, boiling point 116° C./9 mm Hg. This alcohol is reacted with phosphorus tribromide by the procedure of Example 13 to give 1-bromo-3,7-dimethyl-2,6-undecadiene.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[S:3])[NH2:2].Br[CH:24]([CH2:34][CH3:35])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]>>[Cl:18][C:16]1[N:17]=[C:13]([C:11]([NH:10][C@H:7]2[CH2:8][CH2:9][N:4]([C:1]3[S:3][C:24]([CH2:34][CH3:35])=[C:25]([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[N:2]=3)[CH2:5][C@H:6]2[O:21][CH3:22])=[O:12])[NH:14][C:15]=1[CH2:19][CH3:20]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(N)=S)C[C@H]2OC)nc1Cl
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)sc1CC
Yield: 78 %

Procedure:
The same operation as in Example (22b) was performed using cis(±)-N-(1-carbamothioyl-3-methoxypiperidin-4-yl)-4-chloro-5-ethyl-1H-imidazole-2-carboxamide obtained by the method described in Example (65c) (78.5 mg, 0.23 mmol) and butyl 3-bromo-2-oxopentanoate obtained in Example (110a) (95 mg, 0.38 mmol), to obtain 87.8 mg of the title compound (78%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:34][C:18]4([CH2:33][C:20]5([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:35]>O1CCOCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:34][C:18]4([CH2:33][C:20]5([CH2:21][CH2:22][NH:23][CH2:24][CH2:25]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:35]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-Methylsulfonyl-phenyl)-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (0.30 g) dissolved in 4 M HCl in 1,4-dioxane (5 mL) is stirred at room temperature for 1 h. The solution is diluted with 1,4-dioxane and concentrated to give the title compound as HCl salt. LC (method 1): tR=0.66 min; Mass spectrum (ESI+): m/z=385 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18][C:19](=[O:21])[CH3:20].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: CCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-propyl)-4-trifluoromethyl-benzoic acid methyl ester (262 mg, 0.82 mmol) in DCM (1.3 mL) was added to a solution of Dess-Martin periodinane (556 mg, 1.31 mmol) in DCM (2.6 mL) and the mixture was stirred for 1 h at r.t. It was then poured into aqueous sodium thiosulfate and this mixture was extracted with EtOAc. The organic phase was then washed twice with aqueous potassium hydrogencarbonate (pH=8), once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude 2-acetylamino-5-propionyl-4-trifluoromethyl-benzoic acid methyl ester as a white solid which was used without further purification in the next step, ESI-MS: m/z 318 [M+H]+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([O:14][CH:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=2[Cl:25])[CH3:16])[C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:6]([C:7]1[CH:8]=[C:9]([O:14][CH:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=2[Cl:25])[CH3:16])[C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:5]
Reactant: CC(Oc1cc(C#C[Si](C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
5-trimethylsilylethynyl-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (1.5 g, 3.77 mmol) was dissolved in the mixed solvent of THF (10 mL) and MeOH (10 mL), K2CO3 (1.04 g, 7.55 mmol) was added, and the mixture was stirred for 2 h at room temperature. The majority of the solvent was removed under reduced pressure, water (10 mL) was added. The resultant mixture was extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated, the resultant residue was purified via silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to yield 850 mg of the target product as brown solid.