Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]1.CS(C)=O.[H-].[Na+].Br[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[CH2:19][CH2:18]1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1coc(Cn2c(NC3CCN(CCOc4nccs4)CC3)nc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5.1 parts of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidineethanol and 100 parts of dimethyl sulfoxide were added portionwise 0.9 parts of a sodium hydride dispersion 50%. After stirring for 1 hour at room temperature, 2.5 parts of 2-bromothiazole were added dropwise. Upon completion, stirring was continued overnight at room temperature. Water was added and the product was extracted twice with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was taken up in 4-methyl-2-pentanone. The organic phase was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methylbenzene, yielding 0.3 parts of 1-(2-furanylmethyl)-N-[1-[2-(2-thiazolyloxy)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 136.4° C. (compound 71).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12](OC)=[O:13].CCOC(C)=O.O>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1cnc2cc(C)nn2c1N
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2ncc(CO)c(N)n2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a 1 L three-necked round bottom flask was added Methyl 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (20.6 g, 100 mmol, 1.0 eq.) and THF (400 mL). The mixture was cooled to 0° C. and LiBHEt3 (315 mL of a 1.0 M solution in THF, 315 mmol, 3.0 eq.) was added slowly through an addition funnel under nitrogen. After addition, the mixture was stirred at room temperature for 4 h. Additional LiBHEt3 (30 mL of a 1.0 M solution in THF, 30 mmol, 0.3 eq.) was added and the mixture was stirred for an additional 1 h. The mixture was slowly treated with EtOAc (600 mL) and then water (300 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×300 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by a short silica gel column (2.5 inch in height and 4 inch in diameter) using MeOH in CH2Cl2 as the eluent. Concentration by rotary evaporation provided (7-amino-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanol (1-1) as a light yellowish solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27]([C:29]3[N:30]=[CH:31][N:32]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)=[O:28])[CH:23]=2)[CH:18]=1)=[O:16].[Cl-].[NH4+].[C:55]([O:58][CH2:59][CH3:60])(=[O:57])[CH3:56]>CCCCCC.C1COCC1>[OH:28][C:27]([C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([C:15]([NH:14][CH3:13])=[O:16])[CH:18]=2)[CH:23]=1)([C:29]1[N:30]=[CH:31][N:32]([C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:33]=1)[CH2:56][C:55]([O:58][CH2:59][CH3:60])=[O:57]
Reactant: CCOC(C)=O
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
Under nitrogen atmosphere, 7.1 mL (50.6 mmol, 3 eq) of diisopropylamine was added to 200 mL of THF. At −73˜−68° C., 31.6 mL (50.6 mmol, 3 eq) of a 1.6 M solution of n-butyllithium in hexane was added dropwise over 10 minutes. After stirred at 75˜−68° C. for 10 minutes, 5 mL of ethyl acetate was added dropwise at −75˜−70° C. over 5 minutes. After stirred at −75˜−70° C. for 30 minutes, a solution of 8.8 g (16.8 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 22 mL of THF was added dropwise at −75˜−65° C. over 5 minutes. After stirred at −75˜−65° C. for 30 minutes, the mixture was warmed to −30° C. After stirred for 5 minutes, 50 mL of an aqueous saturated ammonium chloride solution was added dropwise at −70˜−40° C., and a temperature was rised to room temperature. After the layers were separated, the aqueous layer was re-extracted with 100 mL of ethyl acetate. The organic layers were combined, and washed with 50 mL of an aqueous saturated sodium chloride solution. After concentration under reduced pressure, 100 mL of n-heptane was added to the concentration residue, followed by stirring at room temperature for 30 minutes. Crystals were filtered, and washed with 50 mL of n-heptane. Vacuum drying (50° C.) to a constant weight afforded 9.82 g of ethyl 3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 96%).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:19]=[C:18]([Br:31])[CH:17]=2)=[CH:8][C:7]=1[CH3:32]>C(O)C.[OH-].[Na+]>[Br:31][C:18]1[CH:17]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]([CH3:32])[CH:8]=2)[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:19]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)ccc1OCC(=O)O

Procedure:
A solution of (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (45 mg, 0.088 mmol) in ethanol (5 ml) and 1N NaOH (0.5 ml) was stirred at 75° C. for 30 min. The reaction mixture was evaporated and the residue dissolved in water (2 ml). Aqueous 1N HCl (0.6 ml) was added and the mixture was extracted with methylene chloride (3×15 ml). The combined organic phases were dried and evaporated to give the title compound in 44 mg (99%) yield.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Dissolve [(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (9.17 g, 26.9 mmol) in CH2Cl2 (45 mL), add TFA (10 mL) and stir at RT overnight. Remove the excess reagent in vacuo. Dilute the residue with CH2Cl2 (100 mL) and wash with 1.0 M NaOH (100 mL). Extract the aqueous layer with CH2Cl2 (3×100 mL). Combine the organic layers, dry with Na2SO4, filter and concentrate to give 6.03 g (93%) of the title compound. MS/ES m/z (79Br) 242 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[C:21]([CH:23]5[CH2:25][CH2:24]5)[N:20]([CH3:26])[C:19]=4[CH:27]=3)[C:11](=[O:28])[CH:10]=2)[N:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:5]5[N:6]=[C:2]([CH:29]6[CH2:31][CH2:30]6)[S:3][CH:4]=5)=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)n4)cc3=O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C5CC5)n4)cc3=O)cc21
Temperature: 150 °C
Yield: 24.7 %

Procedure:
A mixture of 4-((2-bromo-1,3-thiazol-4-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (54 mg), cyclopropylboronic acid (30.4 mg), tetrakis(triphenylphosphine)palladium (6.8 mg), potassium carbonate (65.3 mg), DME (1.5 ml) and water (0.5 ml) was heated at 150° C. for 20 min under microwave irradiation. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (12.2 mg) as a white solid.
Reaction SMILES: O[CH:2]([C:4]1([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]([O:10][CH3:11])([O:8][CH3:9])[CH2:5]1)[CH3:3].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:11][O:10][C:6]1([O:8][CH3:9])[CH2:5][C:4]([CH:2]=[CH2:3])([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1
Reactant: COC(=O)C1(C(C)O)CC(OC)(OC)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1(C(=O)OC)CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
To a solution of methyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclobutanecarboxylate (3.28 g, 15.03 mmol) and pyridine (2.4 mL, 29.83 mmol) in CH2Cl2 (65 mL) was added trifluoromethanesulfonic anhydride (3.0 mL, 17.86 mmol) at −78° C. The mixture was stirred for 10 minutes and then warmed to 0° C. After stirring for 15 minutes at 0° C., DBU (9.0 mL, 60.18 mmol) was added to the reaction mixture and the resulting mixture was stirred for 1 hour at room temperature. The mixture was partially evaporated under reduced pressure and filtrated through the pad of silica gel and washed with CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and evaporated. The residue was diluted with hexane/EtOAc=4:1 and added small amount of CHCl3 and filtrated through the pad of silica gel to give methyl 3,3-dimethoxy-1-vinylcyclobutanecarboxylate (2.21 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([O:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[C:21]([F:37])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([O:26][CH2:27][CH2:28][OH:29])=[C:21]([F:37])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3cc(F)c(OCCO[Si](C)(C)C(C)(C)C)c(F)c3)cc3ccccc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3cc(F)c(OCCO)c(F)c3)cc3ccccc23)CC1
Reaction time: 1.25 h
Yield: 94.7 %

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-{3,5-difluoro-4-[2-(tert-butyldimethylsilyloxy)ethoxy]phenyl}isoquinoline (0.62 g) was dissolved in tetrahydrofuran (6 ml), to which was then added 1.0M tetrabutylammonium fluoride/tetrahydrofuran solution (1.41 ml), and the mixture was stirred for 75 min. The solvent was evaporated, and the resulting residue was dissolved in ethyl acetate, washed with (three times) and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.46 g of the free compound of the title compound as a pale brown powder.
Reaction SMILES: [C:1](#[N:6])/[CH:2]=[CH:3]\[CH2:4][CH3:5].CC(=CC)C#[N:10].CC(C=C)C#N.[C:19](#[N:24])[CH2:20][CH2:21][CH2:22][CH3:23].N>C1C=CC=CC=1.C1CCCCC1>[NH2:10][CH:3]([CH2:4][CH3:5])[CH2:2][C:1]#[N:6].[C:19](#[N:24])/[CH:20]=[CH:21]\[CH2:22][CH3:23]
Reactant: CCCCC#N
Reactant: CC=C(C)C#N
Agent: C=CC(C)C#N
Agent: CC/C=C\C#N
Agent: N
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: CCC(N)CC#N

Procedure:
A mixture of approximately 70 weight percent cis-2-pentenenitrile, 14 weight percent 2-methyl-2-butenenitrile, 4 weight percent 2-methyl-3-butenenitrile, with cyclohexane, benzene, and valeronitrile making up the balance, was reacted with 29 weight percent aqueous ammonia (at 15 percent molar excess relative to cis-2-pentenenitrile) in a stirred batch reactor at about 90° to 100° C., at an autogeneous pressure of about 60 to 118 psig, for approximately ten hours Vacuum distillation of the crude reaction mixture to remove low boiling impurities and water resulted in 91% selectivity to 3-aminopentanenitrile at 97% conversion of the starting cis-2-pentenenitrile
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[OH-].[Na+]>O>[CH2:14]([O:13][C:11]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
D-Aspartic acid (25.0 g, 0.188 mol) and benzyl chloroformate (34.3 ml, 0.282 mol) were added to sodium hydroxide (22.9 g, 0.564 mol) in water (600 ml). The resulting mixture was stirred at room temperature for 3 days. The mixture was then acidified with 6MHCl to pH1 and extracted with ethyl acetate (3×250 ml). The extracts were combined, dried (MgSO4) and evaporated to a clear oil, wt 50.2 g. 1H NMR (90 MHz, CDCl3): δ3.05 (2,bm), 4.65 (1,bm), 5.25 (2,s), 6.2 (1,bs), 7.4 (5,s), 10 (1,bs).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH2:11]C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:18])[CH2:10][CH2:11][CH:17]=[CH:16][CH2:15][CH2:14]1
Reactant: C=CCCC(O)(CCC=C)c1cccc(F)c1F
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: OC1(c2cccc(F)c2F)CCC=CCC1
Temperature: 45 °C

Procedure:
In a 500 mL round-bottomed flask (t=g) was added 5-(2,3-difluorophenyl)nona-1,8-dien-5-ol (1.15 g, 4.56 mmol) in CH2Cl2 (50 mL) to give a colorless solution. Grubbs II (0.193 g, 0.228 mmol) was added, and the mixture was heated at 45° C. for 19 hours. TLC showed clean conversion to a more polar spot. Combined material with 68908-184 and concentrated to dryness and the residue was subject to purification up to 50% Et2O/hexane. The major peak was pooled and concentrated to a colorless oil (0.761 g, 74.5%). 1H NMR showed the majority as the desired product (same as the later synthesized compound using Grubbs I catalyst) and a minor component with double-bond isomerized.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[BH4-].[Na+]>CO>[F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccnc(CO)c1F
Yield: 79 %

Procedure:
3-fluoro-4-methyl-2-pyridinecarbaldehyde (ASYMCHEM, 250 mg, 1.797 mmol) was dissolved under N2 atmosphere, in dry MeOH (5 mL). NaBH4 (ALDRICH, 187 mg, 4.94 mmol) was added. After 2 h reaction was completed. Solvent was evaporated. Residue was dissolved in ethyl acetate and partitioned between NaHCO3 aqueous saturated solution. Organic layer was dried over MgSO4 (anh), filtered and concentrated to obtain the title compound (200 mg, 1.42 mmol, 79%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.21-8.22 (m, 1H), 7.27-7.31 (m, 1H), 5.23 (t, 1H), 4.56 (dd, 2H), 2.27-2.28 (m, 3H). [ES+MS] m/z 142 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@@H:5]1[C:10](=[O:11])[CH:9]=[CH:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@@H:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1
Reactant: COC(=O)C[C@@H]1C(=O)C=CN(C(=O)OCc2ccccc2)[C@H]1c1ccc(C(F)(F)F)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1C(=O)CCN(C(=O)OCc2ccccc2)[C@H]1c1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h
Yield: 88.6 %

Procedure:
A solution of the enone from Step 2 (1.650 g, 3.7 mmol) in dry THF (40 ml) was cooled to −78° C. and L-Selectride® (1.0M in THF, 4.6 ml, 4.6 mmol) was added. The reaction was stirred for 2 mins then quenched with saturated NH4Cl solution. The mixture extracted with EtOAc (×3), the combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 40-50% Et2O/hexanes) to give the ketone (1.473 g, 89%). 1H NMR (360 MHz, CDCl3) δ: 2.24 (1H, dd, J 4.9, 16.8), 2.57-2.70 (3H, m), 3.46-3.52 (1H, m), 3.58 (3H, s), 3.80-3.89 (1H, m), 4.57 (1H, dd, J 5.2, 14.2), 4.93-4.98 (2H, m), 5.10 (1H, d, J 12.1), 7.07 (2H, s), 7.26-7.41 (5H, m), 7.57 (2H, d, J 8.1).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1([CH2:21][CH3:22])[C:18](=[O:19])[N:10]2[CH2:11][CH2:12][CH2:13][CH:14]([C:15]([OH:17])=[O:16])[N:9]2[C:8]1=[O:20])(=O)C>Cl>[CH2:21]([C:7]1([CH2:6][CH2:5][SH:4])[C:18](=[O:19])[N:10]2[CH2:11][CH2:12][CH2:13][CH:14]([C:15]([OH:17])=[O:16])[N:9]2[C:8]1=[O:20])[CH3:22]
Reactant: CCC1(CCSC(C)=O)C(=O)N2CCCC(C(=O)O)N2C1=O
Agent: Cl
Product: CCC1(CCS)C(=O)N2CCCC(C(=O)O)N2C1=O
Yield: 93.8 %

Procedure:
0.33 g of 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid was heated under reflux for 0.5 hour with 10 ml of 2M hydrochloric acid. After evaporation, the residue was dissolved in dichloromethane, the solution was dried over magnesium sulfate and then evaporated to give 0.27 g (94%) of 2-ethyl-hexahydro-2-(2-mercaptoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid in the form of a colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14]I)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Cu])#N.[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C.[Zn]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:23][CH:22]=[CH2:21])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
In an anhydrous DMF solution (28 mL) containing zinc powder (2.48 g, 37.9 mmol) 1,2-dibromoethane (0.17 mL) is injected under argon. The solution is stirred for 20 min at room temperature. TMSCI (50 μL) is injected and the solution is heated with stirring to 60° C. for 30 min. (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (VIII) (2.0 g, 6.08 mmol) in DMF (8 mL) is added drop wise. The solution is then stirred for 20 min at 60° C. LiCl (587 mg, 13.8 mmol) and CuCN (619 mg, 6.9 mmol) in DMF (6.5 mL) are injected at −55° C. and the solution is placed at 0° C. for 10 min. The latter is again placed at −55° C. and allyl bromide (1.05 mL, 12 mmol) is injected. After 5 min, the solution is placed at 0° C. and stirred for 2 hours at this temperature. The zinc which has not reacted is removed by filtration on celite and the filtrate is treated with a saturated NH4Cl solution. The product is extracted with ethyl acetate (EtOAc). The collected organic phases are washed with a saturated NaCl solution, and then dried on MgSO4 and evaporated. After flash chromatography (silica gel, 8% EtOAc/cyclohexane), the product (IX) (1.38 g, 93%) is isolated as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[CH:16]=[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])[S:14][CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:22]>CO>[ClH:22].[ClH:22].[ClH:22].[CH3:20][N:18]([CH2:17][C:15]1[S:14][CH:13]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:16]=1)[CH3:19]
Reactant: CN(C)Cc1cc(CSCCNC2=NS(=O)N=C2N)cs1
Agent: Cl
Solvent: CO
Product: CN(C)Cc1cc(CSCCNC(=N)C(=N)N)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A suspension of 3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (7.8 g; 22.6 mmoles) [prepared according to the procedure of U.S. Pat. No. 4,374,248] in 150 ml of methanol was treated with 15.0 ml of concentrated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 190°-205° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.[C:30]([C:32]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:36]2[N:46]=[C:47]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:48]=[C:35]2[N:34]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=2)[C:33]=1[CH3:70])#[N:31]>CN(C=O)C>[C:30]([C:32]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:36]2[N:46]=[C:47]([N:49]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:50](=[O:59])[O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:48]=[C:35]2[N:34]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=2)[C:33]=1[CH3:70])#[N:31]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reactant: BrCC1CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC3CC3)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 μmol, 2.1 eq.), 18-crown-6 (30 mg, 113 μmol, 2.1 eq.) and 1-(bromomethyl)cyclopropane (15.3 mg, 113 μmol, 2.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (22 mg, 66% of theory).