Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C1(OC)C(=CC=C(C=1)CC=C)O.C(OC(=O)C)(=O)C.[CH3:35][SiH:36]([CH3:38])[Cl:37]>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][Si:36]([CH3:38])([CH3:35])[Cl:37])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: C=CCc1ccc(OC(C)=O)c(OC)c1
Reactant: C[SiH](C)Cl
Agent: C=CCc1ccc(O)c(OC)c1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(CCC[Si](C)(C)Cl)ccc1OC(C)=O
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
A 100 mL round bottomed flask was charged with eugenol acetate (16.5 g, 80 mmol), which had been prepared from the reaction of eugenol with acetic anhydride, and 25 microliters of Karstedt's catalyst. Dimethylchlorosilane (7.56 g, 80 mmol) was added slowly over 20 minutes. After 1.5 hr the reaction was complete (as judged by 1H-NMR) and 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylchlorosilane (21.1 g, 88% yield) was isolated by vacuum distillation (boiling point (bp)=150° C./0.5 mmHg). A 100 mL round bottomed flask was charged with 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylchlorosilane (15.0 g, 50 mmol) and 25 mL of toluene. A 65 weight percent solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (7.0 mL, 50 mmol) was added over 30 minutes. After quenching in 6N HCl (100 mL), the product in toluene was washed 3 times with water, dried over MgSO4 and the toluene removed under reduced pressure. Vacuum distillation gave 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylsilane (8.5 g, bp 90° C./0.5 mmHg). A 100 mL Morton flask was charged with 3-(4-acetoxy-3-methoxyphenyl)prop-1-yl dimethylsilane (8.0 g, 30 mmol), eugenol (6.56 g, 40 mmol), toluene (25 mL) and platinum on carbon (5% Pt on C, 0.05 g). After heating at reflux for 1.5 hr, the reaction mixture was cooled and filtered. The toluene was removed and the crude product stripped of volatiles at 125° C. at a pressure of 0.5 mmHg. Residual acetate groups were removed by treating the coupled product with K2CO3 in methanol/water, diluting the reaction mixture to 5 weight percent HCl, extracting with ether, drying the organic layer over MgSO4 and concentrating under reduced pressure to afford eugenol siloxane bisphenol (8.0 g) wherein p is zero.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[OH:34].CO.CCOC(C)=O>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[O:34][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CCCC1
Yield: 93.8 %

Procedure:
A mixture of 21 (2.4 g, 8.89 mmol), K2CO3 (4.97 g, 35.96 mmol) and 2-fluoro-4-nitrophenol (1.55 g, 9.89 mmol) were heated at 150° C. in diphenyl ether (40 mL) for 2 days. The mixture was purified by column chromatography (eluents EtOAc-hexane 5:95, 2:8, then MeOH-EtOAc 2:98, 5:95) to give the title compound 22 as a yellow solid (3.23 g, 93% yield). MS (m/z): 388.2 (M+H).
Reaction SMILES: [N:1]1C=CC=CC=1.Br.[Br:8][CH2:9][CH2:10]N.[Cl:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[Br:8][CH2:9][CH2:10][CH:13]([Cl:12])[S:14]([NH2:1])(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)CCl
Reactant: NCCBr
Reactant: c1ccncc1
Agent: Br
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)C(Cl)CCBr
Reaction time: 1 h

Procedure:
Pyridine (17.8 ml.) was added over a period of 30 minutes to a cooled solution (15°-20° C.) of 2-bromoethylamine hydrobromide (20.5 g., 0.10 mole) and chloromethanesulfonyl chloride (14.9 g., 0.10 mole) in chloroform. The mixture was stirred for 1 hour and then washed with water (100 ml.) and dilute hydrochloric acid (50 ml.). The solution was dried over magnesium sulfate. The solvent was evaporated in vacuo. There was obtained 10 g. of a dark oil, the title compound. Structure was confirmed by infrared analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[NH:11][C:10]1=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[N:11]([S:38]([CH:35]2[CH2:37][CH2:36]2)(=[O:40])=[O:39])[C:10]1=[O:24]
Reactant: Cc1ncnc2c(F)c3c(cc12)[nH]c(=O)n3-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c3c(cc12)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 3-(2-fluoro-4-iodophenyl)-4-fluoro-8-methyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (50 mg, 0.12 mmol) in THF (10 ml) at −78° C. was added LiHMDS (0.16 ml, 1 M in THF, 0.16 mmol). The reaction mixture was stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (25 mg, 0.18 mmol) was added to the mixture. The reaction was slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution was washed with brine (20 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yields 46 mg (75%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]#N)=[C:11]([Cl:16])[N:10]=[C:9]1[CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH2:22].[CH2:23]([OH:25])[CH3:24]>>[ClH:16].[CH2:1]([N:8]1[C:12]([CH2:13][C:14]([O:25][CH2:23][CH3:24])=[O:22])=[C:11]([Cl:16])[N:10]=[C:9]1[CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c(CC#N)n1Cc1ccccc1
Reactant: O
Reactant: CCO
Agent: Cl
Product: CCCCc1nc(Cl)c(CC(=O)OCC)n1Cc1ccccc1
Reaction time: 1 h

Procedure:
1 g of 1-benzyl-2-n-butyl-4-chloro-5-cyanomethylimidazole was heated in 20 ml of ethanol containing 1 g of hydrogen chloride in a sealed tube at 100° C. for 2 hours. 0.5 ml of water was added to the reaction solution, which was then boiled for 1 hour and evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and, after washing with aqueous sodium bicarbonate, the ethyl acetate layer was evaporated to dryness, and chromatographed on a column of 30 g of silica gel. The column was eluted with benzene-ethyl acetate (4:1), and the main fractions were evaporated to dryness. The residue was dissolved in 1 ml ethanol saturated with hydrogen chloride, and crystallized by adding petroleum ether. After further adding ethyl acetate to separate out in the fully crystallized condition, there was obtained 300 mg of ethyl 1-benzyl-2-n-butyl-4-chloroimidazole-5-acetate hydrochloride. m.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:17].Cl[C:19]1[CH:20]=[C:21]([CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[C:27]2[CH3:31])[N:22]=[N:23][CH:24]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([CH2:25][N:26]3[CH:30]=[CH:29][N:28]=[C:27]3[CH3:31])[N:22]=[N:23][CH:24]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Product: Cc1cc(-c2cnnc(Cn3ccnc3C)c2)ccc1Cl
Product: Cl

Procedure:
The title compound, MS: m/e=299.3 (M+H+), was prepared from 2-(4-chloro-3-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([OH:20])=O)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)=[O:7].[C:22]1([CH:28]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[K+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:30]([CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:29])[CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:20])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:7]
Reactant: COc1ccc(N(C(=O)c2ccco2)C(C)C(=O)O)cc1
Reactant: CCOC(=O)CCCNC(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N(C(=O)c2ccco2)C(C)C(=O)N(CCCC(=O)O)C(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2-furoyl)-2-(p-anisidino)propionic acid and ethyl 4-(1-phenylethylamino)butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(2-furoyl)-2-(p-anisidino)propionyl]-4-(1-phenylethylamino)butyric acid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)[CH:17]=1)[CH3:13]
Reactant: Cc1nc(C)c(CBr)nc1C
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OC)c(OCc2nc(C)c(C)nc2C)c1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.768 g, 0.003 mol), 3-hydroxy-4-methoxybenzoic acid ethyl ester (0.954 g, 0.005 mol), anhydrous potassium carbonate (1.1 g, 0.008 mol), and DMF (60 mL) into a 100 mL three-necked bottle in turn, wherein the solution appears orange, heating to 90° C. with oil bath, stirring to react for 12 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.4), and the reaction solution appears orange, filtering to obtain orange filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain light yellow solid, recrystallizing with anhydrous alcohol to obtain 0.71 g 3-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-4-methoxybenzoic acid ethyl ester, a yield is 60.7%, m.p. 129.8-130.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH2:31][C:32]#[N:33])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:40][CH2:39][CH2:38][CH2:37]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31](=[CH:37][CH:38]4[CH2:40][CH2:39]4)[C:32]#[N:33])=[O:34])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (120 mg, 0.26 mmol, 1.00 equiv), piperidine (27 mg, 0.28 mmol, 1.07 equiv) and cyclopropanecarbaldehyde (28 mg, 0.40 mmol, 1.51 equiv) in methanol (8 mL) was stirred in sealed tube at room temperature for 24 h. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 85.4 mg (64%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 506 (M+1). 1HNMR (300 MHz, CDCl3, ppm) 8.392 (1H, s), 7.676˜7.581 (2H, t), 7.445˜7.393 (2H, t), 7.202˜7.097 (5H, m), 6.601˜6.566 (1H, d, J=10.5), 5.737 (2H, s), 5.010˜4.912 (1H, m), 4.691˜3.185 (4H, m), 2.464˜2.035 (5H, m), 1.275˜0.876 (4H, m).
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[CH2:15](O)[CH2:16][CH2:17][CH2:18][OH:19]>>[C:3]([C:7]1[CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: OCCCCO
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(CCCCO)cc(C(C)(C)C)c1O
Temperature: 235 °C

Procedure:
50 g of potassium hydroxide, 316 g of 2-tert-butyl-6-methylphenol and 866 g of 1,4-butanediol are initially introduced into an autoclave. After introducing nitrogen gas, the autoclave is closed and the mixture is heated at 235° C. (4 bar) for 6 hours, with stirring; a further rise in pressure as a consequence of the reaction is prevented by blowing of gas. When the reaction is complete, the reaction mixture is cooled to 80° C. and the autoclave is emptied. Excess butanediol is removed by distillation. The distillation residue is poured into 11 of water and 500 ml of toluene. The organic phase is then washed with water until neutral and the toluene is stripped off by applying a vacuum. The remaining residue (310 g) contains 68-70% of the title product of the formula ##STR25##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH:14]C(C)(C)C)=[S:11]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH2:14])=[S:11]
Reactant: CC(C)(C)NC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: Cl
Product: NC(=O)NC(=S)Nc1c(Cl)cccc1Cl

Procedure:
A mixture of 32 g (0.1 mole) of 1-(2,6-dichlorophenyl)3-(t-butylcarbamyl)thiourea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, filtered and washed with 10 ml of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanolether to obtain 1-(2,6-dichlorophenyl)-3-carbamylthiourea.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:42]4[CH2:43][CH2:44][CH2:45][CH2:46][O:41]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: C1=COCCC1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a 0.2M solution of the tertiary alcohol of Step 4 in CH2Cl2 were added 5 equiv. of dihydropyran and 0.1 equiv. of triphenylphosphonium bromide and the mixture was stirred at reflux for 1 day. Then, the same amount of dihydropyran and triphenylphosphonium bromide were added and the mixture stirred at reflux another day. Toluene was added and the resulting solution was filtered through silica with EtOAc:toluene 0:100 to 2:98 to afford the title product.
Reaction SMILES: [C:1]([C:3]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[N:4]=1)#[N:2].[Cl-:26].[NH4+:27]>N>[ClH:26].[C@@H:8]1([N:5]2[CH:6]=[N:7][C:3]([C:1]([NH2:2])=[NH:27])=[N:4]2)[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [NH4+]
Reactant: [Cl-]
Agent: N
Product: Cl
Product: N=C(N)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
A mixture of 3-cyano-1-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl)-1,2,4-triazole (7.04 g., 20.0 mmole) ammonium chloride (1.07 g., 20.0 mmol) and anhydrous ammonia (150 ml.) was heated in a bomb at 85° for 18 hours. After removal of excess ammonia, the residue was crystallized from acetonitrile-ethanol to provide 5.30 g. (95%) of product with M.P. 177°-179° dec.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8](Cl)=[O:9].[C:12]1([C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:24][C@H:21]1[CH2:20][CH2:19][C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)=[O:9]
Reactant: N[C@H]1CC[C@@H](c2ccccc2)CC1
Reactant: O=C(Cl)c1cc[nH]c(=O)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](c2ccccc2)CC1)c1cc[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxy-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (Intermediate 17) (38.1 mg, 0.219 mmol) and cis-4-phenylcyclohexanamine (Intermediate 14) (50 mg, 0.29 mmol) in DCM (1 mL) was added Et3N (0.061 mL, 0.44 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was partitioned between H2O and DCM. The DCM layer was dried over Na2SO4 and filtered through a silica gel plug. The solvent was removed under reduced pressure to give Example 36A which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=O.Cl.[CH3:14][NH:15][C:16](=NC)[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]1[N:15]([CH3:14])[C:16]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])=[N:7][N:6]=1
Reactant: C=CCCCC(=NC)NC
Reactant: NNC(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: C=CCCCc1nnc(-c2ccc(Cl)cc2Cl)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.16 g yield starting from 2,4-dichlorobenzohydrazide (0.62 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.48 g). MS (m/z): 296 [MH]+.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]([C:8]1[CH:9]=[C:10]([C:26](=[O:28])[CH3:27])[CH:11]=[C:12]([N:16]2[CH2:20][C@H:19]([O:21][CH2:22][O:23][CH3:24])[C@@H:18]([OH:25])[CH2:17]2)[C:13]=1[O:14][CH3:15])([CH3:7])([CH3:6])[CH3:5].C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:4]([C:8]1[CH:9]=[C:10]([C:26](=[O:28])[CH3:27])[CH:11]=[C:12]([N:16]2[CH2:20][C@H:19]([O:21][CH2:22][O:23][CH3:24])[C@@H:18]([O:25][CH2:1][CH3:2])[CH2:17]2)[C:13]=1[O:14][CH3:15])([CH3:7])([CH3:5])[CH3:6]
Reactant: COCO[C@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@@H]1O
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCO[C@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@@H]1OCOC
Reaction time: 19 h
Yield: 72.6 %

Procedure:
Tetra-n-butylammonium bromide (380 mg, 1.18 mmol) and ethyl iodide (0.4 ml, 5.0 mmol) were added to a solution of 1-{3-(tert-butyl)-5-[(3S,4S)-3-hydroxy-4-(methoxymethoxy)tetrahydro-1H-1-pyrrolyl]-4-methoxyphenyl}-1-ethanone (830 mg, 2.36 mmol) in a toluene (5 ml) −50% aqueous NaOH (5 ml) mixed solvent at room temperature in that order and the mixture was stirred for 19 hours. After further adding ethyl iodide (0.2 ml) and stirring for 9 hours, more ethyl iodide (0.2 ml) was added and stirring was continued for 60 hours. The mixture was diluted with water, extraction was performed with ethyl acetate and the extract was washed with brine. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (650 mg, 73%) as a light yellow oil.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:17]1[O:18][C:19]([C:22](=[O:24])[NH2:23])=[N:20][N:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][NH:7][C@@H:9]([C:17]1[O:18][C:19]([C:22]([NH2:23])=[O:24])=[N:20][N:21]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
((1R)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2-phenylethyl)methylcarbamic acid tert-butylester (350 mg, 1.01 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added dropwise. The solution was stirred for 30 min. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (6 ml) and the solvent was removed in vacuo. The residue was again dissolved in dichloromethane (6 ml) and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (10 ml). This phase was washed with water. The aqueous phase was lyophilized to give 247 mg of crude 5-((1R)-1-methylamino-2-phenylethyl)-[1,3,4]oxadiazole-2-carboxylic acid amide, which was used for the further synthesis.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:16][C:17]([CH2:19]Cl)=[CH2:18]>CN(C)C=O>[CH2:10]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:19][C:17]([Cl:16])=[CH2:18])[C:8]#[N:9])[CH2:11][CH2:12][CH3:13]
Reactant: C=C(Cl)CCl
Reactant: CCCCC(C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC(C#N)(CCCC)c1ccccc1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
A 7.62 g. portion of 2-phenylhexanenitrile and 2.11 g. of 50% sodium hydride were combined in 30 ml. of dry dimethylformamide, and the mixture was stirred for 1.5 hours at 50°-55° C. The mixture was then cooled to 20° C. and 4.88 g. of 2,3-dichloro-1-propene was added dropwise, followed by an additional 10 ml. of dry dimethylformamide. The reaction mixture warmed spontaneously to about 35° C., and it was warmed to 55° C. after the addition and was stirred at that temperature for 1.5 hours. The mixture was then allowed to cool to ambient temperature and was stirred for 64 hours. It was then filtered to remove insoluble inorganics, and the solids were washed with ethyl acetate. The filtrate was evaporated under vacuum to an oil, which was dissolved in diethyl ether and was washed with water. The residue was taken up in ethanol and evaporated to dryness under vacuum to obtain 10.85 g. of the crude product named in the heading above. The product was identified by 60 mHz nuclear magnetic resonance analysis in CDCl3 : δ7.37 (m, 5H); 5.25 (d, 1H, J=2 Hz); 5.08 (d, 1H, J=2 Hz); 2.93 (s, 2H); 1.97 (dt, 2H); 1.25 (m, 4H); 0.83 (t, 3H).