Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH2:11]([N:14]([CH3:18])[C:15](Cl)=[O:16])[CH:12]=[CH2:13]>>[CH2:11]([N:14]([CH3:18])[C:15]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Product: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 90.5 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N-allyl-N-methylcarbamoyl chloride, the reaction is effected as in Example 1, whereby 1-allyl-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 90.5%. Melting point is 90.0° to 91.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C(O)CC(OC(C)(C)C)=O)[C:5]([NH:18][C:19](=[O:24])[C:20]([CH3:23])(C)C)=[CH:4][N:3]=1.[H][H]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][N:3]=1)[NH:18][C:19](=[O:24])[CH:20]=[CH:23]2
Reactant: CC(C)(C)OC(=O)CC(O)c1cc(Cl)ncc1NC(=O)C(C)(C)C
Reactant: [H][H]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1ccc2cc(Cl)ncc2[nH]1

Procedure:
A solution of 4.63 g (13 mmoles) of 2-chloro-5-((2,2-dimethyl-1-oxopropyl)amino)-β-hydroxy-4-pyridine propanoic acid, 1,1-dimethylethyl ester in 70 ml of dioxane and 30 ml of 3N HCl in water was warmed at reflux for a period of 4 hours. The solution was diluted with 100 ml of water and cooled to give a white precipitate. The crystals were filtered, washed with water and dried in a vacuum oven to give 2.18 g (93% of theoretical) of the above-captioned compound having a melting point of 304°-306° C. The carbon, hydrogen and nitrogen content calculated for C8H5ClN2O is C, 53.20; H, 2.79; and N, 15.52 percent by weight which compares to that actually found upon analysis of C, 53.55; H, 2.79; and N, 15.47.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:12][CH:13]3[CH2:14][N:15]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:16][CH:17]3[CH2:18]2)=[O:10])=[CH:7][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: O=C(c1ccc(Br)cc1)N1CC2CNCC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 99.5 %

Procedure:
1.3 (4-Bromo-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone hydrochloride (300 mg; 0.9 mmol) is dissolved in 5 ml of DCM, N-ethyldiiso-propylamine for synthesis (0.46 ml; 2.7 mmol) is added and then cooled to 0° C. Propionyl chloride for synthesis (0.095 ml; 1.09 mmol) is added dropwise followed by stirring at RT for 14 h. The reaction mixture is separated between DCM and water. The organic layer is separated, dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 316 mg (99.5%) 1-[5-(4-bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propan-1-one 3 as a brown oil.
Reaction SMILES: Cl[C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[NH:9][C:10]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:11]([CH3:13])[N:12]=2)[CH:7]=1.[H][H]>[Pd].C(N(CC)CC)C.CO>[CH3:13][C:11]1[N:12]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([NH:22][CH3:23])=[CH:4][C:5]=2[O:20][CH3:21])[NH:9][C:10]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNc1cc(OC)c(-c2nc(C)c(-c3cccnc3)[nH]2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1ccc(-c2nc(C)c(-c3cccnc3)[nH]2)c(OC)c1
Yield: 22.3 %

Procedure:
A mixture of 2-(5-Chloro-4-methylamino-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.50 g) and 10% palladium on carbon (7.5 g) in a mixture of triethylamine (0.64 ml) and methanol (20 ml) was hydrogenated at ambient temperature under atmospheric pressure of hydrogen gas. After removal of the insoluble substance by filtration, the filtrate was evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 4-methyl-2-(4-methylamino-2-methoxyphenyl)-5-(3-pyridyl)imidazole (0.10 g).
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]([Si:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH2:13][CH2:14][C:15]#[N:16])([CH3:10])([CH3:9])[CH3:8]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:7]([Si:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:12][CH2:13][CH2:14][C:15]([NH2:1])=[NH:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NH4Cl (5.35 g, 0.1 mmol) in 60 mL of dry benzend at 0 C was slowly added 50 mL of 2 M solution of trimethylaluminum in toluene. After the addition was complete, the reaction was warmed to RT and was stirred for 2 h until gas evolution had ceased. A solution of 3-(tert-butyl-diphenyl-silanyloxy)-propionitrile (9.27 g, 0.03 mol) in 20 mL of dry benzene was added to the aluminum amide reagent and the resulting was heated up to 80° C. for 20 h. The reaction was slowly cooled to RT and then carefully poured into a slurry of 300 mL of Ch2Cl2 and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/CH2Cl2 (1:2). After concentration, flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:20 to 100:30 to EtOAc/2 M NH3 in MeOH=100:30) gave the desired compound as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 12H), 3.05 (m, 2H), 1.5-2.0 (m, 8H); MS (DCI) m/z 420 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O.C[O-].[Na+].[NH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:27])=[O:21]
Reactant: N
Reactant: CCOC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
5.51 g. of ethyl 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyrate, 200 mg. of sodium methylate and methanolic ammonia are warmed under pressure for 24 hours. The solution is then evaporated in vacuo. The residue is recrystallized from methylene chloride/diethyl ether and then from benzene/cyclohexane (1:1), whereupon 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyramide, m.p. 140°-141°, is obtained.
Reaction SMILES: N(OCC(C)C)=O.N[C:9]1[CH:32]=[C:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=[CH:29][C:10]=1[O:11][C:12]1[C:21]([Br:22])=[C:20]2[C:15]([CH:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:18][O:19]2)=[CH:14][C:13]=1[Cl:28]>CN(C)C=O>[Br:22][C:21]1[C:12]([O:11][C:10]2[CH:9]=[CH:32][C:31]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:30][CH:29]=2)=[C:13]([Cl:28])[CH:14]=[C:15]2[C:20]=1[O:19][CH2:18][CH2:17][CH:16]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Br
Agent: CC(C)CON=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Br
Temperature: 68 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
N,N-dimethylformamide (20 mL) was heated in an oil bath set to 70° C. Isobutyl nitrite (0.90 mL, 7.6 mmol) was added, and to the resulting stirred solution at 68° C. was added a solution of ethyl 7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-8-bromo-6-chlorochroman-4-carboxylate (1.6 g, 6.0 mmol) in N,N-dimethylformamide (6 mL), dropwise over 5 minutes. The resulting solution was stirred at 70° C. for 30 minutes. The resulting red solution was cooled to ambient temperature and partitioned between water (600 mL) and ethyl acetate (50 mL) The organic layer was washed with 1M hydrochloric acid (10 mL) and brine (10 mL), then dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 95/5 to 85/15 hexanes/ethyl acetate, to afford ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate as an orange oil (0.27 g, 17% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[OH:20][C@H:21]1[CH2:25][CH2:24][N:23](O)[CH2:22]1>CCO>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:23]2[CH2:24][CH2:25][CH:21]([OH:20])[CH2:22]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O[C@H]1CCN(O)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCC(O)C2)cn1
Temperature: 85 °C
Yield: 47.3 %

Procedure:
A solution of 2-nitro-5-bromopyridine (320 mg, 2.02 mmol) in EtOH (6 mL) was treated with diisopropylethylamine (710 μL, 520 mg, 4.04 mmol) and (S)-3-hydroxypyrrolidinol (350 mg, 4.04 mmol). The mixture was heated in a sealed tube at 85° C. for 21.5 h then cooled and partitioned between CH2Cl2 and water. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes to 0-30% THF in EtOAc gradient to afford the product, as a yellow solid (200 mg, 47% yield). HRMS m/z calcd for C9H11N3O3 [M+H]+: 210.0873; Found: 210.0873.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=O)[CH3:13])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:12]([CH3:13])[CH2:11][CH2:1][C:2]2[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(CCC(C)=O)ccc1O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CCC(C)NCc2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Yield: 74 %

Procedure:
Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-trifluoromethylbenzylamine (4.73 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0° C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.72 g, 74%). 1H NMR, 13C NMR, and Mass Spectrum of the product were substantially the same as those in Example 2, A (made by the Conditioned Extraction method).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClC(Cl)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:43]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (3.70 g) was dissolved in dichloroethane (20 ml). Benzoyl chloride (0.64 ml) and triethylamine (2.8 ml) were added to the solution under ice-cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (developing solvent:chloroform-methanol), and recrystallized from ethyl acetate to give 1.50 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)benzamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:8]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:46][C@H:47]([CH2:64][OH:65])[CH2:48][N:49]1[CH2:54][CH2:53][CH:52]([C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)=[O:56])[CH2:51][CH2:50]1>ClCCl>[Cl:63][C:60]1[CH:61]=[CH:62][C:57]([C:55]([CH:52]2[CH2:53][CH2:54][N:49]([CH2:48][C@H:47]([NH:46][C:11](=[O:13])/[CH:10]=[CH:9]/[C:7]3[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:14][CH3:15])[CH2:64][OH:65])[CH2:50][CH2:51]2)=[O:56])=[CH:58][CH:59]=1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Reactant: N[C@H](CO)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CO)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (0.31 g, 1.55 mmol), triethylamine (0.2 ml, 1.55 mmol) and 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (0.49 g 1.55 mmol) in dichloromethane (5 ml), is added to a solution of [1-((S)-2-amino-3-hydroxy-propyl)-piperidin-4-yl]-(4-chloro-phenyl)-methanone hydrochloride and triethylamine (0.4 ml, 3.1 mmol) in dichloromethane (5 ml), and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is diluted with dichloromethane (20 ml), washed successively with saturated sodium bicarbonate solution (25 ml) and brine (25 ml), then dried over magnesium sulphate. The solvent is evaporated and the crude residue purified by flash silica chromatography (methanol:dichloromethane; 5:95) to afford (E)-N-{(S)-2-[4-(4-chloro-benzoyl)-piperidin-1-yl]-1-hydroxymethyl-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide. [MH]+482.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[C:49]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>ClCCl>[C:49]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][C:52]([S:55]([NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@@H:12]3[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]3[OH:17])=[C:5]([NH:27][CH2:28][CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:4]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(-c5ccccc5)cc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-][1,3]dioxole4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of [1,1′-biphenyl]-4-sulfonyl chloride (J. Pharm. Sci., 1964, 53, 73) (71 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 15 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a solid (110 mg).
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[C:8](=[O:27])[N:9]([CH2:25][CH3:26])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])C.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][NH2:40])=[CH:35][CH:34]=1)#[N:32].S(=O)(=O)(O)O.O>C(#N)C>[CH2:25]([N:9]1[C:8](=[O:27])[C:7]([C:6]#[C:5]/[CH:4]=[N:40]\[NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[C:10]1=[O:24])[CH3:26]
Reactant: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(CC)c1=O)OCC
Reactant: N#Cc1ccc(NN)cc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CCn1c(=O)c(C#C/C=N\Nc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 5-(3,3-diethoxyprop-1-ynyl)-3-ethyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (2.40 g) in acetonitrile (72 ml) were added 4-cyanophenylhydrazine (1.11 g) and concentrated sulfuric acid (0.30 ml) and the resulting mixture was stirred at room temperature for thirty minutes. The resulting mixture was cooled to 0° C. and thereto was added water (140 ml) dropwise, and the solids were collected by filtration and washed with water to afford (Z)-4-(2-(3-(3-ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)prop-2-yneylidene)hydrazinyl)benzonitrile (2.50 g) as brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:22](OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-4,4-dimethylpentanoic acid (50 mg, 0.204 mmol) and iodomethane (0.102 mL, 1.631 mmol) were dissolved in tetrahydrofuran (2 mL) at 0° C. and sodium hydride (24.46 mg, 0.611 mmol) was added. The reaction was stirred at 0° C. for a half hour and at room temperature overnight. The reaction was cooled to 0° C. and ethyl acetate (1 mL) was added followed by dropwise quenching with water (2 mL). The solvent was removed in vacuo and the crude material was partitioned between ether and water. The ether layer was separated. The aqueous layer was acidified to pH-5 using 1 N citric acid and extracted with ethyl acetate. The organic layer was washed with 1 N sodium thiosulfate and brine, dried (Na2SO4) and concentrated in vacuo. The compound was purified using a 4 g silica gel cartridge with a gradient of 0-3% methanol/dichloromethane over 20 minutes to give (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.63 (s, 1H), 4.57 (ddd, J=74.4, 9.5, 3.1, 1H), 2.69 (s, 3H), 1.83-1.53 (m, 2H), 1.39 (s, 9H), 0.89 (s, 9H); MS (DSI+) m/z 260 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]([CH3:12])[OH:11])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:13]([Si:17]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([Si:17]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:11][N:10]([CH3:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([CH3:14])([CH3:15])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reactant: CN(O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(OCCOCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
In a oven dried flask (50 mL) was added NaH (60% disepersion in mineral oil) 481 mg (12.03 mmol) under argon. The dispersion was washed 3 times with pentane to remove the mineral oil. To the pure NaH was added 5 mL THF (dry). N-BOC-N-methyl hydroxyl amine (a) 1.53 mg (10.43 mmol) in 5 mL THF was added slowly. The reaction mixture was left for ½ an hour until no more gas production could be seen. The solution was put on ice-bath and stirred for ½ an hour after which 4 g (8.02 mmol) of 4-toluene-sulfonic acid 2-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-ethyl ester (c) was added dropwise. The solution was left on ice-bath for ½ an hour and then stirred over-night at RT. The solvents were removed under reduced pressure, and the residue was dissolved in EtOAc (200 mL) and poured into a separatory funnel. The organic layer was washed with 0.1 M NaOH (5×50 mL), H20 (50 ml), 0.1 m KHSO4, and brine (50 ml) and the dried with MgSO4. After removal of the solvent, the residue was purified using flash chromatography on a Companion Combiflash using a gradient of methanol in DCM (methanol: 0-20% over 19 minutes). Structure confirmed by NMR.