Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])=[CH:10][N:11]=1)[C:5]([O:7]C)=[O:6].O1CCC[CH2:14]1.C[Al](C)C.[Cl-].[NH4+]>CCOC(C)=O.CCOC(C)=O.CCCCCC>[F:12][C:9]1[C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]([CH3:14])=[N:11][CH:10]=1
Reactant: COC(=O)c1cc(Br)ncc1F
Reactant: C1CCOC1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)c(F)cn1
Reaction time: 0.17 h
Yield: 374.8 %

Procedure:
To a solution of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol) in tetrahydrofuran (25 ml) tetrakis(triphenylphosphine)palladium (495.0 mg, 0.43 mmol) was added. The mixture was stirred for 10 min, and then trimethylaluminum (5.13 ml, 1.00 M in heptane, 5.13 mmol) was added. The mixture was refluxed for 4 h, and the reaction was monitored by TLC (10% EtOAc-Hexane). Then, the reaction was diluted with EtOAc (75 ml) and a few drops of saturated. ammonium chloride were added. The mixture was filtered through a small silica gel pad, followed by removal of the solvent. The crude product was re-dissolved in 5N NaOH solution in water and stirred at room temperature for 2 hours. The crude product was purified on Flashmaster II to afford 250 mg of 5-fluoro-2-methylisonicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:31]>N.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=[O:31]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCCCC1
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Yield: 95.4 %

Procedure:
A solution of 6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.35 g, 5.45 mmol) in 7M ammonia in methanol (50 ml) was stirred overnight at ambient temperature. The volatiles were removed under vacuum and the residue was triturated with ether, filtered and washed with ether followed by ether/methylene chloride (1/1) and dried under vacuum to give 6-methoxy-7-(3-piperidinopropoxy)-3,4-dihydroquinazolin-4-one (1.65 g, 95%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[C:25]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1F
Yield: 81.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (380 mg) in acetonitrile (10 mL) were added ethyl 3-(2-fluoro-5-hydroxyphenyl)propanoate (300 mg) and cesium carbonate (650 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (480 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH2:14][CH:15]=[O:16])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH:15]=[O:16])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: CCNCC=O
Reactant: COc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido] acetaldehyde.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[Mg]Br>>[F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][C:21]=1[O:23][CH3:24])=[O:5]
Reactant: COc1ccc([Mg]Br)c(OC)c1
Reactant: CON(C)C(=O)c1cccc(F)c1F
Product: COc1ccc(C(=O)c2cccc(F)c2F)c(OC)c1

Procedure:
Prepared according to Method A step B from 2,3-difluoro-N-methoxy-N-methyl-benzamide (3.22 g, 16.0 mmol) and 2,4-dimethoxyphenylmagnesium bromide (29 mL, 0.5 M in THF) to give 1.21 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:10]2=[N:11][CH:12]=[C:13]([C:16]#[N:17])[C:14](Cl)=[C:9]2[CH:8]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25].Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:10]2=[N:11][CH:12]=[C:13]([C:16]#[N:17])[C:14]([NH:25][C:24]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:22]([O:21][CH3:20])[CH:23]=3)=[C:9]2[CH:8]=1
Reactant: COC(=O)CCCc1cc2c(Cl)c(C#N)cnc2s1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COC(=O)CCCc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2s1
Yield: 70.2 %

Procedure:
A mixture of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl ester (60 mg, 0.20 mmol), 3,4,5-trimethoxyaniline (92 mg, 0.50 mmol), and pyridine hydrochloride (10 mg, 0.09 mmol) in 10 mL of 2-ethoxyethanol is heated at reflux for 24 hours. The solution is cooled and the solvent is evaporated. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 62 mg of 4-[5-cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid methyl ester as a tan solid, mp 101–103° C.; 1H NMR (DMSO-d6) δ 1.94 (quintet, J=7 Hz, 2H), 2.41 (t, J=7 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 3.60 (s, 3H), 3.67 (s, 3H), 3.75 (s, 6H), 6.60 (s, 2H), 7.28 (s, 1H), 8.40 (s, 1H), 9.62 (s, 1H); MS 442.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.CCN(CC)CC.[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>C(Cl)Cl>[CH3:22][CH:21]([CH3:23])[CH2:20][C:19]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)=[O:24]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CCCN(C(=O)CC(C)C)C1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Ethyl (S)-Piperidine-3-carboxylate (25 g, 159.02 mmol) in anhydrous DCM (500 mL) was cooled down to 0° C. and treated with Et3N. A solution of isovaleryl chloride (23.27 mL, 190.08 mmol, 1.2 eq.) in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting reaction mixture was kept on the cooling bath and allowed to warm up slowly to room temperature. After 6 hrs the reaction was washed subsequently with aqueous HCl solution (2M), saturated NaHCO3, brine, dried over Na2SO4, filtered, concentrated under vacuum and purified by filtration over a short silica gel column using EtOAc as solvent. The solvent was removed under vacuum to yield the desired product as pale yellow oil (37.4 g, 154.97 mmol, 97.5%) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 20° C.) δ 0.88 (pseudo d, J=6.4 Hz, 6H), 1.13-1.23 (m, 3H), 1.26-1.45 (m, 1H), 1.47-1.75 (m, 2H), 1.82-2.03 (m, 2H), 2.10-2.28 (m, 2H), 2.28-2.39 (m, 0.5H), 2.45-2.56 (m, 0.5H), 2.84 (dd, J=10.0, 12.8 Hz, 0.5H), 2.97-3.11 (m, 1H), 3.38 (dd, J=8.8, 13.6 Hz, 0.5H), 3.63-3.83 (m, 1.5H), 4.00-4.14 (m, 2H), 4.26-4.36 (dm, 0.5H). MS 242 (MH).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@@H:40]([C:48](O)=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:48](=[O:49])[C@@H:40]([CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: O=C(N[C@H](Cc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Yield: 60.9 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-D-phenylalanylamino)-β-D-ribofuranuronic acid (405 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-phenylalanine (543 mg) according to a similar manner to that of Example 5, mp. 206°-210° C. (dec.).
Reaction SMILES: O.[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([S:18][CH3:19])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH2:20][CH3:21])[N:6]([CH2:22][CH2:23][OH:24])[N:5]=1)[CH3:3].[OH:25]OS([O-])=O.[K+]>ClCCl>[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([S:18]([CH3:19])=[O:25])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH2:20][CH3:21])[N:6]([CH2:22][CH2:23][OH:24])[N:5]=1)[CH3:3]
Reactant: CCc1nn(CCO)c(CC)c1Oc1cc(C#N)cc(SC)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1nn(CCO)c(CC)c1Oc1cc(C#N)cc(S(C)=O)c1
Temperature: 25 °C

Procedure:
Wet alumina was prepared by adding water (1 ml) to Brockman grade I alumina (5 g). To a stirred solution of the sulphide from Example 250 (134 mg, 0.40 mmol) in dichloromethane (2 ml) was added of wet alumina (400 mg) followed by Oxone® (123 mg, 0.4 mmol) and the mixture was heated at reflux. After 1 hour a second portion of oxone (123 mg, 0.40 mmol) was added and the mixture was heated for a further 2 hours. After cooling to room temperature the reaction mixture was filtered and the resulting solids were washed with dichloromethane (20 ml). The filtrate was concentrated and was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (a gradient from 99:1 to 90:10, by volume) to provide the title compound (92 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[H][H]>>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: [H][H]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Product: CC1(C)C(O)C(C)(C)C1O

Procedure:
In one embodiment, the present invention provides processes for producing 2,2,4,4-tetramethylcyclobutane-1,3-diol, comprising contacting 2,2,4,4-tetramethylcyclobutane-1,3-dione, a promoted copper-based catalyst, a non-protic solvent, and hydrogen in a hydrogenation zone under conditions of temperature and pressure sufficient to form 2,2,4,4-tetramethylcyclobutane-1,3-diol. In one such embodiment, the 2,2,4,4-tetramethylcyclobutane-1,3-dione and hydrogen are continuously fed into the hydrogenation zone. In one such embodiment, the hydrogenation zone has a temperature ranging from 75° C. to 250° C. In one such embodiment, the pressure ranges from 689 kPa (100 psi) to 41,368 kPa (6000 psi). In one embodiment, the present invention provides processes for producing 2,2,4,4-tetramethylcyclobutane-1,3-diol, comprising contacting 2,2,4,4-tetramethylcyclobutane-1,3-dione, a promoted copper-based catalyst, a non-protic solvent, and hydrogen in a hydrogenation zone under conditions of temperature and pressure sufficient to form 2,2,4,4-tetramethylcyclobutane-1,3-diol, and further comprising continuously recovering an effluent comprising the 2,2,4,4-tetramethylcyclobutane-1,3-diol and the solvent from the hydrogenation zone. In one such embodiment, the process further comprises continuously recycling a portion of the effluent to the hydrogenation zone. In one such embodiment, the process further comprises continuously recovering the effluent from the hydrogenation zone and recovering at least a portion of the 2,2,4,4-tetramethylcyclobutane-1,3-diol from the effluent to form a depleted 2,2,4,4-tetramethylcyclobutane-1,3-diol stream. In one such embodiment, at least a portion of the depleted 2,2,4,4-tetramethylcyclobutane-1,3-diol stream is recycled to the hydrogenation zone. The term “depleted 2,2,4,4-tetramethylcyclobutane-1,3-diol stream” means that the depleted stream has less 2,2,4,4-tetramethylcyclobutane-1,3-diol in it than the effluent from which the depleted stream is derived. In one such embodiment, the hydrogenation zone comprises a tubular, fixed bed, or trickle bed reactor. In one such embodiment, the hydrogenation zone comprises a stirred tank, a continuous stirred tank, or a slurry reactor. In one such embodiment, the 2,2,4,4-tetramethylcyclobutane-1,3-diol has a cis/trans molar ratio of 1.3 or less. In one such embodiment, the 2,2,4,4-tetramethylcyclobutane-1,3-diol has a cis/trans molar ratio of 0.3 or more.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]3[O:49][C:48](=[O:50])[NH:47][C:46]=3[CH:51]=2)O1>C(#N)C.O>[C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:42]2[CH:43]=[CH:44][C:45]3[O:49][C:48](=[O:50])[NH:47][C:46]=3[CH:51]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC1(C)OB(c2ccc3oc(=O)[nH]c3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4oc(=O)[nH]c4c3)cc2)CCOCC1
Temperature: 90 °C
Yield: 52.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 300 mg), potassium acetate (177 mg) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (Example 33, step (i), 157 mg) in a mixture of acetonitrile (25 mL) and water (10 mL) under a nitrogen atmosphere, was treated with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (12 mg) and the mixture stirred and heated 90° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with water. The products were extracted into ethyl acetate (2×100 mL) and the combined extracts dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (160 mg).
Reaction SMILES: Cl[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N-:16]=[N+]=[N-].[Na+].O>CS(C)=O>[CH:7]12[CH2:8][CH:4]([CH2:5][CH2:6]1)[C:3]1[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:16][C:2]2=1
Reactant: CCOC(=O)/C=C/C1=C(Cl)C2CCC1C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Temperature: 105 °C
Yield: 59.8 %

Procedure:
To a solution of 334b (5.0 g, 22 mmol) in DMSO (30 mL) was added NaN3 (2.2 g, 33 mmol) and the mixture was heated at 105° C. for 6 hours. Water (13 mL) was added to reaction the mixture after cooling down to room temperature, and resulting mixture was extracted with methylene chloride (50 mL×3). The organic phase was dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol to give 334c as a brown solid (2.7 g, 60%). MS: [M+H]+ 206. 1H NMR (500 MHz, CDCl3) δ 11.51 (s, 1H), 6.45 (dd, 1H), 4.14-4.19 (m, 2H,), 3.25 (d, 2H,), 1.79-1.82 (m, 2H), 1.73 (d, 1H), 1.22-1.25 (t, J=6.5, 3H), 0.89-0.91 (m, 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[CH:20]([Mg]Br)=[CH2:21].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[NH:15][CH:21]=[CH:20]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc2cc[nH]c12
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
A solution of tert-butyl-dimethyl-[2-(2-nitro-phenyl)-ethoxy]-silane (85.6 g, 304 mmol) in THF (1 L) was cooled to −65° C. and a 1.0 M solution of vinyl magnesium bromide in THF (913 mL, 913 mmol) was introduced while maintaining a temperature below −60° C. The reaction was stirred for 15 minutes at −45° C., additional vinyl magnesium-bromide (152 mL, 152 mmol) was added and the reaction was stirred at −45° C. for 30 minutes. The cold reaction was poured into saturated aq ammonium chloride (800 mL) and diluted with EtOAc (500 mL). The two layers were separated and the aqueous layer was extracted with EtOAc(2×200 mL). The organic layers were combined, washed with brine (400 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (95% hexane/EtOAc) gave the title compound (47.1 g, 56%) as a transparent brown oil. 1H NMR (400 MHz, DMSO-d6) −0.11 (s, 6H), 0.80 (s, 9H), 3.03 (t, J=6.8 Hz, 2H), 3.85 (t, J=6.8 Hz, 2H), 6.39 (dd, J=1.2, 3.2 Hz, 1H), 6.86–6.92 (m, 2H), 7.28 (dd, J=3, 3 Hz, 1H), 7.36 (dd, J=4.8, 4.8 Hz, 1H), 11.02 (br s, 1H). MS (electrospray, m/z) 276 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]([NH:5][CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])=[O:12])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CC(C)(CO)C(=O)NCc1ccccc1Cl
Reactant: CCc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(NC(=O)OCC(C)(C)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of N-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (30 mg, 0.12 mmol), in CH2Cl2 were added DMAP and 4-ethylphenylisocyanate (21 μL, 0.15 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated. The resulting residue was to purify on RP-HPLC to give 3-(2-chlorobenzylamino)-2,2-dimethyl-3-oxopropyl 4-ethylphenylcarbamate (10 mg, 17%). LRMS (M+H+) m/z 389.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:12]2.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH3:28])[CH2:12]2)[CH2:35][C:31]1[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN1Cc2ccc(CNCc3ncc[nH]3)cc2C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN1Cc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
The compound (12.5 mg) obtained in Example 38-1 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (4.4 mg) and sodium cyanoborohydride (4.2 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 8 hours. The residue obtained by concentration of the solution was added with a saturated aqueous sodium hydrogen carbonate solution to neutralize the solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (7.7 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C[O-].[Na+].Cl[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CO>[CH3:25][O:24][C:22](=[O:23])[CH2:21][S:16][C:4]1[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CSc1nc(N)nc(-c2ccccc2)c1C#N
Reaction time: 3 h
Yield: 31 %

Procedure:
Following the method of Perez et al. (Synthesis 1983, 402), to a stirred solution of 1.0 g (4.4 mmol) 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile in 50 ml methanol were added 1.0 ml (5.4 mmol) sodium methylate solution (5.4M in methanol) and 0.39 ml (4.4 mmol) methyl chloroacetate and stirring continued for 3 hours at reflux. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane) followed by trituration in 8/1 ethyl acetate/methanol afforded 0.41 g (32%) (2-Amino-5-cyano-6-phenyl-pyrimidin-4-ylsulfanyl)-acetic acid methyl ester as a light yellow crystalline solid. EI-MS m/e (%): 300 (M+, 38), 299 ([M—H]+, 100), 241 (74), 240 (50).