Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CCCCCCC>[CH3:2][C@@H:1]1[O:22][C@@:3]21[C@:11]1([CH3:12])[C@H:6]([C@@H:7]([OH:13])[CH2:8][CH2:9][CH2:10]1)[CH2:5][CH2:4]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@@H]1O[C@@]12CC[C@H]1[C@@H](O)CCC[C@@]12C
Temperature: 4.400000095367432 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
(Z,3aR,4S,7aS)-1-ethylidene-octahydro-7a-methyl-1H-indene-4-ol (Compound 6: 663.1 mg, 3.18 mmol) synthesized in accordance with the method described in J. Org. Chem. 2001, 66, 626-628 was dissolved in ethyl acetate (3.1 ml), and the solution was cooled to 4.4° C. Meta-chloroperbenzoic acid (913 mg, 3.44 mmol) was added to the reaction solution over 9 minutes. After stirring the reaction solution at 2° C. for 1 hour, aqueous sodium hydrogen carbonate solution (2 ml) and aqueous sodium sulfite solution (1 ml) were added thereto, and the mixed solution was stirred and separated. The obtained organic layer was washed with aqueous sodium hydrogen carbonate solution (2 ml) and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. To the obtained reaction mixture, seed crystals were added, and heptane (1.8 ml) was added thereto, followed by collecting the precipitated crystals by filtration to obtain (1R,3aR,4S,7aS,3′S)-3′,7a-dimethyl-4-hydroxyoctahydrospiro(indene-1,2′-oxirane) (382.8 mg, 61%).
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[CH2:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25][CH2:26][C:27]#[CH:28]>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:5][C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Reactant: C#CCCCc1ccccc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)cc1C#CCCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (80 mg, 53%); 1H NMR δ (CDCl3): 7.78 (d, J=8.21 Hz, 2H), 7.43-7.22 (m, 8H), 6.62 (s, 1H), 3.98 (s, 3H), 2.78 (t, J=7.30 Hz, 2H), 2.43 (t, J=7.19 Hz, 2H), 1.96 (p, J=7.33 Hz, 2H); LCMS m/z: 300.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:7]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a 250 ml dichloromethane solution containing 89 g (1.0 mol) 2-amino-2-methyl-1-propanol at 0° was added dropwise with stirring 70 g (0.5 mol) benzoyl chloride in 250 ml dichloromethane. The reaction mixture was warmed to room temperature and stirred for several hours. The 2-amino-2-methyl-1-propanol hydrochloride was removed from the reaction mixture by filtration and was thoroughly washed with dichloromethane. The filtrate and washings were combined and the dichloromethane removed under reduced pressure to afford 67.55 g (0.35 mol), 70%, 2-benzoylamino-2-methyl-1-propanol as a white solid, mp 80°-82°, sublimation at 75° (0.2 mm); ir (KBr) 1630 (c=o) cm-1 ; pmr (CDCl3) δ 1.50 (s, 6H), 3.67 (s, 2H), 5.27 (bs, 1H), 6.92 (bs, 1H) and 7.1-8.3 (m, 5H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=5)[NH:24][CH:23]=4)[O:12][C:8]3=2)[N:3]=1.C=O.[C:35]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:35][N:17]([CH2:16][CH:13]1[O:12][C:8]2=[C:9]3[C:4](=[CH:5][CH:6]=[C:7]2[O:15][CH2:14]1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=2)[NH:24][CH:23]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCCCCc1c[nH]c2ccc(C#N)cc12)O3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c3c(ccc2n1)OCC(CN(C)CCCCc1c[nH]c2ccc(C#N)cc12)O3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-3-{4-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-butyl}-1H-indole-5-carbonitrile (0.13 g, 0.30 mmol) and formaldehyde (37 wt. % in water, 0.24 g, 3.0 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.35 g, 0.54 mmol) and acetic acid (0.035 mL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen for 4 hours, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.11 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 155° C.).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:54])[NH:46][C:47]1C=CC=C(N)C=1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:54])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:47])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-phenyl)-carbamic acid tert-butyl ester was used in place of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 11.28 (1H, br s), 8.85 (1H, s), 7.69 (1H, s), 7.57-7.27 (6H, m), 7.04 (1H, m), 4.76 (1H, d), 4.63 (1H, d), 4.21 (2H, m), 2.80 (1H, m), 2.18-1.35 (6H, m), 1.32-1.22 (13H, m). The product was further characterised as the hydrochloride salt. Found: C, 59.71; H, 7.33; N, 12.48%; C28H35N5O3.HCl.2.0H2O requires: C, 59.83; H, 7.17; N, 12.46%.
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].CO[C:16](OC)([CH3:18])[CH3:17]>CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:10][C@@:2]12[CH2:1][C@@H:6]([O:13][C:11]1=[O:12])[C@H:5]1[C@H:4]([O:9][C:16]([CH3:18])([CH3:17])[O:8]1)[CH2:3]2
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)O[C@H]2[C@H]3C[C@@](O)(C[C@H]2O1)C(=O)O3
Yield: 86.2 %

Procedure:
A solution of quinic acid (10.0 g, 52.0 mmol), para-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) and 2,2-dimethoxypropane (20 mL, 162.9 mmol) in acetone (150 mL) was refluxed for 4 hours. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated. The concentrate was stored at 0° C. for several hours to afford 9.6 g (86%) of the desired product as white crystals.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].C(N(CC)CC)C>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(Cl)Cl>[C:1]([O:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(=O)NCCCO
Reactant: C=C(C)C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCNC(C)=O
Temperature: -72 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
184.0 g (1.76 mol) of methacryloyl chloride were added dropwise in the course of 2 hours to an initial mixture, cooled to -72° C., consisting of 206.2 g (1.76 mol) of N-(3-hydroxypropyl)-acetamide, 750 ml of methylene chloride, 228 g (2.25 mol) of triethylamine and 250 mg of 2,6-di-tert.butyl-4-methylphenol. The mixture was stirred for a further 2 hours at -52° C. and the precipitated pale precipitate was then filtered off with suction at 0° C. The filtrate was subjected to aqueous work-up and the product was dried and, after concentrating on a rotary evaporator, distilled first at 100° C., and then the residue at 130° C. (in each case 0.1 mm Hg). 174.1 g (53% of theory) of 3- acetamidopropyl methacrylate were obtained in the form of a colorless oil.
Reaction SMILES: C(O[CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(C)(C)C.C(Cl)Cl.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>>[F:18][C:19]([F:24])([F:23])[C:20]([O:22][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:21]
Reactant: CC(C)(C)OCCOC1CCOCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCCOC1CCOCC1)C(F)(F)F

Procedure:
4-(2-tert-Butoxyethoxy)tetrahydropyran (24 g, 0.12 mol) was stirred in a mixture of methylene chloride/trifluoroacetic acid (150 ml/150 ml) at ambient temperature overnight. The solvents were evaporated off and the residual trifluoroacetic acid was azeotroped off with, toluene. The crude oil was purified by flash chromatography using successively petroleum ether, petroleum ether/methylene chloride (1/1) and methylene chloride. The organic phase was washed with water, brine, dried (MgSO4), filtered and the solvent evaporated. Evaporation of the solvent gave 4-(2-trifluoroacetoxyethoxy)tetrahydropyran which was hydrolysed with potassium hydrogen carbonate (48 g, 0.48 mol) in methanol (700 ml) and water (300 ml) at ambient temperature for 3 hours. The solution was neutralised to pH 7 and the solvents evaporated off. The residue was extracted with ethyl acetate, the organic phase washed with water and brine, dried (MgSO4) and the solvent evaporated off to give 4-(2-hydroxyethoxy)tetrahydropyran (6 g, 35%) as a light brown oil.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[NH:20][NH2:21].C(Cl)Cl.Cl>CCO>[NH2:10][C:9]1[N:20]([C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[F:11])[N:21]=[C:4]([CH3:5])[C:6]=1[C:7]#[N:8]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: COc1ccc(NN)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(-n2nc(C)c(C#N)c2N)c(F)c1
Temperature: 105 °C
Yield: 84.5 %

Procedure:
To a stirred solution of 2-(1-ethoxyethylidene)malononitrile (167 mg, 1.23 mmol) was added (2-fluoro-4-methoxyphenyl)hydrazine (220 mg, 1.41 mmol) in EtOH (3 mL). The solution was heated to 105° C. in the microwave for 30 min. CH2Cl2 and 1 M HCl was added and separated, the organic extract was washed with aqueous NaHCO3. The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (256 mg, 85%), which was used in the next step without further purification.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]=[CH:10][C:11]([OH:13])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[N:2]1([CH2:8][CH:9]=[CH:10][C:11]([Cl:17])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=CCN1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=CCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The HCl salt of 4-Piperidin-1-yl-but-2-enoic acid (250 mg, 1.48 mmol) was dissolved in dichloromethane (15 mL). Dimethylformamide (3 drops) was added. Oxalyl chloride (155 μL, 1.77 mmol) was added slowly and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was used as is.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[NH2:39][C@@H:40]([CH3:41])[C:42]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:4]2[S:5][C:6]3[C:11]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:10][C:9]([C:18]4[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=4)=[N:8][C:7]=3[C:3]=2[CH3:2])[CH2:27][CH2:28]1)=[O:43]
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)[C@H](C)N)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 61 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 60 mg Boc-L-Alanine via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 52.7 mg of 354 after reverse phase HPLC purification. MS (Q1) 498.3 (M)+
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:16][F:17])[C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[OH:5].[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].C(N(CC)CC)C>C(O)C>[C:18]([CH2:20][C:21]([NH:2][C@H:3]([CH2:16][F:17])[C@H:4]([OH:5])[C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][CH:11]=1)=[O:22])#[N:19]
Reactant: CCOC(=O)CC#N
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)CC#N)cc1

Procedure:
A mixture of (1R,2S)-2-amino-3-fluoro-1-(4-methylsulfonylphenyl)-1-propanol hydrochloride (5.66 g; 20 mmol), absolute ethanol (27 ml), ethyl cyanoacetate (22.62 g; 200 mmol) and triethylamine (3.03 g; 30 mmol) was refluxed for 21 hours.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccccc2)nc(N2CCOCC2)cc1=O
Yield: 39.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 134 mg of aniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. 95 mg of 2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide are obtained in the form of a purple solid, the characteristics of which are the following:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH:15]=[N:16][CH:17]2[C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+:35].[K+]>O1CCCC1.O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH:15]=[N:16][CH:17]2[C:21]([O-:23])=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[K+:35]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N=CSC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)[O-])N=CSC12
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 110.5 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate (400 mg.) in tetrahydrofuran (12 ml.) was added a solution of potassium carbonate (195 mg.) in water (12 ml.) at 0° C. After the mixture was stirred at the same temperature for an hour and at room temperature for 1.8 hours, the reaction mixture was neutralized to pH 7 with cation-exchange resin Amberlite IRC-50 (Trade Mark; manufactured by Rohm & Haas Co., Ltd.) and then filtered. The filtrate was concentrated and lyophilized to give a powder (388 mg.) of potassium 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:44]1[CH2:49][C@@H:48]2[CH2:50][C@H:45]1[CH2:46][NH:47]2)=O)(C)(C)C>CC#N.O>[CH:45]12[CH2:50][CH:48]([NH:47][CH2:46]1)[CH2:49][N:44]2[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1cc(-c2noc(CCl)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2noc(CN3CC4CC3CN4)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 72.9 %

Procedure:
To a solution of 5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (100 mg, 0.228 mmol) in MeCN (4 mL) was added K2CO3 (95 mg, 0.684 mmol) and (1s,4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (90 mg, 0.451 mmol). After 48 hours the mixture was diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to a yellow oil. This residue was dissolved in 1:1 TFA/CH2Cl2 (6 mL) for 30 minutes, then the reaction mixture was concentrated and basified with NaHCO3 to pH˜9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica (2-8% 2M NH3 in MeOH/CH2Cl2) to provide 5-[5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-3-yl]-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one as a light yellow solid (83 mg). 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.34 (d, 2H), 7.18 (d, 2H), 4.77 (s, 2H), 4.28 (s, 2H), 4.05 (dd, 2H), 3.57 (d, 2H), 3.20 (d, 1H), 3.13 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 3H), 2.61 (d, 1H), 1.86 (d, 1H), 1.64 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]=[C:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][C:64](=[CH2:63])[CH2:65][CH2:66]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C=C1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=C1CCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)CC1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-methylene-piperidine in DMSO at ambient temperature.
Reaction SMILES: N1C=CC(N)=NC1=O.CI.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]([CH2:18]C2C=CC=CC=2)[C:14](=[O:25])[N:13]=1>>[NH2:11][C:12]1[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:25])[N:13]=1
Reactant: Nc1ccn(Cc2ccccc2)c(=O)n1
Agent: Nc1cc[nH]c(=O)n1
Solvent: CI
Product: Cn1ccc(N)nc1=O

Procedure:
4-Amino-1-methyl-1H-pyrimidin-2-one was prepared from cytosine and methyliodide using the methods described above for the preparation of 4-amino-1-benzyl-1H-pyrimidin-2-one.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15].C=O.[BH3-][C:25]#N.[Na+]>CC#N.CC(O)=O>[CH3:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]
Reactant: [BH3-]C#N
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2C)c1
Reaction time: 1 h

Procedure:
To a solution of (R)-N-[3-(pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-acetamide (0.85 g, 2.81 mmol) in 25 mL CH3CN was added 1.13 mL formaldehyde (37% in H2O) and NaBH3CN (0.28 g, 4.50 mmol). The reaction was stirred for 1 h, and the pH of the reaction was neutralized every 15 min by introducing several drops of AcOH. The reaction was concentrated in vacuo and dissolved into Et2O and 6 N NaOH. The layers were separated, and the organic layer was washed twice with 6N NaOH and extracted with 6 N HCl twice. The acidic aqueous layer was basified with NaOH pellets and extracted 4 times with CH2Cl2. The CH2Cl2 layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N: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].[OH:26]O>[Pt].N>[C@@H:8]1([N:5]2[N:4]=[C:3]([C:1]([NH2:2])=[O:26])[CH:7]=[N:6]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](n2ncc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OO
Agent: [Pt]
Agent: N
Product: NC(=O)c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 20 h

Procedure:
4-Cyano-2-(2,3,5-tri-O-acetyl-β -D- ribofuranosyl)-1,2,3-triazole (7) (0.35 g, 0.001 mol) was added to 15% aqueous ammonia (30 ml) and 30% hydrogen peroxide (3 ml). After stirring at room temperature for 6 hr an additional 3 ml of 30% hydrogen peroxide was added and stirring was continued for 20 hr. Platinum black was added to destroy the excess peroxide, the solution was filtered, and the filtrate was evaporated to dryness. The residue was dissolved in a minimum of methanol and applied to a 20 × 20 cm silica gel preparative plate which was developed in ethyl acetate-methanol (9:1). The band containing 4 was removed and the compound was extracted with ethyl acetate-methanol (1:1). The solvent, along with acetamide, was removed in vacuo. The compound was dissolved in hot 2-propanol; cooling of the solution and filtering provided 14 mg of 4.