Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11].O[CH:13]1CCN(C(C)C(OCC)=O)C1=O>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([CH3:13])[C:8]([NH2:10])=[O:9])[C:3]1=[O:11]
Reactant: NC(=O)CN1CCC(O)C1=O
Reactant: CCOC(=O)C(C)N1CCC(O)C1=O
Product: CC(C(N)=O)N1CCC(O)C1=O

Procedure:
According to the process described in paragraph (b) of Example 1, from ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionate there is obtained, after chromatographic filtration on silica gel (granular size 0.2-0.5 mm), elution with acetonitrile/ethanol (1:1) and crystallization from acetonitrile, (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionamide of melting point 139°-141°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH2:10]/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC/C=C/c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(/C=C/CCl)cc1
Reaction time: 0.5 h

Procedure:
(2E)-3-(4-Fluorophenyl)prop-2-en-1-ol (1.36 g) synthesized in Reference Example 24 was dissolved in dichloromethane (45 mL), pyridine (0.78 g) and thionyl chloride (0.72 mL) were added under ice-cooling, and the mixture was stirred for 30 min. The mixture was diluted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane) to give the title compound (1.1 g) as a colorless oil.
Reaction SMILES: [CH:1]1([C:7]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:19]>CO>[ClH:19].[CH:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cnccc1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnccc1C1CCCCC1
Reaction time: 1 h

Procedure:
Methyl 4-cyclohexylnicotinate [cp. Heterocycles 22, 151-157 (1984)] (23.6 g, 0.11 mol), 5N aqueous NaOH solution (100 ml) and methanol (50 ml) are refluxed together with stirring for 1 h. The reaction solution is allowed to cool and acidified with concentrated hydrochloric acid to pH 4. The mixture is evaporated to dryness in vacuo. The residue is slurried in hot ethanol (50 ml), filtered and the filtrates are evaporated to dryness in vacuo. The residue is slurried in cold ethyl acetate (23 ml), filtered and dried to give 4-cyclohexylnicotinic acid hydrochloride.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-morpholinophenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (0.1 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 14 mg (15%) of a yellow solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 13.55 (s, 1H), 9.09 (s, 1H), 8.96-8.78 (m, 2H), 8.72 (s, 1H), 8.65 (s, 1H), 8.25-8.09 (m, 3H), 8.05-7.90 (m, 8H), 4.73 (d, J=5.4 Hz, 2H), 4.13 (s, 4H), 3.82 (s, 2H), 3.47 (s, 4H), 2.75-2.57 (m, 4H). MS (ES, m/z): 679 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1.[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39]>>[CH3:37][S:38]([CH2:41][CH2:42][NH:43][CH2:28][C:26]1[O:27][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:32]=[CH:33][CH:34]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:4]=3)=[CH:31][CH:30]=2)=[CH:24][CH:25]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{4-(3-trifluoromethylbenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 300 MHz (DMSO-d6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88 (s, 1H); 8.43 (d, 1H); 7.97 (d, 1H); 7.90-7.67 (m, δH); 7.34 (d, 1H); 7.19 (d, 2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3. 78 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.19 (s, 3H); MS m/z 597 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][C:3](=[N:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][CH:32]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[CH2:24][CH2:23]2)=[O:18])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.C(Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[ClH:1].[NH2:2][C:3](=[N:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][CH:32]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:29][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:24][CH2:23]2)=[O:18])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: CN1CCc2cc(NC(=O)CCNCc3cccc(N=C(N)c4cccs4)c3)ccc21
Agent: Cl
Product: NC(=Nc1cccc(CNCCC(=O)Nc2ccc3c(c2)CCN3Cc2ccccc2)c1)c1cccs1

Procedure:
The experimental protocol used is the same as that described for compound 54, with benzyl bromide replacing iodomethane. A white solid is obtained. Melting point: 193-195° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([CH3:15])[CH:4]=1>C(O)(=O)C.O=[Mn]=O>[CH:2]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([CH3:15])[CH:4]=1)=[O:1]
Reactant: Cc1cc(CO)cc(C)c1CCC(=O)O
Agent: O=[Mn]=O
Solvent: CC(=O)O
Product: Cc1cc(C=O)cc(C)c1CCC(=O)O
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 84.3 %

Procedure:
To a solution of 3-(4-hydroxymethyl-2,6-dimethyl-phenyl)-propionic acid (960 mg, 4.6 mmol) in acetic acid (20 mL), MnO2 (1440 mg, 16.6 mmol) is added. The mixture is stirred at 80° C. for 4.5 h before it is filtered. The filtrate is evaporated and the crude product is purified by CC on silica gel eluting with DCM containing 8% of methanol to give 3-(4-formyl-2,6-dimethyl-phenyl)-propionic acid (800 mg) as a beige solid; LC-MS: tR=0.81 min; 1H NMR (D6-DMSO): δ 12.2 (s br, 1H), 9.86 (s, 1H), 7.52 (s, 2H), 2.93-2.85 (m, 2H), 2.38-2.30 (m, 8H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@@H:30]([NH:31][C:32]([C@@H:34]([NH:39][C:40]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[CH:46]=2)=[O:41])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:54])=[O:53])[CH2:25]1>C(Cl)Cl>[CH3:37][CH:36]([CH3:38])[CH2:35][C@H:34]([NH:39][C:40]([C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[CH:46]=1)=[O:41])[C:32](=[O:33])[NH:31][C@H:30]1[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:53])=[O:54])[CH2:25][C:24]1=[O:23]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Yield: 96.8 %

Procedure:
Dess-Martin periodinane (0.077 g, 0.182 mmol) was added to a solution of. Benzofuran-2-carboxylic acid {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide (0.058 g, 0.107 mmol) in CH2Cl2 (10 ml) and was stirred at RT for 1 h. The solution was washed with 10% aq. Na2S2O3, then aq. sat. NaHCO3, then brine. Purification by column chromatography (50% to 80% ethyl acetate/hexanes) gave the title compound (0.056 g, 97%): 1H NMR: 8.72 (m, 1H), 8.0 (d, 1H), 8.92 (dd, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.42 (dd, 2H), 7.28 (d, 1H), 7.10 (d, 1H), 5.15 (m, 1H), 4.77 (d, 1H), 4.68 (m, 1H), 4.40 (m, 1H), 3.86 (d, 1H), 2.20–2.08 (m, 2H), 1.78–1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec: M+H+=541.2.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:16])([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:27][S:24]([C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH3:7]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 53 %

Procedure:
Ethyl 2,2-dimethyl-9-bromononanoate (2.0 g, 0.007 mol) was treated with 4-chlorobenzenesulphonamide (3.44 g, 0.018 mol) and potassium carbonate (6.2 g, 0.045 mol) by the method described in Example 5(ii) to give the title compound (1.5 g) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[O:12][CH3:13].[CH2:15](I)[CH3:16]>CN(C)C=O>[CH2:15]([N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[C:11](=[O:14])[O:12][CH3:13])[CH3:16]
Reactant: COC(=O)Nc1ccccc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC)c1ccccc1C
Reaction time: 4 h

Procedure:
5.1 g (0.2 mol) of sodium hydride are added a little at a time to 30 g (0.18 mol) of methyl N-(o-methylphenyl)-carbamate (Example 1a) in 200 ml of dimethylformamide. After the evolution of gas has ceased, 30 g (0.2 mol) of ethyl iodide are added drop-wise, the reaction mixture being lightly cooled in a water bath. A white solid is precipitated. After about 4 hours, the reaction mixture is diluted with water and the aqueous phase is extracted three times with ether. The organic phase is dried over MgSO4 and evaporated down. The residue is distilled. 32.5 g (0.17 mol=93%) of the title compound are obtained as a colorless oil. bp.0.5 =74° C.; 1H-NMR (CDCl3 ; δ (ppm): 7.2 (m, 3H, aromatic); 7.1 (m, 1H, aromatic); 3.8 (m, 1H, N--CHA); 3.6 (s, 3H, OCH3); 3.5 (m, 1H, N--CHB); 2.2 (s, 3H, CH3); 1.1 (t, 3H, CH3)
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]#[N:22].C[O-].[Na+]>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:21]=1[NH2:22]
Reactant: COc1ccc(N=[N+]=[N-])cc1
Reactant: N#CCc1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(F)cc3F)c2N)cc1
Temperature: 0 °C
Yield: 54.3 %

Procedure:
To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (1.000 g, 6.7046 mmol) and 2,4-difluoro phenyl acetonitrile (1.27 g, 8.0455 mmol) in absolute ethanol (20 ml), an ice-cooled solution of sodium methoxide (0.543 g, 10.0569 mmol) in absolute ethanol (10 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜2 g of crude material as brownish solid. This material is purified by crystallization from methylene chloride and petroleum ether, to obtain the title compound as brown solid (1.10 g, 48% yield). M.p. 152-156.5° C. LC-ESI-HRMS of [M+H]+ shows 303.1046 Da. Calc. 303.105742 Da, dev. −3.8 ppm.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)[CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH:8]1[CH2:9][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:25])[CH2:14]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CC[C@H](NC2CNC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 5d (0.96 g, 2.78 mmol) in MeOH (5 mL) was added HCl solution in dioxane (4M, 10 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation. Ether (50 mL) was added to the residue. The off-white solid was collected by filtration, washed with hexanes, and dried under vacuum. The crude compound 5e was used in the next reaction without further purification. MS m/z (M+H+) 246.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:21]1[CH2:22][CH2:23][NH:18][CH2:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCNCC1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Product: C1=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CCNC1

Procedure:
Starting with 5.0 gm (22 mMol) 5-benzyloxyindole and 6.88 gm (45 mMol) 4-piperidone.HCl.H2O, 6.53 gm (97.6%) of 5-benzyloxy-3-[1,2,5,6-tetrahydro-4-pyridinyl]-1H-indole were recovered as a light yellow solid by the procedure described in Preparation I. The material was used in the subsequent step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:28])[CH2:11][N:12]3[C:17]4=[N:18][C:19](Cl)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][CH2:14][C@H:13]3[C:24]([F:27])([F:26])[F:25])=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][O:31]2>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:28])[CH2:11][N:12]3[C:17]4=[N:18][C:19]([N:34]5[CH2:35][C@@H:30]6[CH2:36][C@H:33]5[CH2:32][O:31]6)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][CH2:14][C@H:13]3[C:24]([F:27])([F:26])[F:25])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc2snnc2c1
Agent: Cl
Product: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc2snnc2c1

Procedure:
210 mg (0.49 mmol) of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 79.50 mg (0.58 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 100 mg of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][C:10]([C:9]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:8]=1/[CH:7]=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)C=Cc1cc(C(F)(F)F)ccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
1.3 g of 2-(2-ethoxycarbonylvinyl)-4-trifluoromethylbenzoic acid (4.5 mmol) and 453 mg of 2,2,2-trifluoroethylamine (4.5 mmol) were dissolved in 5 ml of DMF and 0.93 g of DCC was added. The mixture was stirred at RT for 4 h. The urea by-product was removed by filtration and then the solvent was removed under reduced pressure. The residue was recrystallized from DIP to obtain 1.6 g (96%) of white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccccc1Br
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccccc1C
Yield: 97.3 %

Procedure:
2-Bromoanisole (187 mg, 1.00 mmol) reacted with 2-methylphenylboronic acid (150 mg, 1.10 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (116 mg, 2.0 mmol) in toluene at 100° C. to give the title compound (193 mg, 98%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.43 (t, 1H, J=8.2 Hz, aryl coupling J=1.75 Hz), 7.36-7.24 (m 5H), 7.10 (t, 1H, J=7.4 Hz, aryl coupling 0.91 Hz), 7.05 (d, 1H, J=8.2 Hz), 3.84 (s, 3H), 2.24 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 156.53, 138.58, 136.77, 130.95, 130.77, 129.95, 129.52, 128.51, 127.25, 125.40, 120.38, 110.56, 55.31, 19.89. GC/MS(EI): m/z 198 (M+). Anal. Calcd for C14H14O: C, 84.81; H, 7.12. Found: C, 84.97; H, 7.11.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]([Br:24])=[CH:8][C:9]2[O:13][C:12]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][C:10]=2[C:22]=1[Br:23].[K+].[Br-]>>[C:14]([C:12]1[O:13][C:9]2[CH:8]=[C:7]([Br:24])[C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[C:22]([Br:23])[C:10]=2[CH:11]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)COc1c(Br)cc2oc(C(=O)c3ccccc3)cc2c1Br
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(Br)cc2oc(C(=O)c3ccccc3)cc2c1Br

Procedure:
The title compound was prepared as an off white solid (0.060 g, 88%) from (2-benzoyl-4,6-dibromobenzofuran-5-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp 179–181° C.; 1H NMR (DMSO-d6) δ 4.54 (s, 2H), 7.58 (d, J=0.88 Hz, 1H), 7.60–7.65 (m, 2H), 7.74 (tt, J=1.3, 6.8 Hz, 1H), 7.99–8.03 (m, 2H), 8.31 (d, J=0.88 Hz, 1H), 12.98–13.32 (bs, 1H); IR (KBr) 3420, 3080, 2910, 2580, 1740, 1645, 1610, 1540, 1440, 1410, 1330, 1290, 1250, 1175, 1125, 1070, 1000, 970, 915, 860, 800, 715, and 675 cm−1; mass spectrum [(−) ESI], m/z 451 (M−H)−; Anal. Calcd. for C17H10Br2O5: C, 44.97; H, 2.22; N, 0.00. Found: C, 44.71; H, 2.13; N, 0.04.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH3:13]O>>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH3:13])=[O:6]
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(O)[C@@H](N)CC(C)C

Procedure:
Hydrogen chloride was passed into a solution of 110 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid in 10 ml of methanol with stirring, and the mixture was stirring overnight, and the mixture was evaporated to dryness under reduced pressure to obtain 150 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder. [IR (KBr): νco 1740 cm-1 ].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([Sn:11]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])O)[CH2:8][CH2:9][CH3:10].O>C1(C)C(C)=CC=CC=1>[C:1]([O:6][Sn:11]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCCC[Sn](O)(CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)O[Sn](CCCC)(CCCC)CCCC
Yield: 64 %

Procedure:
Methacrylic acid (0.1 mol) and tri-n-butylhydroxystannane (0.1 mol) were dissolved in xylene and subjected to reaction. The water that formed as the reaction proceeded was removed together with the solvent by distillation. The by-product of the reaction was distilled off under vacuum and the residue was dried under vacuum to obtain tri-n-butylstannyl methacrylate (m.p. 46° C.; yield, 64%). This tri-n-butylstannyl methacrylate and ethyl methacrylate were put into a round-bottom flask at a molar ratio of 1:1 and xylene was added to achieve a concentration of ca. 50%. Benzoyl peroxide (1 mol % of the sum of tri-n-butylstannyl methacrylate and ethyl methacrylate) dissolved in xylene was charged into a dropping funnel. After equipping the flask with this funnel, the benzoyl peroxide solution was dripped in an amount of about 10% of the total quantity of the solution. Thereafter, the flask was heated to the reflux temperature and the remaining polymerization initiator was slowly added dropwise until the reaction was completed in 8 hours. After the reaction, the content of the flask was added to n-hexane and subjected to re-precipitation. The resulting precipitate was recovered and dried to obtain a solid product, which was slowly added to ice water and reprecipitated. The precipitate was recovered and dried to obtain poly(tri-n-butylstannyl methacrylate-ethyl methacrylate). Yield, 80%, Mn, 48,000; Mw/Mn=1.9, IR (ν cm-1), 1720, 1160, 760, 700; atomic absorption spectrum (Sn content), 24.90 (found) and 24.98 (calculated).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([O-:11])=[O:10].Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 84 °C
Yield: 49 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 178 mg of p-nitroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 4 hours under a nitrogen atmosphere. A precipitate was formed which was collected by filtratio. 6-Chloro-N-(4-nitrophenyl)pyrimidin-4-amine hydrochloride in the form of bright yellow crystals was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:26]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:25])=[C:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:27]1([C:30]([NH:1][C:2]2[N:26]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[CH:13][C:14]([CH3:25])=[C:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: Cc1ccc(Oc2ccc3nc(N)nn3c2)cc1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 84 h
Yield: 102.5 %

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-methylphenyl}carbamate (3.52 g, 8.92 mmol) in N,N-dimethylacetamide (30 mL) was added cyclopropanecarbonyl chloride (0.811 mL, 8.93 mmol) at 0° C., and the mixture was stirred at room temperature for 84 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→425/75) to give the title compound (3.87 g, 97%) as a colorless oil.