Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].O>CS(C)=O.OO.C(OCC)(=O)C>[NH2:2][C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27]
Reactant: N#Cc1ccc(C(=O)OCc2ccccc2)cc1NC1CCCCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(C(=O)OCc2ccccc2)cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.6 %

Procedure:
To a solution of benzyl 4-cyano-3-(cyclohexylamino)benzoate (66.2 mg, 0.198 mmol) in DMSO (2 mL) was added potassium carbonate (27.4 mg, 0.198 mmol) followed by 30% aqueous hydrogen peroxide (5 drops). The mixture was stirred at room temperature for 45 min, and was then diluted with ethyl acetate. Water was added and then the layers were separated. The aqueous phase was then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (40% ethyl acetate in hexanes) to provide benzyl 4-(aminocarbonyl)-3-(cyclohexylamino)benzoate (45.0 mg, 0.128 mmol, 64% yield) as a yellow film. 1H NMR (400 MHz, CDCl3): 7.81 (d, 1H), 7.46-7.32 (m, 7H), 7.16 (dd, 1H), 5.77 (br s, 2H), 5.36 (s, 2H), 3.48-3.38 (m, 1H), 2.05-1.98 (m, 2H), 1.80-1.72 (m, 2H), 1.66-1.59 (m, 1H), 1.45-1.23 (m, 4H); MS (EI) for C21H24N2O3: 353 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7].S([N:23]=[N+:24]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C1C=CC=CC=1.O1CCCC1>[CH3:3][O:4][P:5]([C:9](=[N+:23]=[N-:24])[C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To sodium hydride (188 mg of a 60% solution in mineral oil, 113 mg clean, 4.70 mmol) in 14 mL of benzene and 2.5 mL of tetrahydrofuran, add the (2-Oxo-propyl)-phosphonic acid dimethyl ester (743 mg, 618 μL, 4.48 mmol) as a solution in 5 mL of benzene at 0° C. dropwise. The mix remains white and produces some gas. After 1 h at 0° C., add tosyl azide (940 mg, 4.70 mmol) as a solution in 2.5 mL of benzene and remove the bath. After 2.3 hours, pour the mix through a plug of Celite® with tetrahydrofuran, benzene and ether. Concentrate and apply to a 4 mm chromatotron plate and elute with 100 mL of Hexanes, and then 200 mL of 20:80 EtOAc/Hexanes, 30:70 EtOAc/Hexanes, 50:50 Hexanes/EtOAc, 85:15 EtOAc/Hexanes and 250 ml of EtOAc to provide 794 mg of (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester as a yellow solid. This material may be used directly. Exact Mass 192.03: mass spectrum (aspci): m/z=165.0 (M+1 (—N2).
Reaction SMILES: [CH:1](/[CH2:9][C:10]([OH:12])=[O:11])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13]S(O)(=O)=O.C[O-].[Na+]>CO.C(OC)(OC)OC>[C:3]1(/[CH:2]=[CH:1]/[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)O
Reactant: O=C(O)C/C=C/c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)C/C=C/c1ccccc1

Procedure:
A solution of 3.24 mg (20 mmol) of (E)-styrylacetic acid in 20 ml of methanol, 2 ml of trimethyl orthoformate and 192 mg (2 mmol) of methanesulphonic acid was stirred at 50° C. under argon for one hour. For the working-up, the mixture was neutralized with 2 mmol of sodium methylate and subsequently the solvent mixture was distilled off under reduced pressure. There was obtained methyl (E)-4-phenyl-but-3-enoate as a colourless liquid in quantitative yield; MS: 176 (M)+.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[S:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])[CH:13]=1>>[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[S:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:22][CH2:23][N:24]([C:3]([O:5][C:21]([CH3:26])([CH3:22])[CH3:19])=[O:4])[CH2:25][CH2:26]2)=[O:20])[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)C3CCNCC3)c2)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1

Procedure:
t-Butyl 4-(4-{2-fluoro-4-[3-(4-fluorophenyl)acetylthioureido]phenoxy}pyridin-2-ylcarbamoyl)piperidine-1-carboxylate (38.8 mg, 0.062 mmol) and trifluoroacetic acid (0.50 ml) gave a crude product of piperidine-4-carboxylic acid (4-{2-fluoro-4-[3-(4-fluorophenyl)acetylthioureido]phenoxy}pyridin-2-yl}amide (ESI-MS (m/z):526). The crude product, formalin (37% aqueous solution; 0.0231 ml), acetic acid (0.0142 ml) and sodium triacetoxyborohydride (26.3 mg) gave the titled compound (1.1 mg, 3.29%) as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC4CCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 115 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.20 g, 1.0 mmol) and 4-(1-acetyl-piperidin-4-yloxy)-benzaldehyde (0.25 g, 1.0 mmol) in N,N-dimethyl acetamide (5 mL), NaHSO3 (0.20 g, 1.1 mmol) and p-TSA (20 mg, 0.10 mmol) were added and the reaction mixture was heated at 115° C. for 16 hours. The reaction mixture was cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water and the solid was collected; the crude product was purified by column chromatography on silica gel (230-400 mesh), using 5% methanol in CH2Cl2 as eluent, to give the title compound. Yield: 0.2 g (47%). MP 275-277° C. 1H NMR (400 Hz, CDCl3): δ 11.94 (s, 1H), 8.16 (d, 2H), 7.10 (d, 2H), 6.70 (d, 1H), 6.50 (d, 1H), 4.76 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.70 (m, 1H), 3.30 (m, 2H), 3.20 (m, 1H), 2.04 (s, 3H), 1.95 (m, 2H), 1.64 (m, 1H), 1.52 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[N:35]1[CH:40]=[CH:39][C:38](CO)=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccncc4)cc3)c2cc1OC
Yield: 13.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-pyridylmethanol (28 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (10 mg, yield 12%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:11]([Mg]Cl)[CH3:12].ClC1C=CC=C(Cl)C=1C[N:19]1C2C(=NC=C(C(O)=O)C=2)C(C)=N1>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:19][N:9]=[C:8]([CH2:11][CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(C(=O)O)cnc12
Reactant: N#Cc1ncc(Br)cc1F
Reactant: CC[Mg]Cl
Product: CCc1n[nH]c2cc(Br)cnc12

Procedure:
The titled compound (225 mg) as a white solid was prepared from 5-bromo-3-fluoropyridin-2-carbonitrile (201 mg) obtained by the method described in the document (Journal of Organic Chemistry, 2009, Vol. 74, p. 4547) and ethylmagnesium chloride according to the methods of the processes (1) and (2) of Example 153.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[C:3]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.C1(=[O:28])CCCCC1.C1([N:35]=[C:36]=[O:37])C=CC=CC=1>C(N(CC)CC)C>[CH3:1][C:2]([CH3:21])=[C:3]1[CH:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[CH:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:36](=[O:37])([O-:28])[NH2:35]
Reactant: O=C1CCCCC1
Reactant: O=C=Nc1ccccc1
Agent: CC(C)=C1C=CC=CC1c1ccc(OCC(O)CO)cc1
Solvent: CCN(CC)CC
Product: NC(=O)[O-]

Procedure:
100 g of phenoxy resin (YP-50, hydroxyl group equivalent=284, Toto Kasei Inc., trade name) and 330 g of cyclohexanone were introduced into a 1 L separable flask fitted with a reflux condenser, thermometer and stirrer, and the mixture heated with stirring to dissolve the resin. Subsequently, 41.9 g phenyl isocyanate and 0.3 g triethylamine were added, and reacted at 130° C. for 3 hours. Next, the product was reprecipitated in ethanol, and dried to give a phenoxy resin to which carbamate had been added. This resin was then dissolved in dimethylformamide (DMF) to give a concentration of 30 mass %, and the resin primer of Example 4 was thus obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][N:26]=1.B(O)O>>[CH3:23][O:24][C:25]1[C:30]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: OBO
Product: COc1ncccc1-c1nc(N2CCOCC2)nc2c1CCN2c1cccnc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@H:26]([OH:29])[CH2:27][NH2:28]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][CH2:27][C@@H:26]([OH:29])[CH3:25])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[C@H](O)CN
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NC[C@H](C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 116 mL of S-(+)-1-amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide. MS (Q1) 397.4 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:20](O)=[O:21])=[O:12].CCN=C=NCCCN(C)C.C1[CH:35]=[CH:36][C:37]2[N:42](O)N=[N:40][C:38]=2C=1.C[N:45]1[CH2:50][CH2:49]O[CH2:47][CH2:46]1>O.CN(C=O)C>[C:38]([CH:37]([NH:42][C:20]([C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]1[NH:13][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[O:21])[CH2:36][C:35]1[CH:47]=[CH:46][N:45]=[CH:50][CH:49]=1)#[N:40]
Reactant: On1nnc2ccccc21
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)O)cc2ccccc21
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)Cc2ccncc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To (1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarboxylic acid from Example 3 (200 mg, 0.67 mmol) was added EDCI (150 mg, 0.78 mmol), HOBT (110 mg, 0.82 mmol), anhydrous DMF (4 mL), N-methylmorpholine (0.15 mL, 1.3 mmol), and 4-pyridylglycine nitrile hydrochloride salt (4) (160 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 20 hrs, then 50 mL of water was added and extracted with three 50 mL portions of ethyl acetate. The combined organic layers was washed with three 50 ml portions of water and three 50 mL portions of saturated NaHCO3, dried over sodium sulfate, filtered and concentrated to give a crude foam. Purification by column chromatography (5:95 methanol:dichloromethane) gave 1-methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(cyano-pyridin-4-ylmethyl-methyl)-carbamoyl]cyclohexyl}-amide ,165 mg, 58%). MS: 430 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[Br:11]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: N#CCc1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(Br)ccc1N
Temperature: 0 °C
Yield: 53.2 %

Procedure:
To a cooled solution of (2-aminophenyl)acetonitrile (13 g, 98 mmol) in dimethylformamide (150 mL) at 0° C., was added N-bromosuccinimide (19.3 g, 108 mmol) in portions for 30 minutes and maintained at 0° C. for 1 hour. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3×100 mL) and saturated sodium chloride (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent to afford (2-amino-5-bromophenyl)acetonitrile (11 g, 53%) as solid. 1HNMR (CDCl3) δ 7.35 (s, 1H), 7.25 (d, 1H), 6.65 (d, 1H). 3.7 (br, 2H), 3.52 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:15])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[OH:16]O>[NH4+].[OH-]>[CH3:15][C:4]1[C:3]([C:1]([NH2:2])=[O:16])=[C:7]([NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[S:6][N:5]=1
Reactant: Cc1nsc(NC(=O)CC(C)C)c1C#N
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nsc(NC(=O)CC(C)C)c1C(N)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of N-(4-cyano-3-methyl-isothiazol-5-yl)-3-methyl-butyramide (method 24) (8 g, 35.8 mmol) in 30% aqueous NH4OH (200 mL), was added dropwise 100 mL of hydrogen peroxide at r.t. After the completion of the addition the reaction mixture was stirred at 60° C. overnight after which the TLC showed the complete disappearance of SM. The reaction mixture was concentrated to 40 mL and extracted with chloroform (3×100 mL). The organic layer was dried (Na2SO4) and concentrated to obtain 3-methyl-5-(3-methyl-butyrylamino)-isothiazole-4-carboxylic acid amide (6.1 g, 71%) as a light yellow solid. 1H NMR (300 MHz) δ 1.03 (d, 6H), 2.24 (m, 1H), 2.43 (d, 2H), 2.69 (s, 3H), 5.98 (bs, 2H), 11.77 (bs, 1H).
Reaction SMILES: CO.[H][H].[O:5]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([C:23](OC)=[O:24])[C:19](OC)=[O:20])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:33][C:34]([NH2:36])=[O:35]>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[CH2:27]([C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][CH:16]=2)[C:23](=[O:24])[NH:36][C:34](=[O:35])[NH:33][C:19]1=[O:20])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCCCCC(C(=O)OC)(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Reactant: NC(N)=O
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCC1(c2ccc(Oc3ccccc3)cc2)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Yield: 66.7 %

Procedure:
Mg(OCH3)2was prepared as follows: To a 25 mL round-bottom flask under argon was added Mg tunings (90 mg, 3.70 mmol), dry CH3OH (2 mL), 2 drops of CCl4 and a catalytic amount of Mg powder. An exothermic reaction took place and hydrogen gas evolution was observed. After the initial exothermic reaction subsided, the reaction mixture was heated to reflux for 1 hour and then cooled to room temperature. Dimethyl 2-(4-phenoxyphenyl)-2-n-hexylmalonate (500 mg, 1.30 mmol) and urea (162 mg, 2.70 mmol) were added to the Mg(OCH3)2. The reaction mixture was heated at 85-90° C. for 1 hour and then excess CH3OH was distilled off until a fluid-paste was obtained and this paste was then heated at 85-90° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc, and washed with 1N HCl. The acidic aqueous layer was re-extracted with EtOAc. The combined EtOAc extracts were washed with water, brine, dried (MgSO4), and concentrated. The resulting oil was purified with HPLC (porasil) using 30% EtOAc/hexanes as eluent to afford 330 mg of 5-n-hexyl-5-(4-phenoxyphenyl)pyrimidine-2,4,6-trione as a white foam: 1H NMR (400 mHz DMSO-d6) δ 11.71 (2NH, s), 7.42-6.99 (9H, m), 2.22 (2H, t), 1.24 (8H, m), 0.85 (3H, t); HRMS Calcd for C22H24N2O4 380.1736; Found 380.1740.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].C(O)C>C(OCC)(=O)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:28][C:27]4[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1ccc(CN2CCC(C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 17.6 %

Procedure:
1.00 gram (3.47 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.52 gram (3.47 millimoles) of p-dimethylaminobenzaldehyde, 0.63 gram (10.0 millimoles) of sodium cyanoborohydride and 10 milliliters of ethanol were stirred together at room temperature for 24 hours. At the end of this period, the mixture was diluted with 150 milliliters of ethyl acetate and the ethyl acetate solution washed successively with two 50 milliliter portions of 15 percent aqueous sodium bisulfite, one 50 milliliter portion of saturated sodium bicarbonate, and one 100 milliliter portion of brine and then dried over magnesium sulfate. The solvent was vaporized from the dried solution in vacuo to obtain a yellow oil. The oil was flash chromatographed on silica gel with 50/50 ethyl acetate/hexane as eluant to obtain 250 milligrams of a colorless oil which crystallized on standing overnight. The product after recrystallization from acetonitrile had a melting point of 163°-165° C. Elemental analyses of the product were as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=2)[O:14][CH:15]=1.[CH2:29](Br)[CH:30]=[CH2:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:26])[CH3:27])[CH:17]=2)[O:14][CH:15]=1)[CH:30]=[CH2:29]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OC(C)C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OC(C)C)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 67 mg quantity of 1-(2-hydroxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 223 was dissolved in 5 ml of dimethylformamide. A 31 μl quantity of allyl bromide and 73 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature overnight. A 50 μl quantity of allyl bromide was further added thereto, and the mixture was stirred at 50° C. for 8 hours, and at room temperature overnight. The reaction mixture was added to water, and extraction was then performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 3:1), and crystallized from n-hexane to give 33 mg of colorless powdery 1-(2-allyloxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:16]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[O:15][C@:8]([O:13][CH3:14])([C:9]([O:11]C)=[O:10])[CH2:7][C@@H:6]1[OH:23])(=[O:3])[CH3:2].[OH-].[Na+:25]>>[C:1]([NH:4][C@H:5]1[C@H:16]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[O:15][C@:8]([O:13][CH3:14])([C:9]([O-:11])=[O:10])[CH2:7][C@@H:6]1[OH:23])(=[O:3])[CH3:2].[Na+:25]
Reactant: COC(=O)[C@]1(OC)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@]1(C(=O)[O-])C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To methyl 5-acetamido-3,5-dideoxy-2-O-methyl-β-D-glycero-D-galacto-2-nonulopyranosonate (3.06 g, 9.07 mmol) was added 0.1N aqueous solution of sodium hydroxide (100 ml, 10.0 mmol) under ice cooling and then the mixture was stirred at room temperature for 22 hours. The reaction mixture was neutralized by addition of Dowex (50 W×8, H+) resin. The resin was filtered off and the filtrate was concentrated to obtain sodium 5-acetamido-3,5-dideoxy-2-O-methyl-β-D-glycero-D-galacto-2-nonulopyranosonate as an oil.