Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([C@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)C(Br)C(=O)O
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Product: CC(C)[C@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-3-methylbutyric acid according to Method D3.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38](Cl)[S:39][CH:40]=2)=[O:35])[CH3:32])[CH:22]=[C:23]([F:30])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:23]1[CH:22]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38]([C:5]3[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)[S:39][CH:40]=2)=[O:35])[CH3:32])[CH:20]=[C:19]([F:18])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 28.2 %

Procedure:
3,5-Bis(trifluoromethyl)phenylboronic acid (67.1 mg, 0.26 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (21 mg, 28%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[CH2:23]1>C1(C)C=CC=CC=1>[CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[CH2:23][C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[C:26]([OH:28])=[O:27])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Yield: 71.3 %

Procedure:
A solution of 2.1 g of (E)-3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]benzeneamine, 1.25 g of homophthalic anhydride and 30 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 2.31 g of (E)-2-[2-[3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 189°-190° C. from tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccc(C)c(C2CC(=O)c3c(C)ccnc3C2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)c1
Yield: 97.1 %

Procedure:
A mixture of 7-(2,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (100 mg), aminoguanidine hydrochloride (46 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (2 ml) was refluxed for 1 hour and 30 minutes. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dimethylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 58) (131 mg) as pale yellow crystals.
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C@@H:19]([CH2:27][N+:28]([O-:30])=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=O)=CC=1)([O-])=O.C(O)(=O)C>C(O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:19]([C@@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]2[OH:12])[CH2:27][N+:28]([O-:30])=[O:29])=[CH:21][CH:22]=1
Reactant: O=C(O[C@@H]1CCCC[C@H]1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])C[C@@H](c1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 490 ml (12.1 mmol) of sodium hydroxide in 40 ml of ethanol is added dropwise to a solution of 3.5 g (8.09 mmol) of rac-(1R*)-trans-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexyl p-nitrobenzoate in 80 ml of ethanol. The mixture is stirred at room temperature for 16 hours, treated with 1 ml of acetic acid and the solvent is distilled off in a water-jet vacuum. The residue is treated with water, whereupon the mixture is extracted twice with 100 ml of ether each time. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on a 30-fold amount of silica gel and there is obtained rac-(1R*)-trans-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanol in the form of a yellowish oil.
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[CH:16][CH:17]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C(C)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(NC(C)c2ccccc2)cc1

Procedure:
N-(α-methyl benzylidene)-p-anisidine (VII) prepared by the procedure described in example IVA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent to give N-(α-methyl benzyl)-p-anisidine (VIII). VIII had a melting point of 64° C.
Reaction SMILES: C(O[C@H]1CN(C2N=CC=CN=2)C[C@H]1NC1C(CC)=NC([C:24]2[C:25](C)=[N:26][C:27](OC)=[CH:28][CH:29]=2)=C(CC)N=1)C.BrC1C=CC=CN=1.[CH3:42][N:43]([CH3:70])[C:44]1[N:49]=[CH:48][C:47]([C:50]2[N:51]=[C:52]([CH2:67][CH3:68])[C:53]([NH:58][C@H:59]3[C@@H:63]([O:64][CH2:65][CH3:66])[CH2:62][NH:61][CH2:60]3)=[N:54][C:55]=2[CH2:56][CH3:57])=[C:46]([CH3:69])[CH:45]=1>>[CH3:70][N:43]([CH3:42])[C:44]1[N:49]=[CH:48][C:47]([C:50]2[N:51]=[C:52]([CH2:67][CH3:68])[C:53]([NH:58][C@H:59]3[C@@H:63]([O:64][CH2:65][CH3:66])[CH2:62][N:61]([C:25]4[CH:24]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:60]3)=[N:54][C:55]=2[CH2:56][CH3:57])=[C:46]([CH3:69])[CH:45]=1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Agent: Brc1ccccn1
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromo pyridine and 5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.19, 7.99, 7.47, 6.58, 6.46, 6.41, 5.25, 4.90, 4.25, 4.02, 3.80–3.72, 3.55, 3.40, 3.13, 2.70, 2.54, 2.12, 1.29, 1.16; IR (liq.) 2969, 2930, 2871, 2414 (w), 1941 (w), 1602 (s), 1558 (s), 1490 (s), 1474 (s), 1443 (s), 1395 (s), 1374, 1166, 1124, 770 cm−1 HRMS (ESI) calcd for C27H37N7O+H1 476.3138. found 476.3134.
Reaction SMILES: O[CH:2]([CH2:7][CH:8]([S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH3:9])[CH2:3][C:4](=[O:6])[CH3:5].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:11]([S:10][CH:8]([CH3:9])[CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:12][CH:13]=1
Reactant: CC(=O)CC(O)CC(C)Sc1ccc(C(F)(F)F)cc1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCC(C)Sc1ccc(C(F)(F)F)cc1
Yield: 94.7 %

Procedure:
13.58 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-heptanone were dissolved in 150 ml of toluene, and 1.0 g of oxalic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 12.65 g of 6-(4-trifluoromethylphenylthio)-3-hepten-2-one (trans : cis =6.7 : 1) was obtained (purity: 95.4%) having an nD21 of 1 5101. The yield was 94.7%.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:38][C:39]1[C:40]([O:46][CH3:47])=[N:41][C:42](I)=[N:43][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C(#N)C.C1COCC1.O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:38][C:39]1[C:40]([O:46][CH3:47])=[N:41][C:42]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@H:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:26][CH:25]=2)=[N:43][CH:44]=1
Reactant: COc1nc(I)ncc1Br
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1nc(-c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)ncc1Br
Temperature: 110 °C
Yield: 60 %

Procedure:
Prepared using General Procedure 10: A mixture of tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-13 (30.0 mg, 0.06 mmol), 5-bromo-2-iodo-4-methoxypyrimidine (22.3 mg, 0.07 mmol), and sodium carbonate (12.5 mg, 0.12 mmol) in acetonitrile (0.80 mL), THF (0.80 mL) and H2O (0.40 mL) was degassed for 10 min. Pd(dppf)Cl2:CH2Cl2 (5 mg, 0.005 mmol) was added and the reaction mixture heated at 110° C. in a microwave for 30 min. Once cooled, the reaction was diluted with NaHCO3 (5 mL), extracted with EA (3×5 mL) and the combined organics dried over MgSO4 and concentrated. The residue was purified by column chromatography (EA/hexanes) to afford 20.0 mg (60%) of tert-butyl (S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate as a white solid. LCMS-ESI (m/z) calculated for C29H34BrN3O4: 568.5. found 514.2 [M−tBu+H]+, tR=11.0 min. (Method 2).
Reaction SMILES: C1(CCCCC[C@H:12]([C@@H:16]([NH:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:17])[C:13]([OH:15])=[O:14])C=CC=CC=1.[C:26](OC=O)(=[O:28])C>N1C=CC=CC=1>[CH:26]([N:18]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH:16]([CH3:17])[CH2:12][C:13]([OH:15])=[O:14])=[O:28]
Reactant: CC(=O)OC=O
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCCCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Product: CC(CC(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of (2R,3S)-2-(5-phenyl-1-pentyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (105 mg, 0.30 mmol) in pyridine (1.5 mL) at 0° C. is added formic acetic anhydride (0.3 mL). The resulting solution is allowed to warm to 25° C., stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-(5-phenyl-1-pentyl)-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (105 mg, 92% yield).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[N:15]=[C:14]2[NH:16][C:17](=O)[N:18]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[C:19](=[NH:20])[C:13]2=[CH:12][N:11]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:9][C:10]1[N:15]=[C:14]2[N:16]([CH3:17])[C:1](=[O:4])[N:18]([C:21]3[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=3[Cl:27])[C:19](=[NH:20])[C:13]2=[CH:12][N:11]=1
Reactant: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
484 mg of potassium carbonate and 456 mg of methyl iodide were added to a 5-mL N,N-dimethylformamide solution containing 1.00 g of the 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 1, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was added to ethyl acetate and a 0.5 N hydrochloric acid aqueous solution with stirring to separate the organic layer. After washing with saturated saline, the solution was dried with anhydrous sodium sulfate, and the solvent was distilled away. The crude product was solidified using chloroform-methanol-hexane, and 700 mg of a yellow solid was obtained as a subject compound.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.[O:44]1[CH2:49][CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH2:46][CH2:45]1>>[O:44]1[CH2:45][CH:46]=[C:47]([C:2]2[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][N:20]=4)[N:15]=[CH:14][CH:13]=3)=[O:10])[CH:5]=[CH:4][CH:3]=2)[CH2:48][CH2:49]1
Reactant: O=C(Nc1cccc(I)n1)Nc1ccnc2cccnc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: O=C(Nc1cccc(C2=CCOCC2)n1)Nc1ccnc2cccnc12

Procedure:
The title compound was prepared as described in example 27 step 2, substituting 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea by 1-(6-iodopyridin-2-yl)-3-(1,5-naphthyridin-4-yl)urea (example 58, step 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate by 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:20][CH2:19]1)[C:16](O)=[S:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:21]([N:23](CC)CC)[CH3:22].CC(OC(=S)C1OC1)CCCCCCCCCCCC.C([NH+](CC)CC)C.ClC(OCC)=O.C(N)C>O1CCCC1>[CH2:21]([NH:23][C:16](=[S:17])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])[O:20][CH2:19]1)[CH3:22]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCC(C)C1(C(O)=S)CO1
Agent: CCCCCCCCCCCCC(C)OC(=S)C1CO1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(C)C1(C(=S)NCC)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.3 g (0.001 mole) of 2-tetradecylthioglycidic acid in 10 ml of anhydrous tetrahydrofuran (THF) at 0° C. (ice-water bath) is added 1.01 g (0.001 mole) of triethylamine in a small amount of THF. The mixture is stirred at 0° C. for about 30 minutes. To the thus-formed triethylammonium 2-tetradecylthioglycidate is added 0.108 g (0.001 mole) of ethyl chloroformate in small amount of THF and the mixture is stirred at about 0° C. (ice-water bath) for about 3 hours to prepare the corresponding mixed anhydride (a ppt. of Et3NHCl is observed). A stoichiometric excess of ethylamine in THF is then added and the mixture stirred at room temperature for 16 hours. The THF solvent is concentrated to approximately 1/4 volume, water is added and the mixture extracted with ether. After drying the ether extract (Na2SO4), the solvent is removed in vacuo giving the desired product, N-ethyl-2-tetradecylthioglycidamide, in good yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[O:19][N:18]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2noc(-c3ccc(OCc4ccccc4)cc3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2noc(-c3ccc(O)cc3)n2)cc1
Reaction time: 95 h
Yield: 8 %

Procedure:
5-(4-(Benzyloxy)phenyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (50 mg, 139 μmol) and 10% Pd/C (1 mg, 10 μmol) were suspended in methanol (3.0 mL) and THF (3.0 mL). The solution was stirred in a round bottom flask fitted with a condenser and septa and placed under H2 at 55° C. for 95 hours. The solution was filtered through Celite and the solvent was removed under reduced pressure and then purified by silica gel column chromatography (EtOAc/Hex 1:2) to give the product (3 mg, 9%) as a white solid. 1H NMR (500 MHz, CDCL3) δ(ppm): 3.88 (3H, s), 5.55 (1H, s), 6.98 (2H, d, J=9.0 Hz), 7.01 (2H, d, J=8.4 Hz), 8.01 (2H, d, J=9.0 Hz), 8.12 (2H, d, J=8.2 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 55.6 (CH3), 114.4 (CH), 116.3 (CH), 117.4, 119.7, 129.3 (CH), 130.6 (CH), 159.6, 162.1, 168.7, 175.4. MS (FAB+): 269 (MH+). HRMS for C15H12N2O3 (MH+): calculated: 269.0926; found 269.0929.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].ClS([N:20]=[C:21]=[O:22])(=O)=O>ClCCl>[C:21]([O:1][CH:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:22])[NH2:20]
Reactant: CCOC(=O)C#CC(O)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C#CC(OC(N)=O)c1ccccc1
Yield: 98 %

Procedure:
To 100 ml of a dichloromethane solution containing 8 g (39.2 millimoles) of ethyl 4-hydroxy-4-phenyl-2-butynoate, 3.5 ml (40.2 millimoles) of chlorosulfonyl isocyanate was added at a temperature of -20° C., and the mixture was reacted for 30 minutes at -10° C. under stirring. Then, hydrolysis and purification treatment were conducted in the same manner as in Example VI-38, whereby 9.5 g (yield: 98%) of ethyl 4-carbamoyloxy-4-phenyl-2-butynoate in crystal form was obtained.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[N:16]12[CH2:24][CH:20]([C:21](=O)[CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(CC)CC)C.[C:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:33].[ClH:40]>O.C1(C)C=CC=CC=1>[ClH:40].[N:16]12[CH2:24][CH:20]([C:21](=[C:34]([C:32]#[N:33])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:22]1)[CH2:19][CH2:18][CH2:17]2
Reactant: O=C1CN2CCCC1C2
Reactant: CCOC(=O)CC#N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=C1CN2CCCC1C2
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(+) 1-Azabicyclo[3.2.1]octan-6-one (-) camphorsulfonate (61.8 g, 135.0 mmol) and triethylamine (20.4 g, 202 mmol) and ethyl cyanoacetate (61.8 g, 547 mmol) were mixed and stirred at room temperature for 6 days. Toluene (120 ml) and water (120 ml) were added to the reaction mixture and the pH was adjusted to 2 with concentrated hydrochloric acid. The phases were separated and the water phase extracted with toluene (30 ml). The combined organic phases were washed with water (20 ml). The combined water phases were adjusted to pH=9.4 with NH3 (25% in water) and extracted with toluene (1×120 ml, 1×60 ml). The combined toluene extracts were evaporated. The residue was dissolved in ethanol (120 ml) and concentrated hydrochloric acid (16 ml) was added. The title compound precipitated in 22 g yield. Upon evaporation of the mother liquor and crystallization from ethanol (40 ml) further 14.6 g of the title compound was isolated.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.Br[C:29]([CH3:31])=[CH2:30]>>[CH:29]([O:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)([CH3:31])[CH3:30]
Reactant: C=C(C)Br
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OC(C)C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) and 2-bromopropene following the procedure described for Example 264. 1H-NMR (CDCl3, 200.15 MHz): δ 7.14 (d, 2H, J=8.3), 6.86–6.82 (m, 6H), 4.40 (qn, 1H, J=5.9), 4.11 (q, 4H, J=5.9), 3.98 (dd, 1H, J=7.3, 4.6), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.3), 3.01–2.90 (dd, 1H, J=14.2, 7.2), 2.22 (qn, 2H, J=5.9), 1.30 (d, 6H, J=6.2).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Yield: 104.8 %

Procedure:
To a solution of 1-acetylpiperazine (48 g) in acetonitrile (100 ml) were added 2,5-difluoronitrobenzene (50 g) and potassium carbonate (44 g) and the mixture was refluxed under heating for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give the title compound (88 g) as a red solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS[C:28](=[NH:33])[NH:29][N+:30]([O-:32])=[O:31].C(#N)C>CO>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:28]([NH2:33])=[N:29][N+:30]([O-:32])=[O:31])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: COc1ccc(N)cc1CNC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(NC(N)=N[N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Yield: 32.7 %

Procedure:
A mixture of the compound (130 mg) obtained in Example 119, triethylamine (0.09 ml), S-methyl-N-nitroisothiourea (84 mg), acetonitrile (3 ml) and methanol (1 ml) was heated under reflux for 20 h. The reaction mixture was distilled under reduced pressure and the residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=1:1) to give 57.2 mg of the titled compound (yield, 33%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][C:22](=[O:23])[NH:14][N:13]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NNC(=O)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2ccc3ccccc3c2)o1
Temperature: 0 °C
Reaction time: 17 h
Yield: 96.9 %

Procedure:
To a stirred mixture of naphthalene-2-carboxylic acid hydrazide (2.0 g, 10.7 mmol, prepared as described in example 1) and triethylamine (1.1 g, 10.7 mmol) in dry tetrahydrofuran (40 ml) was added carbonyl diimidazole (2.2 g, 13.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 17 h. The resulting reaction mixture was evaporated in vacuo and to the residue was added water (50 ml) and ethyl acetate (50 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride (2×25 ml), dried (MgSO4) and filtered and evaporated in vacuo affording 2.2 g of crude product which was recrystallised from a mixture of ethyl acetate and heptane 1:1 (60 ml) affording after drying in vacuo at 50° C. 1.2 g (52%) of the title compound as a solid.