Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5(O)[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][C:18]=4[O:31][CH3:32])=[N:11][C:10]=3[C:9]([CH3:33])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH:24]=5)=[CH:19][C:18]=4[O:31][CH3:32])=[N:11][C:10]=3[C:9]([CH3:33])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C2(O)CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C2=CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 51.4 %

Procedure:
To a 10 ml toluene solution of 160 mg (0.35 mmol) of the compound obtained in Example 122, 135 mg (0.71 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 22 hours with the use of a Dean-Stark dehydrator. The reaction mixture was returned to room temperature, and washed with a saturated aqueous solution of sodium hydrogen carbonate. The system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to obtain 78 mg (51%) of the captioned compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([OH:25])=O)=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([NH:40][C:39]5[CH:41]=[CH:42][C:36]([CH2:35][N:28]([CH:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)[CH3:27])=[CH:37][CH:38]=5)=[O:25])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCCCC4)cc3)ccc2CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCCC5)cc4)ccc3CCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To a solution of 2-(4-piperidinophenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (0.45 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.31 g) and 1-hydroxybenzotriazole (0.18 g) in dimethylformamide (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-chloride (0.37 g) under ice-cooling. Under nitrogen atmosphere, the mixture was warmed to room temperature. To the mixture were added 4-dimethyl-aminopyridine (catalytic amount) and triethylamine (0.54 ml), and the mixture was stirred over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 2-(4-piperidinophenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-6,7-dihydro-5H-benzocyclo-hepten-8-carboxamide (Compound 224) (0.44 g) as pale orange crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=3[C:19]#[N:20])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.F[C:27](F)(F)[C:28](O)=[O:29].C(Cl)(=O)C>>[C:19]([C:18]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:17]=1[O:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][C:28](=[O:29])[CH3:27])[CH2:3][CH2:4]2)[CH2:15][CH2:14]1)#[N:20]
Reactant: N#Cc1cc(F)ccc1OC1CCN(CC[C@H]2CC[C@H](N)CC2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3C#N)CC2)CC1

Procedure:
According to the synthesis of N-Trans(4-{2-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide (example 8), the title compound was prepared from Trans 2-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-5-fluoro-benzonitrile; trifluoroacetic acid salt and acetylchloride MS (m/e): 381.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:31])(=[O:30])[N:25]=CN(C)C)=[CH:20][CH:19]=3)[C:9]=2[CH2:32][N:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:30])(=[O:31])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[CH2:32][N:33]([CH3:35])[CH3:34])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (compound 35c, 1.0 g, 1.87 mmol) was suspended in ethanol (20 ml) and a solution of NaOH (0.37 g, 9.36 mmol) in water (2 ml) was added to it at 25° C. The reaction mixture was heated at 75° C. under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was then diluted with water (5 ml) and cooled using ice bath. To the cooled mixture was then added aqueous 10% HCl to bring pH of the mixture to between 5 and 6. The resulting solid was filtered and dried under reduced pressure to obtain the title compound (0.8 g, 94.78%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:10][N:9]=[C:8]([CH2:19][OH:20])[N:7]=1)=[O:5])C.C(O)C>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][C:8]([CH2:19][OH:20])=[N:9][CH:10]=1
Reactant: CCOC(=O)c1nc(CO)ncc1-c1ccccc1Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc(CO)ncc1-c1ccccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 3.40 g (11.6 mmol) (2-chloro-phenyl)-2-hydroxymethyl-pyrimidine-4-carboxylic acid ethyl ester in 15 ml ethanol 0.69 g (17.42 mmol) NaOH in 15 ml H2O was added and the mixture stirred for 1 hr. The pH of the solution was adjusted to 1 and the solid was filtered off to give after drying 2.80 g (91%) 5-(2-chloro-phenyl)-2-hydroxymethyl-pyrimidine-4-carboxylic acid as a pale brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Br)[CH2:23][CH3:24]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:17])[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[Mg]Br
Reactant: CON(C)C(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-acetamide (10.51 mmol, 3.0 g) in anhydrous THF at 0° C. was added n-propyl magnesium bromide (2.0 M solution in THF, 20 mL) drop-wise over 30 min. After completion of addition, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched by adding saturated aqueous NH4Cl drop-wise followed by addition of ethyl acetate. The organic layer was separated, dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography by eluting with 5% ethyl acetate in hexanes to provide 1-(4-benzyloxy-phenyl)-pentan-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:24])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)nc1
Yield: 34.1 %

Procedure:
To a solution of 6-methyl-nicotinic acid methyl ester (0.54 g, 3.57 mmol) in carbon tetrachloride (10 mL) was added 2,2′-azobis(2-methyl-proprionitrile) (0.030 g, 0.18 mmol) and N-bromosuccinimide (0.703 g, 3.95 mmol). The solution was stirred at reflux for 12 hours, cooled and concentrated in vacuo. Flash chromatography on silica gel provided the title compound (0.28 g).
Reaction SMILES: CC1C=CC(C([O:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([CH:20]([N:26]([CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[NH:10]2)=O)=CC=1.O1CCCC1.[OH-].[Li+].Cl>O>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9](=[O:8])[NH:10][C:11]([CH:20]([N:26]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:44])[CH3:45])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)OC2NC(C(C(=O)N(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)c3ccc(C)cc3)=Nc3cc(Cl)ccc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[1-[{3-[(tert-butoxycarbonyl)amino]propyl}(4-methylbenzoyl)amino]-2-(dimethylamino)-2-oxoethyl]-7-chloro-3,4-dihydroquinazolin-4-yl 4-methylbenzoate in a 1:1 mixture of tetrahydrofuran and water (20 ml), was added lithium hydroxide (284 mg, 2 eq.) at room temperature. The mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with 1M of aqueous hydrogen chloride to pH 6-7 and later extracted into methylene chloride. The organic layer was washed with more water, dried over magnesium sulfate, filtered and concentrated. The product was purified by flash chromatography to give tert-butyl 3-[[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]-propylcarbamate (257 mg) as a yellow solid.
Reaction SMILES: [NH:1]([N:41]=[N+:42]=[N-:43])[C@H:2]([C:10]([NH:12][C@H:13]([C:29]([NH:31][C@H:32]([C:37]([O:39]C)=O)[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[NH2:45][NH2:46]>CO>[NH:1]([N:41]=[N+:42]=[N-:43])[C@H:2]([C:10]([NH:12][C@H:13]([C:29]([NH:31][C@H:32]([C:37]([NH:45][NH2:46])=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-]
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-])C(=O)NN
Reaction time: 8 h

Procedure:
N3-Phe-Phe(4-NHBoc)-Leu-OMe (160 mg, 276 μmol) was dissolved in MeOH and hydrazine hydrate (800 μl, 16.6 mmol, 60 equiv.) was added and the mixture was stirred overnight. Co-evaporation with toluene (3×) yielded the title compound which was used without further purification. LC/MS: Rt 7.54 minutes (linear gradient 10->90% MeCN+0.1% TFA, 15 minutes), (ESI-MS (m/z): 581.13. 1H NMR (400 MHz, CD3OD): δ ppm 7.40-7.17 (m, 7H), 7.02 (d, J=8.5 Hz, 2H), 4.61 (t, J=7.0 Hz, 1H), 4.35 (t, J=7.3 Hz, 1H), 4.13 (dd, J=8.6, 4.8 Hz, 1H), 3.15 (dd, J=14.0, 4.7 Hz, 1H), 3.00-2.81 (m, 3H), 1.60-1.45 (m, 3H), 1.51 (s, 9H), 0.93 (d, J=6.0 Hz, 3H), 0.89 (d, J=5.9 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]([NH:12][CH:13]=[C:14]([C:20](=[O:27])[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:15]([O:17]CC)=O)=[CH:10][CH:9]=[N:8]1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:27])[C:15]([OH:17])=[C:10]2[CH:9]=[N:8]1
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)c1cccnc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: O=C(c1cccnc1)c1cnc2c(cnn2Cc2ccco2)c1O
Temperature: 25 °C

Procedure:
7.3 g. of α-[[[1-(2-furanylmethyl)- 1H-pyrazol-5-yl]-amino]methylene]-β-oxo-3-pyridinepropanoic acid, ethyl ester (0.02 mol.) are heated in 20 ml. of diphenylether at 250° for 10 minutes. The mixture is cooled to room temperature and 20 ml. of ether are added. The product, [1-(2-furanylmethyl)-4-hydroxy-1H-pyrazolo]3,4 -b]pyridin-5-yl]-3-pyridylmethanone precipitates and is recrystallized from butyl alcohol, yield 3.8 g. (60%); m.p. 152°-153°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>S(=O)(=O)(O)O>[F:5][C:6]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Yield: 93 %

Procedure:
A mixture of 70% nitric acid and concentrated sulfuric acid (1:1, 30 mL) is added dropwise over 30 min to a solution of 2-fluorobenzonitrile (12.11 g, 0.10 mol) in concentrated sulfuric acid (50 mL), stirred under N2 at 0° C. After a further 3 h at 0° C. the yellow solution is poured onto ice (400 g), and the solid is collected by Buchner filtration, rinsed with water (4×50 mL), and dried in vacuo to give 2-fluoro-5-nitrobenzonitrile (15.43 g, 93%) as a pale yellow crystalline solid. 1H NMR (CDCl3) δ8.56 (1H, dd, J=2.8, 5.5 Hz), 8.51 (1H, ddd, J=2.8, 4.4, 9.1 Hz), 7.44 (1H, dd, J=7.8, 9.0 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[N:1]1([C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
To a solution of ethyl piperidine-3-carboxylate (4 g, 25.4 mmol) in THF (30 mL) and water (30.0 mL) was added Na2CO3 (6.74 g, 63.6 mmol). The resulting suspension was stirred at rt for 20 min. After this time, benzyl carbonochloridate (4.12 g, 24.17 mmol) was added in dropwise. After addition, the stirring solution became milky, then white precipitates formed. After stirring at rt for 2 h, the reaction was partitioned between EtOAc and water. The separated aqueous phase was extracted with EtOAc (2×). The combined organics were washed with water and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The oily residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex. The desired fractions were concentrated to afford the desired product, 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (5.68 g, 19.50 mmol, 77% yield) as a colorless oil. Anal. Calcd. for C16H21NO4 m/z 291.3, found: 292.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.28 (m, 5 H), 5.26-4.97 (m, 2 H), 4.34-4.06 (m, 3 H), 4.06-3.91 (m, 1 H), 3.13 (br. s., 1 H), 2.96-2.81 (m, 1 H), 2.46 (br. s., 1 H), 2.15-1.96 (m, 1 H), 1.78-1.56 (m, 2 H), 1.49 (br. s., 1 H), 1.33-1.17 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][C:21]#[N:22]>C(O)C>[CH3:4][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:20][C:21]#[N:22])([CH3:1])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of (3-aminopropyl)carbamic acid 1,1-dimethylethyl ester (6.00 g, 34 mmol), prepared by the method of Saari et al., J. Med. Chem., 33, 97 (1990), in absolute ethanol (90 mL) was treated with sodium carbonate (3.96 g, 37 mmol) followed by a solution of bromoacetonitrile (2.6 mL, 37 mmol) in ethanol (30 mL) over 45 min. After stirring at room temperature overnight, the contents of the flask were filtered, preadsorbed onto silica gel, and purified by flash chromatography (7 cm diameter, elution with 2.5% methanol in dichloromethane) to afford [3-(cyanomethylamino)propyl]carbamic acid 1,1-dimethylethyl ester as a yellow oil (3.99 g, 55%); IR (neat, cm-1): 3330, 2240, 1700; MS (+CI): 214 (MH+, 20), 187 (76), 158 (100), 131 (44); 1H NMR (CDCl3, 400 MHz): δ 4.80 (br s, NH), 3.61 (s, 2H), 3.22 (q, J=6.5 Hz, 2H), 2.79 (t, J=6.5 Hz, 2H), 1.69 (p, J=6.5 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]1[CH2:8][CH2:7][CH2:6][N:5]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.[N-]=C=O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:3][C:4]2[CH2:8][CH2:7][CH2:6][N:5]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: NC1=NCCC1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [N-]=C=O
Agent: [Na]
Solvent: CC(C)=O
Product: O=C(NC1=NCCC1)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 15.3 g. sodium in 1900 ml. dry acetone, 80 g. 2-amino-1-pyrroline hydrochloride, and 102 g. 4-chlorophenyl isocyanate in 500 ml. dry acetone, except that ice-bath cooling was applied during the addition of the isocyanate, there was obtained after recrystallization from ethyl acetate 66 g. 1-(4-chlorophenyl)-3-(1-pyrrolin-2-yl)urea; m.p. 147°-150° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)nc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(OC)cn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (1.38 g) in ethyl acetate (6 mL) and 2-propanol (3 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (9 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 1.06 g, 88%).
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.Cl.O1CCOC[CH2:13]1>CO>[OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:13])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(O)cn1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnc(O)cn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Commercially available 5-hydroxypyrazine-2-carboxylic acid (1.00 g, 7.14 mmol) was dissolved in methanol (5 mL), and a 4N hydrochloric acid/dioxane solution (25 mL) was added, followed by stirring at 60° C. for 1.5 hours and heating to reflux at 80° C. for 2.5 hours. The reaction solution was brought back to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate (20 mL) was added to the resulting residue to allow it to be suspended. The resulting precipitate was filtered off, and washed with ethyl acetate, followed by vacuum drying, to afford the desired compound (673 mg, yield 61%) as an orange-brown solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:16]([O:19][C:20](Cl)=[O:21])[CH:17]=[CH2:18]>O>[CH2:16]([O:19][C:20]([NH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:21])[CH:17]=[CH2:18]
Reactant: NCc1ccc(OCC(=O)O)cc1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)NCc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.97 g of 4-aminomethylphenoxyacetic acid is suspended in 15 ml of water, 2.4 ml of 5N NaOH solution are added thereto and, after cooling with ice, 0.63 ml of chloroformic acid allyl ester is added thereto over a period of 5 minutes After removing the cooling bath, the reaction mixture is stirred at room temperature for 20 minutes. The reaction mixture is then washed twice with ethyl acetate, and the aqueous phase is adjusted to pH 2 with 4N HC1 and extracted with ethyl acetate. The organic solution is washed with brine and dried over sodium sulphate. The title compound is obtained after evaporating off the solvent.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].O>C(#N)C>[C:1]1([CH2:7][C:8]([N:13]=[C:12]=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ccccc1)N=C=S
Temperature: 80 °C

Procedure:
According to the descrition of technical literature, commercially available 2-phenylethanoyl chloride (80 mg) was dissolved in acetonitrile (20 ml). Potassium thiocyanate (300 mg) was added to the solution, and the mixture was heated at 80° C. for 2 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated to give 2-phenylethanoyl isothiocyanate. 2-Phenylethanoyl isothiocyanate thus obtained was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 85%) (Referenc: Elmore, D. T. et al., Journal of chemical Society 1956, 4458).
Reaction SMILES: I[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[N:10]=[N:11][N:12]3[C:17]=2[C:16]2[CH:18]=[CH:19][NH:20][C:15]=2[N:14]=[CH:13]3)[CH2:5][CH2:4]1.[F:21][C:22]([S:25]([O-:27])=[O:26])([F:24])[F:23].[Na+].O>CN(C)C=O>[F:21][C:22]([F:24])([F:23])[S:25]([CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[N:10]=[N:11][N:12]3[C:17]=2[C:16]2[CH:18]=[CH:19][NH:20][C:15]=2[N:14]=[CH:13]3)[CH2:5][CH2:4]1)(=[O:27])=[O:26]
Reactant: IC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: O=S([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1)C(F)(F)F

Procedure:
1-[trans-4-(Iodomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine (50.0 mg, 0.131 mmol) and sodium trifluoromethylsulfinate (205 mg, 1.31 mmol) in N,N-dimethylformamide (3 mL) were stirred at 100° C. for 26 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2→1/1 (v/v)) and preparative HPLC (Waters XBridge Prep C18 μm ODS, 19×100 mm, acetonitrile/0.1% aqueous formic acid solution=20/80→80/20(v/v)) to give the title compound as a colorless solid (6.30 mg, yield 12%).