Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[S:8][C:7]=2[CH:16]=1)[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=2[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(CC)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc2cc(C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
The above 6-ethyl-2-ethoxycarbonylbenzo[b]thiophene (1.26 g) was dissolved in tetrahydrofuran (4 ml) and methanol (8 ml), and added thereto was lithium hydroxide monohydrate (677 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in water and the solution was made acidic with a 10% aqueous hydrochloric acid solution. The precipitates were collected by filtration and washed with water to give 6-ethylbenzo[b]thiophen-2-ylcarboxylic acid (1.15 g) as colorless crystals. ESI-1-Mass m/Z 205 (M−H). (4) The above 6-ethylbenzo[b]thiophen-2-ylcarboxylic acid was tread in a manner similar to Reference Example 47-(2) to give the desired 6-ethylbenzo[b]thiophene as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:25])[C:15]([C:22]([OH:24])=[O:23])=[CH:16][N:17]2[CH2:20][CH3:21])=[CH:12][C:11]=1[F:26]>N1C=CC=CC=1>[ClH:9].[CH2:20]([N:17]1[C:18]2[C:13](=[CH:12][C:11]([F:26])=[C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH:3]([CH2:2][OH:1])[CH2:8]3)[CH:19]=2)[C:14](=[O:25])[C:15]([C:22]([OH:24])=[O:23])=[CH:16]1)[CH3:21]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: OCC1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CO)C3)cc21
Product: Cl
Temperature: 130 °C

Procedure:
A mixture of 2 g of 2-hydroxymethylpiperazine, 1 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 8 ml of pyridine was heated at 130° C. in a sealed bottle, under argon, overnight. The solvent was removed and the residue adsorbed onto silica gel, then added to a column of flash grade silica gel. The column was eluted with methanol:water (95:5). The product fraction was collected, dissolved in methanoldichloromethane and converted to the hydrochloride salt, mp >275° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:44][CH2:45][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:47][CH2:48]2)=[CH:39][CH:38]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc2N2CCCCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (95.0 mg, 0.41 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was cooled to room temperature and purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield the title compound (57.3 mg, 32%) as a white solid. 1H NMR (DMSO-d6) δ: 13.44 (br. s., 1H), 10.82 (s, 1H), 9.52 (br. s., 1H), 7.84 (d, J=2.0 Hz, 1H), 7.36-7.42 (m, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H), 4.58 (d, J=13.1 Hz, 1H), 4.21 (d, J=4.5 Hz, 2H), 3.97 (dd, J=11.6, 2.8 Hz, 1H), 3.46 (d, J=11.6 Hz, 2H), 2.96-3.07 (m, 2H), 2.79-2.85 (m, 1H), 2.67 (td, J=12.8, 2.7 Hz, 1H), 2.06-2.10 (m, 1H), 1.95-2.02 (m, 2H), 1.72-1.91 (m, 3H), 1.64-1.67 (m, 1H), 1.33-1.58 (m, 3H). [M+H] calc'd for C23H27ClN4O, 411. found, 411.
Reaction SMILES: Br[CH2:2][C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:26]([O-])([O-])=O.[K+].[K+].[I-].[Na+]>C(#N)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[N:12][C:3]=1[CH:2]([N:23]1[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]1)[CH3:26]
Reactant: BrCc1ncc2ccccc2n1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(c1ncc2ccccc2n1)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 41.9 %

Procedure:
To a mixture of the title compound from Step C (240 mg, 1.01 mmol) and N—BOC-piperazine (189 mg, 1.01 mmol), in acetonitrile (5 ml) was added K2CO3 (210 mg, 1.52 mmol) and sodium iodide (152 mg, 1.01 mmol) and the resulting mixture heated at reflux overnight. The mixture cooled and partitioned between water and EtOAc; organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue purified by column chromatography (eluent: 5% MeOH in DCM) to afford the title compound 145 mg (42%) as an orange oil, which solidified on standing. 1H NMR (CDCl3): 1.45 (s, 9H), 1.60 (d, J 6.8 Hz, 3H), 2.46 (m, 2H), 2.69 (m, 2H), 3.49 (m, 4H), 3.97 (q, J 6.8 Hz, 1H), 7.66 (m, 1H), 7.93 (m, 2H), 8.06 (d, J 8.3 Hz, 1H), 9.44 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C1C[O:29]CC1.C(#N)C>CCOC(C)=O>[OH:29][C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]1[C:4](=[O:3])[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)=[C:6]([CH3:14])[C:7](=[O:13])[C:8]=1[CH3:12]
Reactant: C1CCOC1
Reactant: Cc1c(O)c(C)c(-c2ccc(C(F)(F)F)cc2)c2c1CCC(C)(C)O2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1=C(CCC(C)(C)O)C(=O)C(c2ccc(C(F)(F)F)cc2)=C(C)C1=O

Procedure:
The purified residue containing 2,2,5,7-tetramethyl-8-(4-(trifluoromethyl)phenyl) chroman-6-ol from the above reaction (60 mg) was dissolved in THF/acetonitrile (1:1, 2 ml) and cooled in an ice-water bath. To the resulting solution was added dropwise an aqueous solution of ceric ammonium nitrate (170 mg, 310 μmol in 1 mL) until a reddish color persisted. When the titration endpoint was reached, the mixture was diluted in 5 mL EtOAc, washed once with brine (2 mL). The remaining organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (5→25% EtOAc/hexanes) producing 80 mg of 2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-(4-(trifluoromethyl)phenyl)cyclohexa-2,5-diene-1,4-dione, a yellow oil. 1H NMR (CDCl3, 400 MHz) 7.67 (d, 2H), 7.26 (d, 2H), 2.60 (m, 2H), 2.11 (s, 3H), 1.92 (s, 3H), 1.54 (m, 2H), 1.25 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[P:5]([CH2:10][CH:11]([F:17])[C:12](OCC)=[O:13])([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[NH4+:21]>C(O)C>[NH2:21][C:12](=[O:13])[CH:11]([F:17])[CH2:10][P:5]([CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])(=[O:6])[O:7][CH2:8][CH3:9]
Reactant: CCOC(=O)C(F)CP(=O)(OCC)C(OCC)OCC
Reactant: [NH4+]
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(F)C(N)=O)OCC
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-2-fluoropropanoate (16.0 g, 51.1 mmol) in ethanol (22 mL) was added concentrated ammonium hydroxyde (14.8 N, 3.5 mL, 51.1 mmol). The solution was stirred for 16 h and evaporated. The residue was purified by chromatography on a wet-packed silica gel column (7×37 cm) eluting with 96.5:3.5 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 3.43 g (27%) of ethyl (3-amino-2-fluoro-3-oxopropyl)(diethoxymethyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 5.70 (s, 1H), 5.21-5.49 (dm, 1H), 4.7 (dd, 1H), 4.18-4.31 (m, 2H), 3.65-3.91 (m, 4H), 2.21-2.81 (m, 2H), 1.30-1.40 (m, 3H), 1.20-1.28 (m, 6H).
Reaction SMILES: [CH2:1]1[C@@H:8]2[C@@H:4]([CH2:5][C:6](=[O:9])[CH2:7]2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]([CH3:17])([CH2:15]O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:17])[CH2:13][O:14][C:6]2([CH2:7][CH:8]3[CH:4]([CH2:3][C:2](=[O:10])[CH2:1]3)[CH2:5]2)[O:9][CH2:15]1
Reactant: CC(C)(CO)CO
Reactant: O=C1C[C@H]2CC(=O)C[C@H]2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC2(CC3CC(=O)CC3C2)OC1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
To a of solution cis-tetrahydropentalene-2,5-(1H,3H)-dione (2.99 g, 21.6 mmol) and 2,2-dimethylpropane-1,3-diol (2.254 g, 21.6 mmol) in toluene (70 mL) was added p-toluenesulfonic acid monohydrate (0.206 g, 1.08 mmol) and the mixture was heated at 110° C. for 24 hrs with a Dean Stark apparatus. The reaction mixture was cooled to room temperature, poured over solid K2CO3, stirred 5 mins then filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (12 to 100% EtOAc in hexanes) to give 5,5-dimethyltetrahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′(3′H)-one (2.224 g, 9.92 mmol, 45.8% yield) as a colorless oil which solidified upon standing. MS ESI: [M+H]+ m/z 225.7.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].Cl>C(O)C>[N+:14]([C:11]1[CH:10]=[C:6]2[C:5](=[CH:13][CH:12]=1)[NH:3][NH:2][C:7]2=[O:8])([O-:16])=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Yield: 45 %

Procedure:
Hydrazine hydrate (4 mL, 124 mmol) was added to a solution of 2-chloro-5-nitro benzoic acid (5 g, 24.8 mmol) in absolute ethanol (30 mL), and the resulting mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure. Residue was triturated with methanol to give 6.5 g of crude intermediate. 2N aq. HCl (40 mL) was added to the crude product, and the mixture was refluxed for 8 h. Reaction mixture was cooled to 0° C., solids were collected via filtration, washed with cold water and dried under vacuum. Residue was purified by flash chromatography using 1% methanol in chloroform as eluent to afford title compound (2 g, 27%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.4 (bs, 1H), 11.3 (bs, 1H), 8.67 (s, 1H), 8.12 (dd, J1=2.1 Hz, J2=9.0 Hz, 1H), 7.5 (d, J=9.0 Hz, 1H); ESI-MS m/z: 179 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+:2]=[N-:3].[O:28]1[CH:32]=[CH:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:7]2[C:8]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[O:10])=[C:4]([N:1]3[CH:32]=[C:31]([CH2:30][CH2:29][OH:28])[N:3]=[N:2]3)[CH2:5][C@H:6]12)[CH3:25]
Reactant: C1=COCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=[N+]=[N-])C[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(n3cc(CCO)nn3)C[C@H]12

Procedure:
A mixture of p-nitrobenzyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate (75 mg, 0.2 mmol) and 2,3-dihydrofuran (0.25 ml) in anhydrous tetrahydrofuran (5 ml) containing excess sodium bicarbonate is kept at 4° C. for 1 week. The mixture is filtered and the filtrate evaporated under vacuum. The residue is purified by preparative thin layer chromatography on silica gel to afford p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[4-(2-hydroxyethyl)-1,2,3-triazol-1-yl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[C:11](=[N:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:37]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[N:1]=[N:37][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[N:18][NH:17][C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: Cn1cc(-c2ccc(N)c(N)c2Oc2ccc(F)cc2F)c2cn(COCC[Si](C)(C)C)nc2c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3[nH]nnc3c2Oc2ccc(F)cc2F)c2cn[nH]c2c1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (103 mg, 0.200 mmol) in acetic acid (0.40 mL) was treated with water (1.0 mL) followed by sodium nitrite (69.0 mg, 1.00 mmol) and stirred at 20° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate (2×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the SEM-protected intermediate which was used without further purification. The crude intermediate was diluted with methylene chloride (4.00 mL) and trifluoroacetic acid (4.00 mL) and stirred at 40° C. for 3 h. The reaction mixture was concentrated, diluted with acetonitrile, adjusted to pH 7 with 1 M NaOH, and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (16 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 14.05 (br s, 1H), 7.86-7.72 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.31-7.22 (m, 1H), 6.85-6.73 (m, 2H), 3.53 (s, 3H); LCMS calculated for C19H13F2N6O2 (M+H)+: m/z=395.1. found: 395.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:11][CH3:12])=[CH:3][CH:2]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23]CC)=[O:22])C.[OH-].[K+].C>O>[CH2:11]([N:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=2)[C:19](=[O:18])[C:20]([C:21]([OH:23])=[O:22])=[CH:26]1)[CH3:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCNc1cccc(-c2ccncc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccncc3)cc21
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
A mixture of 100 mg of 3-(4-pyridyl)-N-ethylaniline (90% pure) and 108 mg of diethyl ethoxymethylenemalonate was heated at 165° C. for 0.5 hour. Then 2 g of polyphosphoric acid were added to the mixture, and heating was continued for another hour. A solution of 3 g of potassium hydroxide in 40 ml of water was then added to the reaction mixture, bringing it to a pH of 12-13; and the solution was heated on a steam bath for 30 minutes until it became clear. A pinch of activated charcoal was added, and the reaction mixture was stirred while hot for another 10 minutes and filtered. The residue was taken into 20 ml of methanol, heated, and then cooled. Filtration yielded 43 mg of 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinolinecarboxylic acid as a slightly impure white solid. Another 19 mg of the product were found in the filtrate, bringing the total yield to 47%, based on the amount of 3-(4-pyridyl)-N-ethylaniline employed.
Reaction SMILES: [O:1]=[C:2]1[N:7]([NH2:8])[CH2:6][C:5]([CH3:9])=[N:4][NH:3]1.[CH3:10][C:11]1[C:16]([CH:17]=O)=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)C.Cl>[O:1]=[C:2]1[N:7]([N:8]=[CH:17][C:16]2[C:11]([CH3:10])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][C:5]([CH3:9])=[N:4][NH:3]1
Reactant: Cc1ncccc1C=O
Reactant: CC1=NNC(=O)N(N)C1
Agent: Cl
Solvent: CCO
Product: CC1=NNC(=O)N(N=Cc2cccnc2C)C1
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g (4 mmol) of 2,3,4,5-tetrahydro-3-oxo-4-amino-6-methyl-1,2,4-triazine in 250 ml of ethanol are added, at room temperature, 0.48 g (4 mmol) of 2-methylpyridine-3-carbaldehyde and 1 drop of concentrated HCl. The reaction mixture is stirred for 1/2 hour and then filtered. The isolated solid is washed with ether and dried, affording the title compound of formula ##STR26## in the form of a colourless solid; m.p. 226°-229° C. (yield: 0.6 g; 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](=[S:30])([O:14][CH:15](Br)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:11][S:12](=[S:30])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8])=[O:13]
Reactant: CCOCCOCCOCCOCC(Br)OS(C)(=O)=S
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=S)OCCOCCOCCOCCOCCOC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.5 %

Procedure:
4-aminobenzoic acid (0.145 g, 1.06 mmol) and 1-bromo-3,6,9,12-tetraoxatetradecyl methanethiosulfonate (0.42 g, 1.06 mmol) were dissolved in dry DMF (30 mL). Cesium carbonate (0.385 mg, 1.1 mmol) was added and the mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was pied by column chromatography on SiO2. Elution was with dichloromethane/methanol (100:3) and after evaporation, 16-(4-aminophenyl)-16-oxo-3,6,9,12,1 5-pentaoxahexadecyl methanethiosulfonate (0.120 g, 0.27 mmol; 25% yield) remained as a pale yellow oil. 1H NMR (500 MHz, (CD3)2SO) δ 7.62 (d, J=8.7 Hz, 2H), 6.55 (d, J=8.7 Hz, 2H), 5.94 (s, br., 2H), 4.25 (t, J=4.8 Hz, 2H), 3.70-3.67 (m, 4H), 3.57-3.55 (m, 2H), 3.54-3.47 (m, 13H), 3.36 (t, J=5.9 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][NH2:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.OO.[O-]Cl.[Na+]>O.CO>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:9][N:10]=[N:1]1
Reactant: NCC1(CN)CCCCC1
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: O
Product: C1CCC2(CC1)CN=NC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
C-(1-Aminomethyl-cyclohexyl)-methylamine (10.0 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, H2O2 (44.3 mL of a 30% solution, 6 equiv.) and NaClO (125.5 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred for 45 min. at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure, yielded 8.7 g of a clear, light-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 1.24-1.53 (m, 10H), 4.17 (s, 4H).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=2)[C:57](O)=[O:58])=[CH:52][CH:51]=1>>[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([CH:56]([C:60]2[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=2)[C:57]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:58])=[CH:54][CH:55]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with bis(4-chlorophenyl)acetic acid, mp 175°-176° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)[CH2:25][CH2:26]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: c1ccc(C(c2ccccn2)N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccccn3)CC2)cc1
Yield: 51.9 %

Procedure:
Using 2.8 g of methyl 4-bromomethylphenylacetate, 2.9 g of 1-[phenyl-(2-pyridyl)methyl]piperazine, 2 ml of triethylamine, and 100 ml of dioxane, the reaction procedure of Example 1 was otherwise repeated and recrystallized from benzene-hexane to provide 2.47 g of methyl 4-[[4-[phenyl-(2-pyridyl)methyl]-1-piperazinyl]methyl]phenylacetate melting at 122° C.-123° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1.[CH2:17]([O:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24])[CH3:18]>O1CCCC1>[CH3:18][CH2:17][O:19][CH2:20][CH2:21][NH:22][C:23]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:24]
Reactant: CCOc1nc(O)ns1
Reactant: CCOCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCCNC(=O)n1sc(OCC)nc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
1 ml of triethylamine was added to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 140 ml of tetrahydrofuran and then 23 g of ethoxyethyl isocyanate were added dropwise. The mixture was stirred for 2 hours at 25° C and was concentrated to dryness. The residue was chromatographed over silica gel and elution with a 4-6 benzene-ethyl acetate mixture yielded 14 g of 2-(N-β-ethoxyethylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at <50° C.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.OC1[C:27]2[N:26]=NN[C:23]=2[CH:22]=[CH:21]C=1.C(N(CC)CC)C.C1(CN)CC1>C(Cl)Cl>[CH:23]1([CH2:27][NH:26][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:21][CH2:22]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: NCC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Cyclopropyl carboxylic acid (1.0 g, 11.63 mmol) was added to a 50 mL two neck round bottom flask, along with DCM (25 mL). This mixture was cooled to 0° C., EDCI (4.15 g, 13.95 mmol) was added portionwise to the mixture with stirring under nitrogen atmosphere, and the temperature was maintained for 0.5 h. After this time, hydroxybenzotriazole (1.88 g, 13.95 mmol) was added to the 0° C. mixture which was stirred for 10 min, then triethylamine (1.7 g, 11.63 mmol) was added, and stirring of the mixture was continued at the same temperature for another 0.5 h. Then, cyclopropylmethylamine (0.825 g, 11.63 mmol) was added, and the reaction was allowed to reach RT, and stirring was continued overnight. The solvent was then removed in vacuo, and the crude residue was purified by passing through a column over 60-120 silica gel, eluting with dichloromethane, to afford the title compound (1.6 g), yield: 87%.