Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])(CC)C.C1CCCCC1.[C:41]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]3[C:15](=[O:16])[O:48][C:41]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:13]3[CH2:14]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
1,1-Dimethylethyl 4-[(4-methylphenyl)methyl]-1-piperazine carboxylate (58 g, 0.2 mol) and N,N,N′,N′-tetramethylethylenediamine (35 g, 0.3 mol) were dissolved in tetrahydrofuran (400 mL), and the mixture was cooled to −78° C. under argon atmosphere. A 1.0 M solution of sec-butyllithium in hexane and cyclohexane (240 mL, 0.24 mol) was added dropwise over 1.5 hours, and the mixture was stirred at −78° C. for 3 hours. Then, the temperature was elevated to −30° C. for 2 hours. After cooling to −78° C. again, a solution of benzophenone (55 g, 0.3 mol) in tetrahydrofuran (200 mL) was added dropwise over 1 hour, and the resulting mixture was stirred overnight while elevating the temperature to room temperature. After ice cooling, an aqueous saturated ammonium chloride solution (300 mL) was added thereto, and the mixture was stirred for 30 minutes with ice cooling. Ethyl acetate (300 mL) was added thereto, and the process of phase separation was performed. The resulting organic layer was washed with water (500 mL) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and to the residue was added diisopropyl ether-hexane (3:1, v/v, 300 mL). The obtained crystals were collected by filtration and washed with diisopropyl ether-hexane (3:1, v/v) to obtain the title compound (66 g, yield 82%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13](Cl)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13]([N:21]([CH3:20])[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18]
Reactant: Cn1c(-c2nnc3ccc(Cl)nn23)cnc1[N+](=O)[O-]
Reactant: CNCCN(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1ccc2nnc(-c3cnc([N+](=O)[O-])n3C)n2n1

Procedure:
0.65 g. 3-(1-methyl-2-nitro-5-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were reacted in 13 ml. dimethyl formamide with 0.5 g. trimethylethylenediamine at 60° C. for 15 minutes. After working up the reaction mixture in a manner analogous to that described in Example 47, there was obtained 0.6 g. (75% of theory) of the desired 3-(1-methyl-2-nitro-5-imidazolyl)-6[N-methyl-N-(β-dimethyl-aminoethyl)-amino]-s-triazolo[4,3-b]pyridazine in the form of yellow crystals which have a melting point of 196° - 198° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]([F:13])([F:12])[F:14])=[CH:4][N:3]=1
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(F)(F)F)cnc1N
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 50 (950 mg, 4.59 mmol), methanol (15 mL) and Raney Ni (about 200 mg) was shaken under H2 (30-40 psi) for 2 h, then filtered. The filtrate was evaporated to dryness, giving 810 mg (100%) of the diamine 51 as a deep yellow powder, mp 97°-99° C. 1H NMR (CDCl3), 3.389 (bs, 2H), 4.556 (bs, 2H), 7.049 (s, 1H), 7.932 (s, 1H).
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11]>C(O)C>[C:1]([NH:5][C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=S
Reactant: NC(CO)CO
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)CO
Temperature: 20 °C
Reaction time: 94 h

Procedure:
30.4 cm3 of tert-butyl isothiocyanate are added to a solution of 14.6 g of 2-amino-1,3-propanediol in 245 cm3 of ethanol, and the mixture is then stirred at a temperature in the region of 20° C. for 94 hours. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and the residue is slurried in a mixture of 160 cm3 of petroleum ether and 26 cm3 of ethanol, and the product is filtered off and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 60° C. 30 g of 1-tert-butyl-3-(2-hydroxy-1-hydroxymethylethyl)thiourea are obtained in the form of a white solid [1H NMR spectrum (250 MHz, (CD3)2SO-d6, δ in ppm): 1.42 (s: 9H); 3.38 (mt: 2H); 3.54 (mt: 2H); 4.17 (unresolved complex: 1H); 4.70 (t, J=5 Hz: 2H); 7.08 (d, J=8 Hz: 1H); 7.38 (s: 1H]).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:36]=[CH:35][N:34]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccnc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 32 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (32%).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([OH:25])[C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18]>CCCCCC>[OH:25][C:22]1[C:23]2[O:24][C:1]([CH3:2])=[N:13][C:14]=2[CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:21]=1
Reactant: COC(=O)c1cc(N)c(O)c(O)c1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: CCCCCC
Product: COC(=O)c1cc(O)c2oc(C)nc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To stirred triethyl orthoacetate (35.0 mL, 190 mmol) was added methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (6.00 g, 27.3 mmol). The stirred suspension was refluxed for 20 min and cooled to room temperature. The reaction mixture was poured into hexane (200 mL). The formed precipitate was separated by filtration and vacuum-dried to afford the desired benzoxazole (4.98 g, 24.04 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.74 (br. s, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H), 3.85 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:20]([NH:21][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCc1ccccc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCc1ccccc1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-phenylethaneamine as starting materials to give the aimed compound. Compound 29 was obtained by the purification using silica gel column chromatography.
Reaction SMILES: C([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(O)=O.[Br:29]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(CCCC(Br)CCCCCCC(=O)OCC)OC(C)=O

Procedure:
A mixture of ethyl 8-carboxy-12-acetoxyheptadecanoate (31.5 g., 0.079 mole), red mercuric oxide (12.8 g., 0.059 mole), and carbon tetrachloride (200 ml.) is stirred at room temperature while bromine (12.6 g., 0.079 mole) is added dropwise during one hour. The resulting mixture is heated at reflux for 1 hour. The mixture is then cooled, filtered, washed with dilute hydrochloric acid, water and brine and dried over sodium sulfate. The solution is evaporated in vacuo to leave the product as a yellow residual oil weighing 24.5 g. The product is purified by chromatography on a column containing 250 g. of silica gel using chloroform as eluting solvent. There is obtained 14.4 g. of purified ethyl 8-bromo-12-acetoxyheptadecanoate, a yellow oil with Rf 0.49 on silica gel thin layer chromatography with chloroform elution. pmr (CDCl3) δ 0.90 (3H,t); 2.03 (3H, s CH3CO); 4.07 (1H, m HCBr); 4.13 (2H, q); 4.92 (1H, m HCO).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([N:20]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C@@H:22]3[CH2:29][NH:30][CH2:31][CH2:32][C@@H:21]23)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:1]([CH2:9][CH2:10][C:11]([N:30]1[CH2:31][CH2:32][C@H:21]2[N:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C@@H:22]2[CH2:29]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: c1ccc(N2c3ccccc3[C@@H]3CNCC[C@H]32)cc1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To the suspension arising from the admixture of 865 mg. (4.20 mmole) of dicyclohexylcarboiimide and 748 mg. (4.20 mmole) of 3-benzoylpropionic acid in 30 ml. of dichloromethane at 0° C. was added 1.0 g. (4.0 mmole) of dl-trans-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 10 ml. of the same solvent. The resulting mixture was stirred and allowed to warm to room temperature over 2 hours. After cooling again to 0° C. the reaction mixture was filtered, washed with dichloromethane and the filtrates evaporated to obtain a residue of dl-trans-2-[(3-benzoyl)propionyl]-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole which was used without purification in the next step.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[OH:1][CH:2]([CH2:15][N:25]1[CH2:26][CH2:27][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)CN1CCC(c2ccccc2)CC1

Procedure:
A solution of 1.980 g (9.744 mM) of N-(2,3-epoxy-propan-1-yl)phthalimide and 1.73 g (10.7 mM) of 4-phenylpiperidine in 50 ml of ethanol was refluxed for one hour, at the end of which time the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) and crystallized from diethyl ether-hexane to provide the title compound.
Reaction SMILES: [N:1]1([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:44][C:45]([NH:47][CH2:48][C:49]1[N:50]=[C:51]2[C:56](=[C:57]3[C:62]=1[CH:61]=[CH:60][CH:59]=[CH:58]3)[CH:55]=[CH:54][CH:53]=[CH:52]2)=[O:46]>CC#N.CC#N.CN(C=O)C>[O:46]=[C:45]([NH:47][CH2:48][C:49]1[N:50]=[C:51]2[C:56](=[C:57]3[C:62]=1[CH:61]=[CH:60][CH:59]=[CH:58]3)[CH:55]=[CH:54][CH:53]=[CH:52]2)[CH2:44][N:10]1[CH2:9][CH2:8][N:7]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:3][CH2:2][N:1]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11]1
Reactant: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCc2nc3ccccc3c3ccccc23)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1

Procedure:
Tri-tert-butyl 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (33.5 mg, 65.1 mop was dissolved in dry CH3CN (10 mL) and magnetically stirred under N2(g). Anhydrous K2CO3 (30.0 mg, 0.217 mmol) was added, followed by 2-chloro-N-(phenanthridin-6-ylmethyl)acetamide (Weitz et al., J. Am. Chem. Soc., 2012, 134, 16099-16102) (15.4 mg, 54.2 mmol) dissolved in 15 mL CH3CN/DMF (2:1), and the reaction mixture was heated to reflux for 27 hours under N2(g). The reaction mixture was then filtered and concentrated under reduced pressure to yield a colorless glass that was used without further purification in the next step. 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 27H), 2.70-3.21 (m, 16H), 3.37-3.42 (m, 6H), 5.41 (d, J=15 Hz, 2H), 7.66-7.87 (m, 3H), 8.02 (d, J=7.0 Hz, 1H), 8.22 8.28 (d, J=6.5 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.63 (d, J=7.5 Hz, 1H), 8.77 (d, J=7.0 Hz, 1H). HRMS (ESI): calc for [C42H62N6O7]+ ([M+H]+): m/z 763.4753. found: 763.4739.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].N12CCCN=C1CCCCC2.[NH:31]1[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:31]3[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][CH2:39][OH:40])[CH2:32]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: OCCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNCCO)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 0.50 g (1.84 mmole) of 1-ethyl-6,7,8-trifluoro-4-oxo-quinoline-3-carboxylic acid, 5 ml acetonitrile, 0.28 g (1.84 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.28 g (1.94 mmole) of 2-[(3-pyrrolidinylmethyl)amino]ethanol was refluxed one hour and then stirred at room temperature overnight. The reaction was filtered and the precipitate washed with ether until dry to give 0.58 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid, mp 215°-216° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([CH2:24][CH3:25])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([CH2:24][CH3:25])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: CCc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 86.6 %

Procedure:
3-(3-cyano-5-ethyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (309 mg) was dissolved in N,N-dimethylformamide (3 mL), and lithium chloride (443 mg) was added to the solution, and then the mixture was stirred at 120° C. for 2.5 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (257 mg) as a brown crystal.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O>CC(C)=O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)cc3)cs2)c(C)s1
Yield: 104.3 %

Procedure:
30 mg (0.122 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 1.2 mL of reagent grade acetone. 2-bromo-4′-methoxy acetophenone (0.146 mmol; 28 mg; Aldrich Chemical Co.) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and a solid was filtered and washed with methanol and dried in vacuo to afford 46 mg (90% yield) of methyl 4-[4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoate (3.7 g, 9.7 mmol) in THF/MeOH/H2O (V:V:V=4:1:1) (50 mL) were added lithium hydroxide monohydrate (1.3 g, 29.1 mmol). The mixture was stirred at room temperature for 3 hours and quenched with water (200 mL). To the solution was added 1M HCl to adjust the pH value to 2-3, then a white solid precipitated and was filtered to afford the desired compound (3.3 g, yield 96.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Cl[CH2:12][CH:13]=O.NC(N)=O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:12]=[CH:13][N:10]=1
Reactant: NC(=S)Nc1ccccn1
Reactant: O=CCCl
Agent: NC(N)=O
Solvent: CCO
Product: c1ccc(Nc2nccs2)nc1
Reaction time: 3 h

Procedure:
To a flask was added 2-pyridyl thiourea (5-1) (3.48 g, 22.7 mmol), 30 mL ethanol, and 50% by weight chloroacetaldehyde (14.4 mL, 113.5 mol). The flask was then heated to reflux. As the mixture was heated, the urea slowly dissolved in solution. After 3 hours, the ethanol was removed under reduced pressure. Saturated aqueous NaHCO3 was then added to the flask and a white precipitate formed after vigorous bubbling. The precipitate was filtered and washed with water. The white solid was then dried under vacuum overnight with P2O5 drying agent. 1H NMR (CDCl3): δ10.95 (bs, 1H), 8.37 (d, 1H, J=4.2 Hz), 7.61 (t, 1H, J=7.0 Hz), 7.49 (d, 1H, J=3.5 Hz), 6.94 (d, 1H, J=8.3 Hz), 6.88 (t, 1H, J=7.1 Hz), 6.85 (d, 1H, J=3.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([N:17]4[C:21]5=[N:22][CH:23]=[CH:24][CH:25]=[C:20]5[NH:19][C:18]4=[O:26])=[CH:14]3)=[N:9]2)=[N:6][CH:7]=1.I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][N:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)[N:9]=3)[CH:14]=2)[C:18]1=[O:26])[CH3:29]
Reactant: CCI
Reactant: Cc1ccc(-n2cc3cc(-n4c(=O)[nH]c5cccnc54)ccc3n2)nc1
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc3nn(-c4ccc(C)cn4)cc3c2)c2ncccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
A mixture of 3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31 mg) and iodoethane (15.5 mg) in DMF (2 mL) was stirred at 50° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/Hexane to give the title compound as white crystals (5.4 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O)([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].[NH4+].[Br-:31].[Li+]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Br:31])([O-:3])=[O:2]
Reactant: [Br-]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CO
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CBr
Yield: 22.9 %

Procedure:
1.8 g (6.2 mmol) of 2-[(2,6-dinitrophenyl)amino]-benzyl alcohol was dissolved in a mixture of 50 ml of dictloromethane with 50 ml of ethyl ether. Under ice-cooling and stirring, 2.2 ml (15.5 mmol) of triethylamine and 0.58 ml (7.4 mmol) of methane-sulfonuyl chloride were successively added thereto. After stirring for 30 minutes, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After concentrating, the residue was dissolved in 150 ml of acetone. Then 2.7 g (31 mmol) of lithium bromide was added and the resulting mixture was heated under reflux for 1 hour. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to thereby give 0.5 g of 2((2,6-dinitrophenyl)amino)-benzyl bromide. This product was dissolved in 10 ml of dimethylformamide. After adding 216 mg (2.8 mmol) of thiourea, the mixture was stirred at room temperature for 5 hours. Then 10 ml of dimethylformamide, 157 mg (2.8 mmol) of potassium hydroxide and 2 ml of water were successively added thereto and the reaction mixture was heated at 100° C. for 3 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. After concentrating, the residue was purified by silica gel column chromatography. Thus 0.22 g of the title compound was obtained.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[S:26]([O:31]C)([O:29][CH3:30])(=[O:28])=[O:27]>O>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[CH3:30][O:29][S:26]([O-:31])(=[O:28])=[O:27]
Reactant: COS(=O)(=O)OC
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: COS(=O)(=O)[O-]

Procedure:
7.3 g of salt are prepared, likewise the preceding example, starting from 6.73 g (2.10-2 moles) of apovincamine and from about 2 mls of dimethyl sulfate. The final product has a melting point of 280° C. and is water soluble but poorly soluble in alcohol.