Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:23][N:24]([CH3:39])[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35](Cl)(=[O:37])=[O:36]>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:35]([C:30]3[C:31]4[C:26](=[C:25]([N:24]([CH3:39])[CH3:23])[CH:34]=[CH:33][CH:32]=4)[CH:27]=[CH:28][CH:29]=3)(=[O:37])=[O:36])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 53.3 %

Procedure:
Using the general method of Example 245 except that chloroform was used as the solvent, 1-(3-aminopropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with 5-dimethylamino-1-naphthalenesulfonyl chloride (5.87 mmol) to provide 1.45 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamide as a yellow solid, m.p. 210-215° C. Analysis: Calculated for C28H32N6O3S.1.50 H2: % C, 60.09; % H, 6.30; % N; 15.02; Found: % C, 59.89; % H, 6.22; % N, 14.86.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:59]([C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:66](=[O:67])[C:65]2[CH:64]=[CH:63][C:62]([N+:59]([O-:61])=[O:60])=[CH:70][CH:69]=2)[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1-c1ccc(OC2CCCCC2)cc1
Yield: 77.5 %

Procedure:
To a stirred mixture of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Example 43, 1.18 mmol, 0.64 g), PPh3 (1.43 mmol, 0.375 g) and p-nitrobenzoic acid (1.5 mmol, 0.251 g) in anhydrous THF (15 mL) at −60° C. was added DIAD (1.43 mmol. 0.289 mL) over 10 min. The stirring was continued and let the reaction slowly attain room temperature over 3 h. The reaction mixture was diluted with ether (300 mL), washed with water (100 mL) followed by saturated sodium bicarbonate (100 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel flash column chromatography by eluating with 20% ethyl acetate in hexanes to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.63 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([N:13]=[C:14]=[O:15])=[O:12].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C=NC(=O)CCl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CN(c2cccc(Br)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromoaniline (1.0 mL, 9.18 mmol) and chloroacetyl isocyanate (0.780 mL, 9.18 mmol) in dioxane (100 mL) was stirred at room temperature for 2 hr. Dioxane (50 mL) and DBU (3.40 mL, 23.0 mmol) were added and the solution stirred at room temperature for 16 hr. The solution was concentrated in vacuo and the residue taken up in EtOAc and H2O. The mixture was then acidified with 1N HCl, then the aqueous phase extracted with EtOAc. The combined organics were then washed with H2O and brine and dried over Na2SO4. The solution was concentrated in vacuo and the residue recrystallized from EtOAc/hexanes to give 1-(3-bromophenyl)-2,4-imidazolidinedione as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 2H), 7.24-7.30 (m, 2H), 7.50-7.52 (m, 1H), 7.87 (s, 1H), 11.27 (s, 1H).
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:26][C:27]1[CH:41]=[CH:40][C:30]([CH2:31][S:32][CH:33]2[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.O>CCCCCC.CS(C)=O>[CH3:4][O:5][CH:6]=[C:36]1[CH2:37][CH2:38][CH:33]([S:32][CH2:31][C:30]2[CH:40]=[CH:41][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(SCc2ccc(Cl)cc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COC=C1CCC(SCc2ccc(Cl)cc2)CC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
After 146 mg (3.34 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 18 ml of dimethyl sulfoxide, followed by stirring of the resulting suspension at 55° C. for 2 hours. The mixture was cooled to room temperature and 1.26 g (3.34 mmol) of methoxymethyltriphenylphosphonium chloride were added to the mixture. Further, a solution in which 426 mg (1.67 mmol) of 4-[(4-chlorobenzyl)thio]cyclohexanone were dissolved in 5 ml of dimethyl sulfoxide was added to the resulting mixture. Water was added to the mixture and the resulting mixture was extracted with toluene. After the extract was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 20 g of silica gel and eluted with a mixed solvent of methylene chloridehexane (1:4) to obtain 370 mg (yield: 78%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=2[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]1.[CH3:27][NH2:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:28][CH3:27])[C:18]=2[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c12
Reactant: CN
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c2c1C
Yield: 95.5 %

Procedure:
1-(2,4-Difluoro-5-hydroxyphenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) was added to an aqueous solution (about 40%; 3.0 g) of methylamine to conduct a reaction at 75° C. for 4 days. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (4 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (295 mg) as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]1[C@@H:13]2[CH2:14][NH:15][CH2:16][C@@H:12]2[CH2:11][N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)C(C)C)(C)C>CS(C)=O.O>[Cl:8][C:4]1[N:3]=[C:2]([N:15]2[CH2:14][C@@H:13]3[CH2:9][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C@@H:12]3[CH2:16]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: Clc1cncc(Cl)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(Cl)n3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 89.4 %

Procedure:
2,6-dichloropyrazine (1.02 g, 6.85 mmol) was dissolved in DMSO (7 mL). The product from Example 1C (1.61 g, 7.58 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.61 mmol) were added to the reaction mixture. The reaction was stirred at ambient temperature for 23 h. The reaction was diluted with water (200 mL) and extracted with CH2Cl2 (4×100 mL). The organic extracts were combined and washed with and brine (150 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc, Rf=0.38) to afford the title compound as a white solid (1.99 g, 89%). MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[CH3:16].COC1C=CC(C(Cl)=O)=CC=1.FC1C=C(F)C=CC=1C1C=CC=CC=1C(N)C.C(N(CC)CC)C>CCCCCC.COC(C)(C)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([C:18]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)=[O:27])[C:2]=2[CH:7]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1ccc(C(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)cc1
Agent: CC(N)c1ccccc1-c1ccc(F)cc1F
Agent: COc1ccc(C(=O)Cl)cc1
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1

Procedure:
N-[1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzamide—The title compound was prepared from 4-methoxybenzoyl chloride (731 mg, 4.28 mmol), 1-(-2′,4′-difluoro-biphenyl-2-yl)-ethylamine (1 g, 4.28 mmol), and triethylamine (717 uL, 5.1 mmol) according to the procedure and in the same manner as described in Example 33, step c. The product was isolated from a Biotage® (40 Mi) column for flash column chromatography (5-30% methyl tert-butylether in hexane) resulting in the isolation of a white solid, 1.53 g (97%). mp 134.5-135° C.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=5.43 Hz, 3 H) 3.80 (s, 3 H) 4.96 (m, J=5.95 Hz, 1 H) 6.97 (d, J=9.05 Hz, 2 H) 7.18 (m, 2 H) 7.36 (m, 3 H) 7.64 (d, J=4.14 Hz, 2 H) 7.83 (d, J=7.50 Hz, 2 H) 8.66 (s, 1 H); MS (ESI) m/z 368 ([M+H]+); Anal. calcd for C22H19F2NO2: C:71.92 H:5.21 N:3.81 Found: C:72.11 H:5.23 N:3.77
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH2:26]([C:28]1[S:32][C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[N:30][N:29]=1)[CH3:27].C(N(CC)CC)C.O>CS(C)=O>[CH2:26]([C:28]1[S:32][C:31]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])=[N:30][N:29]=1)[CH3:27]
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1nnc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)s1
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine hydrochloride (0.100 g; Example 1a, Step 5), phenyl 5-ethyl-1,3,4-thiadiazol-2-ylcarbamate (0.081 g, 1.2 equiv), and triethylamine (0.045 mL, 1.2 equiv) in dimethyl sulfoxide (1 mL, 0.3 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and then the solution was extracted with ethyl acetate (2×). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a 12 g silica gel column using 10-30% ethyl acetate/dichloromethane over 30 minutes as the eluent to give the title compound as a white foam. 0.056 g, 42% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (3H, t, J=7.6 Hz), 2.46 (2H, t, J=5.7 Hz), 2.61 (2H, t, J=5.7 Hz), 2.95 (2H, q, J=7.8 Hz), 3.67 (2H, t, J=5.8 Hz), 3.77 (2H, t, J=5.8 Hz), 6.40 (1H, s), 6.96-7.05 (3H, m), 7.08 (1H, d, J=7.8 Hz), 7.37 (1H, t, J=8.0 Hz), 7.89 (1H, dd, J=8.8, 2.5 Hz), 8.43 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20]C4C=C5C(CCN(C)C5=O)=CC=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[Cl:33]CCCCO[C:39]1[CH:48]=[C:47]2[C:42]([CH2:43][CH2:44][N:45]([CH3:50])[C:46]2=[O:49])=[CH:41][CH:40]=1.CO.Cl>CO>[ClH:33].[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:44]4[CH2:43][C:42]5[C:47](=[CH:48][CH:39]=[CH:40][CH:41]=5)[C:46](=[O:49])[N:45]4[CH3:50])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CN1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2C1=O
Reactant: CN1CCc2ccc(OCCCCCl)cc2C1=O
Agent: Cl
Solvent: CO
Product: CN1C(=O)c2ccccc2CC1OCCCCN1CCN(c2cccc3sccc23)CC1

Procedure:
By a similar method as in Example 1, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one was prepared from 7-(4-chlorobutoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one, and after it was made into a methanol solution, 0.5N hydrochloric acid methanol solution was added thereto, precipitated crystals were separated by filtration, recrystallized from a mixed solvent of methanol-ethyl acetate and thereby 7-[(4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one hydrochloride was obtained in the form of a white powder.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13](=O)([O-])[O-].[K+].[K+].Cl[C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1>CC(C)=O>[CH:1]1([N:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:22]2[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][N:25]=[C:20]([CH3:13])[N:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCN(c1nc(C)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
Methyl 3-(cyclopentylamino)propanoate (1.78 g, 10.4 m mole) and potassium carbonate (1.52 g, 11.0 m mol) in acetone (25 ml) was stirred at 0° C. during the addition of a solution of 2,4-dichloro-5-nitropyrimidine (2.04 g, 10.4 m mol) in acetone (15 ml). The mixture was stirred at ambient temperature overnight, concentrated and diluted with ethyl acetate/water. The mixture was extracted ×3 with ethyl acetate, dried over magnesium sulphate and concentrated to an amber oil which solidified on standing. Flash chromatography on silica gel eluting with 30% ethyl acetate/petrol gave methyl 3-(N-cyclopentyl-N-(2-methyl-5-nitropyrimidin-4-yl)amino)propionate as a pale yellow solid (2.24 g, 65%). NMR CDCl3 1.50-2.07 (8H, m), 2.70-2.82 (2H, m), 3.65-3.90 (6H, m), 8.72 (1H, s).
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC([CH:15]2[NH:19][C:18]([C:20]3[CH:25]=[CH:24]C(OC)=CC=3OCC)=NC2C)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:51][CH2:50]N(C)[CH2:48][CH2:47]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH2:64]C2CCCC2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:47][CH2:48][CH:15]([N:19]4[CH2:18][CH2:20][CH2:25][CH2:24]4)[CH2:50][CH2:51]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH3:64])=[CH:37][CH:38]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 17) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 525.2635, calculated for C29H38N4O3Cl [(M+H)+]525.2627.
Reaction SMILES: [N+](C1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.C([O-])(=O)C([O-])=[O:20].[K+].[K+].[OH-].[Na+].O>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:17](=[O:20])[C:5]3[C:10](=[N:9][CH:8]=[CH:7][CH:6]=3)[C:11]=12
Reactant: O=C([O-])C(=O)[O-]
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2cccnc2-c2ncccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a 1 L one-necked flask was added a mixture of 30 g (0.13 mol, 68%) 5-nitro-1,10-phenanthroline, 51 g (0.61 mol) potassium oxalate, 12.5% NaOH(aq) 150 ml and 450 ml water. The mixture was then heated to reflux (100° C.) and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was added with 1 L ethyl acetate, stirred for 30 minutes, and filtered to collect the filtrate. The residual solids were added into 300 ml ethyl acetate, stirred for 30 minutes and filtered to collect the filtrate. The combined filtrates were extracted to separate the organic layer, dehydrated by MgSO4, concentrated, and recrystallized from 200 ml methanol, so as to obtain light yellow solids cyclopenta[2,1-b;3,4-b′]dipyridin-5-one 13.3 g (0.07 mol, yield 54%).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([C:32]([O:34]CC)=[O:33])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:26])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:16]([O:18]CC)=[O:17])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]>CCO>[CH2:14]([O:13][C:11]([C:9]([CH3:10])([CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:3])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:26])[C:32]([OH:34])=[O:33])[C:16]([OH:18])=[O:17])=[O:12])[CH3:15]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)C(=O)OCC)C(=O)O
Reaction time: 54 h
Yield: 80.7 %

Procedure:
A solution of KOH (2.44 g, >85%, >37.0 mmol) in EtOH (80 mL) was added to 106h (9.00 g, 18.5 mmol). After stirring for 54 h, another portion of KOH (1.21 g, >85%, >18.5 mmol) was added and stirring was continued for 16 h. The reaction mixture was evaporated in vacuo and Et2O (250 mL) and H2O (250 mL) were added. The aqueous layer was separated, acidified with aqueous HCl (2 M, 50 mL) and extracted with Et2O (250 mL) and CH2Cl2 (250 mL). The combined organic layers were dried and the remaining residue was purified by column chromatography (silica, heptane:EtOAc:HOAc=3:2:0.01) and vacuum dried at 50° C. to give 107h (6.43 g, 81%) as a yellow oil. 1H NMR: δ 10.40 (br s, 2H), 4.21 (q, J=7.1 Hz, 4H), 2.42 (t, J=7.4 Hz, 4H), 1.90-1.84 (m, 4H), 1.59 (quintet, J=7.4 Hz, 4H), 1.43 (s, 6H), 1.32-1.19 (m, 4H), 1.27 (t, J=7.2 Hz, 6H). 13C NMR: δ 210.9, 177.7 (2×), 172.1 (2×), 61.5 (2×), 53.5 (2×), 42.2 (2×), 35.3 (2×), 23.8 (2×), 23.7 (2×), 19.8 (2×), 13.9 (2×). HRMS calcd for C21H35O9 (MH+): 431.2281. found: 431.2298.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)[CH3:8])[CH:2]=1.[O-][CH2:18]C.[Na+].CI>C(O)C>[CH3:18][S:15][C:12]1[NH:11][C:10](=[O:16])[C:9]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH3:8])=[CH:14][N:13]=1
Reactant: CC[O-]
Reactant: CC(c1cccnc1)c1c[nH]c(=S)[nH]c1=O
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1ncc(C(C)c2cccnc2)c(=O)[nH]1
Reaction time: 2 h
Yield: 113 %

Procedure:
5-[1-(3-Pyridyl)ethyl]-2-thiouracil (3.4 g) was added to a solution of sodium ethoxide (from 0.74 g sodium) in ethanol (35 ml). Methyl iodide (2.42 g) was added over 0.5 hour at 0°. After standing for a further 2 hours at 0° the solution was evaporated to dryness. The residue was taken up in water and the pH adjusted to 7.0 and the mixture was allowed to stand at 0° overnight. The solid was filtered off to give 2-methylthio-5-[1-(3-pyridyl)ethyl]-4-pyrimidone (3.04 g) m.p. 201°-204° (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[C:14]2=[O:26])=[CH:8][CH:7]=1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41]1.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:32]([N:40]4[C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:42][CH2:41]4)=[O:38])=[CH:23][CH:24]=3)[C:14]2=[O:26])=[CH:10][CH:11]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: COC(=O)CCc1ccc(Cn2cccc(-c3ccc(N)cc3)c2=O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Cn2cccc(-c3ccc(NC(=O)N4CCc5ccccc54)cc3)c2=O)cc1
Reaction time: 18 h

Procedure:
A solution of 3-{4-[3-(4-aminophenyl)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}propionic acid methyl ester in tetrahydrofuran (5 mL) was added to a stirred solution of triphosgene (0.135 g, 0.45 mmol) in tetrahydrofuran (5 mL) at 0° C. After 2 hours a solution of indoline (0.054 g, 0.45 mmol) in tetrahydrofuran (2.5 mL) was added and stirring continued at room temperature for 18 hours. The mixture was then poured into ethyl acetate (25 mL) and washed sequentially with hydrochloric acid (10 mL, 1M), saturated aqueous sodium bicarbonate (10 mL) and brine before drying over anhydrous magnesium sulfate. After filtration and evaporation to dryness the residue was chromatographed on silica gel with a gradient of 1:1 rising to 3:1 ethyl acetate to hexane to give the title compound as a solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[NH2:30])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[NH:30][C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:2]1(=[O:1])=[O:18])[CH2:27]2
Reactant: O=C(O)CN1CCCN(c2ccccc2)S1(=O)=O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCN(c2ccccc2)S1(=O)=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
To 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetic acid (100 mg, 0.37 mmol) in DCM (5 mL), were added 2-adamantan amine HCl (105 mg, 0.56 mmol), TEA (74.9 mg, 0.74 mmol) and EDCI (212.8 mg, 1.11 mmol). The reaction mixture was agitated for 5 hr at room temperature and extracted using CH2Cl2 and brine. The organic layer was dried over MgSO4. The residue was purified by silica gel column chromatography to give N-(adamantan-2-yl)-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetamide (80 mg, 54%). 1H NMR (300 MHz, CDCl3): δ 7.41-7.26 (m, 5H), 7.02-6.99 (brd, 1H), 4.07 (m, 1H), 3.94 (s, 2H), 3.81-3.74 (m, 4H), 2.03-1.94 (m, 4H), 1.85-1.74 (m, 10H), 1.66-1.60 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][SH:9])=[CH:3][CH:2]=1.Br[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][S:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: SCCc1ccncc1
Reactant: OCCBr
Product: OCCSCCc1ccncc1

Procedure:
Furthermore, by following this method 2-(4-pyridyl)ethyl mercaptan is reacted with 2-bromoethanol to yield 4-[2-(2-hydroxyethylthio)ethyl]pyridine, with 2-bromo-1-propanol to yield 4-[2-(2-hydroxy-1-propylthio)ethyl]pyridine, with 3-bromo-2-butanol to yield 4-[2-(3-hydroxy-2-butylthio)ethyl]pyridine, with ethyl 2-chloropropionate to yield ethyl 2-[2-(4-pyridyl)ethylthio]propionate, with methyl 2-phenyl-2-bromoacetate to yield methyl 2-phenyl-2-[2-(4-pyridyl)ethylthio]acetate, with alpha-bromoacetophenone to yield alpha-[2-(4-pyridyl)ethylthio]acetophenone, and with chloroacetone to yield 2-(4-pyridyl)ethylthioacetone.