Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1.[CH3:31][NH:32][CH3:33]>>[ClH:1].[ClH:1].[CH3:31][N:32]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1)[CH3:33]
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(CCl)cc1
Reactant: CNC
Product: CN(C)Cc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)Nc2nccs2)cc1
Product: Cl

Procedure:
5-(4-Chloromethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (900 mg) obtained in Example 94 and 50% aqueous dimethylamine solution (5 ml) were reacted and treated in the same manner as in Example 95 to give 5-(4-dimethylaminomethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide dihydrochloride (645 mg), melting point 273-279° C. (decomposition).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:21]([O:25][C:26]([N:28]([C:45]1[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=1)[S:29]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)=[N:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:27])[CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([C:33]2[C:32]([S:29]([N:28]([C:26]([O:25][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:27])[C:45]3[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=3)(=[O:31])=[O:30])=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:39][CH:40]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CBr)cc1
Yield: 70.5 %

Procedure:
N-Bromosuccinimide (2.99 g) and azobisisobutyronitrile (275 mg) were added to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylphenyl)pyridine-3-sulphonamide (7.9 g) in carbon tetrachloride (150 ml) and the mixture was heated under reflux for 4 hours. Insoluble material was removed by filtration and the fitrate was concentrated by evaporation. The residue was redissolved in ethyl acetate (200 ml) and the solution was washed with water (100 ml) and saturated sodium chloride solution (100 ml). The solution was dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ethyl acetate/hexane (3:7 v/v, 80 ml) to give 2-(4-bromomethylphenyl)-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-pyridine-3-sulphonamide (6.5 g), m.p. 125-128° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.O>CN(C)C=O>[CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CBr)cc2)cc1
Reactant: CNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(C)c3ccccc3)cc2)cc1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
N-Methylaniline (57 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride (21 mg, 0.53 mmol) was added under ice-cooling. The reaction mixture was stirred for 30 min., and methyl 4-[[4-(bromomethyl) phenyl]methoxy]benzenepropanoate (0.15 g, 0.41 mmol) was added. The mixture was stirred at room temperature for 3 hrs, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=18:1) to give the title compound (74 mg, yield 45%) as a yellow powder.
Reaction SMILES: [C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)(O)=[O:2].Cl.C[N:32](C)[CH2:33][CH2:34][CH2:35]N=C=NCC.C(N)CC.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:33]([NH:32][C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)=[O:2])[CH2:34][CH3:35]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(CC(C)C(=O)O)cc23)c(OC)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCN
Product: CCCNC(=O)C(C)Cc1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of methyl 4-[7-(2-carboxypropyl)naphth-1-ylmethyl]-3-methoxybenzoate (1.176 g), 4-dimethylaminopyridine (440 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (690 mg), propylamine (0.295 ml) and methylene chloride (20 ml) was stirred for 18 h. Ethyl acetate (100 ml) was added, the solution was washed (1N hydrochloric acid, brine) and dried (MgSO4). Evaporation and flash chromatography, eluting with 2:30:70 triethylamine:ethyl acetate:petroleum ether, gave a solid. Recrystallization from methylene chloride and hexane, followed by grinding to a powder and vacuum drying, afforded methyl 4-[7-[2-(propylcarbamoyl)propyl]naphth-1-ylmethyl]-3-methoxybenzoate (910 mg, 70%) as a colorless solid; mp 129.5°-130.0° C.; MS(CI), m/e=434(M+H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)[O:12]2)=[C:4]([NH:24][CH2:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=1.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CS(C)=O>[CH:14]([OH:17])=[O:45].[C:33]1([CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][NH:24][C:4]2[N:3]=[C:2]([NH:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)[O:12]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCN1CCOCC1
Reactant: O[C@@H]1[C@H](O)[C@@H](Cn2nccn2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(Cl)nc21
Solvent: CS(C)=O
Product: O=CO
Product: O[C@@H]1[C@H](O)[C@@H](Cn2nccn2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(NCCN3CCOCC3)nc21

Procedure:
Intermediate 3 (0.043 mg), 4-(2-aminoethyl)morpholine (0.053 mg), dimethyl sulphoxide (0.05 ml) ) in a sealed vial (eg Reactivial™) were heated at 90° C. for 16 hours. Purification by Autoprep HPLC afforded after freeze-drying the title compound as a pale yellow solid (0.019 g). LC-MS System A Rt=3.71 min, m/z 627 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[C:16]1([OH:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:26][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc2ccccc12
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3ccccc23)cc1=O
Yield: 80 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and naphthalen-1-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (9.1 g, 80%) as a solid; ESI-MS 379 [M+H+]; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), >96% (purity). 1H-NMR (300 MHz, CDCl3) δ 8.22-8.21 (d, 1H), 8.05-7.91 (m, 3H), 7.65-7.58 (m, 3H), 7.42-7.39 (d, 1H), 5.78-5.77 (t, 1H), 5.53-5.48 (m, 1H), 2.45-2.35 (m, 1H), 2.17-2.04 (m, 1H), 1.85-1.14 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH:10]1(/[CH:16]=[C:17](\B2OC(C)(C)C(C)(C)O2)/[CH2:18][OH:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:10]1(/[CH:16]=[C:17](\[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)/[CH2:18][OH:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(Br)cc1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccc(/C(=C\C2CCCCC2)CO)cc1
Yield: 58.3 %

Procedure:
Following the method of example 46a, Suzuki coupling of 1-bromo-4-methoxy-benzene (0.65 g, 3.48 mmol) with (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -prop-2-en-1-ol (1.05 g, 3.94 mmol) in the presence of tetrakis(triphenylphosphino)palladium(0) (0.25 g, 0.22 mmol) and cesium fluoride (1.69 g, 11 mmol) in dioxane (20 mL) gives the title compound (0.5 g). 1H-NMR (CDCl3) δ=0.92-2.15 (m, 10H), 2.62-2.77 (m, 1H), 3.82 (s, 3H), 4.23-4.29 (m, 2H), 6.02-6.11 (m, 1H), 6.86-6.94 (m, 2H), 7.11-7.17 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([F:37])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1.[Al+3].[Cl-:39].[Cl-].[Cl-].CCS>C(Cl)Cl>[ClH:39].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[C:24]([F:37])[CH:23]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: [Cl-]
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(F)c2)cc1
Agent: [Al+3]
Solvent: CCS
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccc(OCCN2CCCCC2)c(F)c1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
960 mg (1.85 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]3-fluorophenyl]methanone was dissolved in 30 mL of methylene chloride and cooled to 0° C. and 2.5 g (18.5 mmol) of AlCl3 was added in portions over a 10 minute interval. To the reaction mixture was added 2.75 mL (37 mmol) of EtSH and the reaction was stirred for 15 minutes. The reaction was heated to reflux and allowed to proceed for 1.5 hours. The reaction was allowed to cool and quenched with 100 mL of ice water. The crude product precipitated out and was collected by decanting off the liquids. The solid was dissolved in 50 mL of MeOH and chromatographed on a silica gel column eluted with a solvent of MeOH-CHCl3 (1:9). The appropriate fractions were determined by tlc and combined. The combined fractions were evaporated to dryness in vacuo. The residue was dissolved in 25 mL of MeOH and precipitated by adding a MeOH-HCl solution until no more precipitate formed. The liquid was decanted off and the salt re-dissolved in a minimal amount of MeOH. Ether was then added and the product was allowed to crystallize at −20° C. This yielded 470 mg of the title compound.
Reaction SMILES: CN(CCC1C=CC=CC=1)[C:3](=O)[CH2:4]N1C2C(=CC(OCC3C=CC=CC=3)=CC=2)C(C=CC(OCC)=O)=C1.[CH3:38][N:39]([CH2:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:40](=[O:66])[CH2:41][N:42]1[C:50]2[C:45](=[C:46]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:47]=[CH:48][CH:49]=2)[C:44]([CH:59]=[CH:60][C:61]([O:63]CC)=[O:62])=[CH:43]1.CN(CCC1C=CC=CC=1)C(=O)CN1C2C(=C(OCC3C=CC=CC=3)C=CC=2)C(C=CC(O)=O)=C1>>[CH3:38][N:39]([CH2:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[C:40](=[O:66])[CH2:41][N:42]1[C:50]2[C:45](=[C:46]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:47]=[CH:48][CH:49]=2)[C:44]([CH:59]=[C:60]([C:61]([OH:63])=[O:62])[CH2:3][CH3:4])=[CH:43]1
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2cccc(OCc3ccccc3)c12
Agent: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC(=O)O)c2c(OCc3ccccc3)cccc21
Product: CCC(=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2cccc(OCc3ccccc3)c12)C(=O)O

Procedure:
When N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamide in the procedure of Example 23 is replaced with N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboethoxyvinyl)indol-1-yl]acetamide then the product prepared is N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide as a white powder. (m.p. 170°-174° C.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]([O:14][CH2:15][CH3:16])=[S:13])[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[O:20]>C(#N)C>[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]([O:14][CH2:15][CH3:16])=[S:13])[N:3]=1)=[O:32])(=[O:28])=[O:29])=[O:20]
Reactant: CCOC(=S)SCc1cc(OC)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: CCOC(=S)SCc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)n1

Procedure:
7.0 g of 2-amino-4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidine and 6.5 g of 2-methoxycarbonylphenylsulfonylisocyanate are suspended in 20 ml of abs. acetonitrile, and the suspension is stirred at 20° to 25° C. for 2 hours. A clear solution is firstly formed during this time, and the final product subsequently crystallises out. To isolate the final product, the reaction mixture is cooled to 0° C. and then filtered. The yield is 9.0 g (67% of theory) of N-(2-methoxycarbonylphenyl-sulfonyl)-N'-(4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidin-2-yl)-urea, m.p. 160°-162° C. (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)c(F)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
2.09 g of 3-hydroxypyridine and 5.52 g of potassium carbonate were added to a dimethylformamide (20 ml) solution of 3.18 g of 3,4-difluoronitrobenzene, and the reaction liquid was stirred at 90° C. for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to obtain the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and benzoyl chloride (55 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[H-].[Na+].[C:20]1([S:26]([Cl:29])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[ClH:29].[ClH:29].[C:20]1([S:26]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCN(Cc2ccc3[nH]ccc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-Methylpiperazine-1-ylmethyl)-1H-indole (0.8733 mmol, 0.2 gram) (obtained from Example 1) was dissolved in 2 mL N,N-dimethyl formamide. The above solution was then added slowly to 25 mL flask, containing a suspension of sodium hydride (1.31 mmol, 31.4 mg) in 1 mL DMF under nitrogen atmosphere, while maintaining the temperature below 10° C. The reaction mixture was then stirred for a period of 1 hour at 25° C. To this well stirred solution, benzenesulfonyl chloride (1.31 mmol, 0.2312 gram) was added slowly while maintaining the temperature below 10° C. The reaction mixture was further stirred for a period of 2 hours. After the completion of the reaction, the reaction mixture was poured onto 20 grams of ice-water mixture under stirring and the resulting mixture was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extracts were then washed with water (20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The volatiles were removed under the reduced pressure to obtain thick syrupy mass, which was purified over silica gel column, eluent being ethyl acetate and triethylamine (0.2 to 1.0%). This material was converted to dihydrochloride salt in diethylether solvent.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:14]([OH:16])=O)=[CH:6][CH:5]=1.[CH3:18][C:19]1([CH3:30])[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[C:22](=[O:28])[CH2:21][C:20]1=[O:29].C(N(CC)CC)C>C(#N)C.C[Si](C#N)(C)C>[F:17][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:14]([CH:21]2[C:20](=[O:29])[C:19]([CH3:30])([CH3:18])[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[C:22]2=[O:28])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=C(O)c1ccc(OC(F)F)c2ncccc12
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)c2ccc(OC(F)F)c3ncccc23)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.4 g (1.7 mmol) of 8-difluoromethoxy-5-quinolinecarboxylic acid was dissolved in 20 ml of acetonitrile, 0.4 g (1.9 mmol) of N,N-dicyclohexylcarbodiimide and 0.3 g (1.7 mmol) of 2,2,4,4-tetramethylcyclohexane-1,3,5-trione were added and the mixture was stirring at 25° C. for 20 hours. 0.4 g (4.0 mmol) of triethylamine and 2 drops of trimethylsilyl cyanide were then added, and stirring was continued at 30–35° C. for a further 3 hours. The precipitate was filtered off, and the filtrate was concentrated, 20 ml of 5% strength potassium carbonate solution were added and the mixture was washed with methyl tert-butyl ether. The aqueous phase was subsequently adjusted to pH 3 using concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was removed and the residue was chromatographed over silica gel (mobile phase: methylene chloride/methanol). This gave 0.2 g of a colorless powder;
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/[C:4](O)=O.[CH:9]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][C:10]=1[C:23](=S)[NH2:24].[OH2:26]>C(O)C>[CH2:10]([NH:24][C:23]([C:10]1[CH:11]=[CH:12][C:13]2[S:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:21]([CH:19]([CH3:18])[CH2:20][N:21]3[CH2:4][CH2:3][CH2:2][CH2:1]3)[C:22]=2[CH:9]=1)=[O:26])[CH2:9][CH3:22]
Reactant: NC(=S)c1ccc2c(c1)Nc1ccccc1S2
Reactant: O=C(O)/C=C/C(=O)O
Reactant: O
Solvent: CCO
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Fumaric acid (2.7 g) is added to a solution of N-propyl-10-[1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (9.5 g), in ethanol (100 cc). The solution obtained is concentrated to dryness under reduced pressure (300 mm Hg; 4 kPa) at 40° C. The meringue-like yellow residue is taken up with acetic acid (200 cc). Mercuric acetate (7.3 g) is added to the solution obtained and the mixture is stirred for 16 hours at a temperature in the region of 20° C. The black suspension obtained is diluted with distilled water (200 cc) and filtered. The yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc) and then treated with sodium hydroxide (d=1.33) to pH 13. The aqueous phase is separated after settling has taken place and extracted with ethyl acetate (250 cc). The organic phases are combined, washed successively with distilled water (2×100 cc) and with a saturated aqueous sodium chloride solution (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (9.2 g) is thereby obtained. This residue is purified by chromatography on a column (height: 22 cm; diameter: 4 cm) of silica gel (0.2-0.063 mm), eluting with a mixture of methylene chloride and methanol (95:5 by volume). The first 1500 cc are discarded and the next 1500 cc are concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-propyl-10-[1-(pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (7.3 g), in the form of a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH2:39]/[C:40](=[N:43]/[H])/[NH:41][OH:42])[CH:35]=[CH:36][C:37]=1[Cl:38]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:42][N:41]=[C:40]([CH2:39][C:34]4[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=4)[N:43]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1ccc(Cl)c(Cl)c1)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)c(Cl)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 66.1 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (46 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (66 mg, 66%).