Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH3:1][C:2]1([CH3:12])[CH:6]2[CH2:7][N:8]([C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:9][CH2:10][N:5]2[C:4](=[O:11])[O:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC1(C)OC(=O)N2CCNCC21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OC(=O)N2CCN(C(=O)Oc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
Hexahydro-1,1-dimethyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.10 g, 0.59 mmol) was dissolved in tetrahydrofuran (10 mL). Triethylamine (0.17 mL, 1.2 mmol) and phenyl chlorocarbonate (0.11 mL, 0.88 mmol) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:2). After purification, the crystals, which were precipitated while concentrating under reduced pressure, were collected by filtration to obtain the title compound (0.14 g, yield 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C1CCC(=O)O1
Reactant: CN(C)CCO
Solvent: c1ccncc1
Product: CN(C)CCOC(=O)CCC(=O)O

Procedure:
The 2-dimethylamino ethanol (10 g, 0.11 mol) was dissolved in pyridine (100 mL) followed by the addition of succinic anhydride (16 g, 0.16 mol). The mixture was stirred at room temperature for 18 h before the pyridine was removed under vacuum at 40 C. The remaining solid was recrystallized from MeOH/Ether. The characterization data were consistent with the chemical structure and formula.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]([CH:37]=[O:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH:37]([N:11]([CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])=[O:38]
Reactant: CCOP(=O)(CCN(C=O)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CN(C=O)CCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of crude [2-(formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonic acid diethyl ester (78 mg, 0.14 mmol) in acetonitrile (1 mL) was added TMSBr (177 μL, 1.4 mmol) and 2,6-lutidine (163 μL, 1.4 mmol). The solution was stirred at room temperature for 1 hour when it was quenched by addition of methanol and 1N aqueous HCl. The product was extracted with EtOAc and purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 29 mg of the product as a white solid. The NMR data of this compound shows two rotamers with the ratio of approximately 70:30. 1H NMR (300 MHz, CD3OD) δ 1.62 and 1.64 (s, 3H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 3.38-3.55 (m, 4H), 3.78 (s, 3H), 3.80 and 3.91 (s, 2H), 5.22 (s, 2H), 5.39-5.52 (m, 1H), 8.03 and 8.18 (s, 1H) ppm; MS (m/z) 414.2 [M+H]+, 436.2 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 90.6 %

Procedure:
2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005) (1.25 g, 4.80 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (1.30 g, 6.28 mmol, 130 M %). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5006) (1.68 g, 4.35 mmol, 91% yield). M.p. 154-155° C. 1H-NMR (200 MHz, CD2Cl2): δ 7.52 (m, 1H, H4′), 7.25 (m, 1H, H4″), 7.19 (dd, J=7.8, 1.0 Hz, 1H, H5), 7.13-7.00 (m, 3H, H3′,5′,6), 6.81 (m, 2H, H3″5″), 6.72 (dd, J=7.8, 1.0 Hz, H7), 5.33 (s, 2H, CH2PhF2), 4.00 (s, 3H, OCH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=O)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].CO.C([O-])=O.[NH4+].[BH3-]C#[N:24].[Na+]>Cl.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([NH2:24])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCC(=O)CC(=O)OCC
Reactant: [BH3-]C#N
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCC(N)CC(=O)OCC

Procedure:
Diethyl-3-oxoadipate (10 g, 46 mmol) was added to methanol (225 ml) followed by ammonium formate (27.4 g, 460 mmol) and NaBH3CN (2.7 g, 46 mmol) at 25° C. After 24 h the methanol was removed in vacuo to leave a white mass. Methylene chloride was added and the mixture filtered. The methylene chloride was evaporated resulting in an oil which was dissolved in 1N HCl (200 ml) and extracted with ether (100 ml). The ether layer was discarded and the aqueous layer was made basic using solid K2CO3. The product was extracted into methylene chloride dried over Na2SO4 and evaporated to give Diethyl-3-aminopimaleate (7.5 g). 1H NMR (d6-DMSO) δ 1.25 (t, 3H, J=8Hz), 1.26 (t, 3H, J=8Hz), 1.8 (m,2H), 1.55 (bs, 2H), 3.18 (m, 1H), 4.13 (q, 4H, J=8Hz), 4.15 (q, 4H, J=8Hz); MS (FAB) m/e 218.3 (M+H+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[O:14][C@H:13]([CH2:15][O:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:12]([F:36])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[NH:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][CH:5]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([F:36])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[NH:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@@H](OC(C)=O)O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](F)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N[C@H]1C(OC(C)=O)O[C@H](CO)[C@@H](F)[C@@H]1OC(C)=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
The compound (13) (10.864 g) was dissolved in an aqueous 90% acetic acid (330 ml) and the solution was stirred at 50° C. for 3 hours. After the completion of the reaction, the solution was concentrated. The residue was dissolved in ethanol to deposit triphenylcarbinol, and the mixture was filtered and concentrated again to obtain a syrup. The syrup was purified by a column chromatography [chloroform/methanol (100:1)] using Wako gel C-200 to give 5.150 g of the compound (14) (yield: 91.5%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Br:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH:27]([NH2:29])[CH3:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[Br:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH:27]([NH:29][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=3[Cl:1])[CH3:28])[CH2:20][CH2:21][C:22]([F:25])([F:26])[CH2:23][CH2:24]2)=[CH:15][CH:14]=1
Reactant: CC(N)C1(c2ccc(Br)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CC(NC(=O)c1cccc(Cl)c1Cl)C1(c2ccc(Br)nc2)CCC(F)(F)CC1

Procedure:
From 2,3-dichlorobenzoic acid and 1-(1-(6-bromopyridin-3-yl)-4,4-difluorocyclohexyl)ethanamine. LCMS (MH+): m/z=493.1, tR (minutes, Method D)=0.83
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:33]([O-])=O)=[C:4]([OH:32])[C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])=[CH:6][C:7]=1[Cl:8].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH2:44]>C(O)(C)C>[Cl:8][C:7]1[C:2]2=[N:1][C:11](=[O:14])[CH2:12][C:13](=[O:44])[N:33]=[C:3]2[C:4]([OH:32])=[C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:22])[CH3:23])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])[CH:6]=1
Reactant: O
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)c([N+](=O)[O-])c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2

Procedure:
In a mixture of 200 ml of water and 40 ml of isopropanol was dispersed 20 g of the 3-amino-4-chloro-2-nitro-6-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol prepared in (4) above, and 100 g of sodium hydrosulfite was slowly added to the dispersion while stirring and heating on a steam bath. After refluxing, the reaction mixture was concentrated, and the precipitated solid was collected by filtration, washed with water, and dried to provide 17 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9].[N-:15]=[N+:16]=[N-:17].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]([N:15]=[N+:16]=[N-:17])=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(C=CC(=O)Cl)ccc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=CC(=O)N=[N+]=[N-])ccc1C

Procedure:
The 3-(3-methoxy-4-methylphenyl)acryloyl chloride was dissolved in acetone (800 ml). The resulting solution was added slowly (15 min) at 0° C. to a mixture of sodium azide (13 g) in water (100 ml) and acetone (100 ml) while vigorously stirring and cooling with an ice-bath. After addition was complete the reaction mixture was stirred at 0° C. for 90 minutes while vigorously stirring. The reaction mixture was then poured out on ice-water (300ml). After stirring for 15 minutes the mixture was filtered and the solid residue washed with excess water. The remaining solid residue was dissolved in dichloromethane (45 ml). The liberated water was removed with a separatory funnel. The dichloromethane layer was dried with Na2SO4 and filtered to give a dichloromethane solution of 3-(3-methoxy-4-methylphenyl)acryloyl azide for immediate use in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH2:8][CH2:7][CH:6]=2>[Pd].C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C2=c3cc(O)ccc3=CCC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc3ccc(O)cc23)CC1
Yield: 34.7 %

Procedure:
10% Palladium on carbon (1.16 g) and 7-hydroxy-1-(4-methyl-1-piperazinyl)-2,3-dihydronaphthalene (1.48 g, 6.06 mmol) were slurried in toluene (100 mL) and refluxed 16.5 h. The mixture was cooled, filtered, and concentrated. The product was purified by flash chromatography on silica gel (1×6 inches). Elution with 50% ethyl acetate/hexane followed by 100% ethyl acetate gave 0.51 g (34%) of the title product as a light pink foam. A sample was recrystallized from ether to give a cream colored solid for analysis: mp 184°-185° C. Analysis calculated for C15H18N2O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.05; H, 7.03; N, 11.42.
Reaction SMILES: [F:1][C:2]1([F:59])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH:44]([CH3:46])[CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:47]([F:58])[C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[CH2:4][CH2:3]1.FC1(F)CCC(C2C3C(OCC4C=CC(OC)=CC=4)CC(C)(C)CC=3N=C(C3CCN(C4N=CC(COCC)=CN=4)CC3)C=2C(F)C2C=CC(C(F)(F)F)=CC=2)CC1>>[F:59][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH:44]([CH3:45])[CH3:46])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:47]([F:58])[C:48]2[CH:49]=[CH:50][C:51]([C:54]([F:55])([F:57])[F:56])=[CH:52][CH:53]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(COC(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Product: CC(C)OCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Yield: 67.7 %

Procedure:
Reactions similar to those of Example 26 were performed except for using 54 mg (0.065 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(propan-2-yloxy)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 23 instead of 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline to provide 31 mg of the title compound as a white solid (yield: 67%).
Reaction SMILES: C1(C)C=CC=CC=1.C[O:9][C:10]1[CH2:14][CH:13]([OH:15])[C:12](=O)[C:11]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].CO.Cl>C1C=CC=CC=1>[OH:15][CH:13]1[CH2:14][C:10](=[O:9])[C:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:12]1
Reactant: COC(=O)CCCCCCC1=C(OC)CC(O)C1=O
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCC1=CC(O)CC1=O
Reaction time: 2 h

Procedure:
A solution of 15.5 parts by volume of a 1.83 M sodium dihydro bis(2-methoxyethoxy)aluminate in benzene solution in 87 parts of toluene and a solution of 6.92 parts of methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-eneheptanoate in 176 parts of toluene are simultaneously added, dropwise, to 87 parts of dry toluene which has been cooled to -70°. The addition takes place at a rate such that the temperature does not go above -60° and at a rate such that the sodium dihydro bis(2-methoxyethoxy)aluminate is added slightly faster that the diester. The addition takes place over a period of about 15 minutes and the reaction then is allowed to stir at -70° for 31/2 hours. After that time, the temperature is allowed to rise to 0° and the reaction mixture is stirred at that temperature for 15 additional minutes. Then 4 parts of methanol in 8.7 parts of toluene is added, followed by the addition of 150 parts by volume of 1 N aqueous hydrochloric acid. The aqueous and organic layers which form are separated and the organic layer is washed successively with aqueous potassium bicarbonate and water and dried over anhydrous sodium sulfate. The solvent is stripped under reduced pressure to afford methyl 3-hydroxy-5-oxocyclopent-1-eneheptanoate. That crude product is then dissolved in 222 parts of tetrahydrofuran and treated with 30 parts by volume of a 1 N aqueous hydrochloric acid solution. The total mixture is allowed to stand at about 4° for about 16 hours and then the tetrahydrofuran is removed under reduced pressure. The remaining material is diluted with ethyl acetate, and the organic layer is washed with potassium bicarbonate and water and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the crude material which remains is crystallized from ethyl ether to afford pure methyl 3-hydroxy-5-oxocyclopent-1-eneheptanoate, melting at about 50°-51°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](Cl)=[O:25]>>[Cl:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1sccc1Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4sccc4Cl)nc23)CC1
Yield: 57.5 %

Procedure:
Beginning with 0.30 gm (1.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.29 gm (1.56 mMol) 3-chloro-2-thiophenecarbonyl chloride, 0.28 gm (57%) of the title compound were prepared as an orange foam essentially by the procedure described in Example 4.
Reaction SMILES: [C:1]1([CH3:8])[C:6](O)=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])(=[O:11])[CH3:10].C1(C=CC(O)=CC=1)[OH:22].C(O)(=O)C=C.CN(C)CC1C=CC=CC=1>>[C:8]1(=[O:22])[O:12][C:9](=[O:11])[CH:6]2[CH2:5][CH2:4][CH:3]=[CH:2][CH:1]12.[C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])(=[O:11])[CH3:10]
Reactant: Cc1ccccc1O
Reactant: Oc1ccc(O)cc1
Agent: C=CC(=O)O
Agent: CCOCCOCCOC(C)=O
Agent: CN(C)Cc1ccccc1
Product: O=C1OC(=O)C2CCC=CC12
Temperature: 110 °C

Procedure:
A reflux condenser, a thermometer, a bleed tube, and a stirrer were set to a four-necked flask. In order to prepare a reaction solution, 203 parts by mass of cresol novolac epoxy resin “YDCN-700-5” (available from NIPPON STEEL CHEMICAL CO., LTD., epoxy equivalent weight: 203), 103 parts by mass of diethylene glycol monoethyl ether acetate, 0.2 parts by mass of hydroquinone, 72.7 parts by mass of acrylic acid, and 0.6 parts by mass of dimethyl benzyl amine were added to the four-necked flask. The reaction solution was heated at 110° C. for 10 hours to cause the addition reaction. Subsequently, into thus-obtained solution in the four-necked flask, 60.8 parts by mass of tetrahydrophthalic acid anhydride and 78.9 parts by mass of diethylene glycol monoethyl ether acetate were added, and then thus-obtained solution was heated at 81° C. for 3 hours to react them. Consequently, a 65 mass % solution (carboxyl group containing resin solution C-3) of resin containing a carboxyl group was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH:10]([N-]C(C)C)([CH3:12])[CH3:11].[Li+].C(Br)C=C.O>O1CCCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1)[CH2:12][CH:10]=[CH2:11]
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccnc(C#N)c1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C=CCCc1ccnc(C#N)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of 4-methylpyridine-2-carbonitrile (2.0 g) in THF (60 mL) was added 2.0 M LDA in heptane/THF/ethylbenzene (10.2 mL) at −78° C. The mixture was stirred at −78° C. for 2 hr. Allyl bromide (2.4 g) was added to the mixture at −78° C. The reaction mixture was stirred at −78° C. for 2.5 hr and at RT for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=9/1) to give the title compound (0.34 g, 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>ClCCCl>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCCl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cn1
Reaction time: 0.17 h

Procedure:
5-Chloro-2-aminopyridine (450 grams; 3.5 moles) and 5000 ml. of 1,2-dichloroethane were slurried together. The flask was then purged with nitrogen and a cold water bath applied, resulting in a lowering of the temperature to 20° C. 2,6-Dichlorobenzoyl isocyanate (912 grams; 4.2 moles) was added dropwise over one hour, holding the temperature at <30° C. The reaction mixture was stirred for 10 minutes, the cold water bath was removed, and a hot tap water bath (about 55° C.) was applied. The flask temperature rose to 42° C. and was held at 40° C. for 30 minutes. TLC showed that all starting material had been reacted. Solvent was removed on a rotary evaporator, and the solid residue was slurried with 1 liter of methanol, chilled and filtered. Yield was 1177 grams. m.p. 219°-222° C. Identity of the product was confirmed by NMR and IR.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 1.66 g (23.9 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 2.95 g (35.1 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 2.0 g (15.97 mmol) of octanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a crude residue. The residue was chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8]([C:10]([CH3:12])=[CH2:11])=[CH2:9]>C1(C)C=CC=CC=1>[CH3:9][C:8]1[CH2:7][CH:2]([C:1]([O:5][CH3:6])=[O:4])[CH2:3][CH2:11][C:10]=1[CH3:12]
Reactant: C=C(C)C(=C)C
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(C)=C(C)C1
Yield: 87 %

Procedure:
A solution of methyl acrylate (1 eq.) and 2,3-dimethylbuta-1,3-diene (1.1 eq.) in toluene (2M) was pumped through a heated coil reactor at 220° C. with a residence time of 17 minutes. The resulting mixture was concentrated under reduced pressure and yielded the product as colorless oil (87% yield).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[N:46]#[C:47]Br.C(=O)(O)[O-].[Na+]>O>[NH2:46][C:47]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(N)nc12
Reaction time: 2 h
Yield: 26.6 %

Procedure:
To a suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (242 mg) in water (3 ml) was added cyanogen bromide (46 mg) at ambient temperature. The mixture was stirred at the same temperature for 2 hours and then allowed to stand at the same temperature overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and the solution was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-amino-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (67 mg) as a powder.