Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CO
Solvent: ClCCl
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 90 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 g, 0.3 mmol) and phenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) in the manner described in Example 115C. The final product was purified by column chromatography (25-100% EtOAc/hexanes then 5-10% MeOH/DCM) to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (150 mg, 0.27 mmol, 90%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.03 (s, 1H), 8.57 (s, 1H), 7.61-7.57 (m, 2H), 7.49 (s, 1H), 7.43-7.38 (m, 2H), 7.31-7.24 (m, 2H), 6.95 (d, 1H), 6.86 (s, 1H), 4.19-4.11 (m, 2H), 4.00 (s, 3H), 3.99 (s, 3H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 559 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:40])[O:2][C@@:3]([CH3:39])([C:6](=[O:38])[C@@H:7]([NH:15][C:16](=[O:37])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH:27][C:28]([C:30]1[S:34][C:33]([CH3:35])=[N:32][CH:31]=1)=[O:29])[CH2:24][O:25][CH3:26])[CH2:18][O:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][I:5].[CH2:42]([OH:44])[CH3:43]>>[C:1](=[O:40])([O:2][C@@:3]([CH3:39])([C:6](=[O:38])[C@@H:7]([NH:15][C:16](=[O:37])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH:27][C:28]([C:30]1[S:34][C:33]([CH3:35])=[N:32][CH:31]=1)=[O:29])[CH2:24][O:25][CH3:26])[CH2:18][O:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][I:5])[O:44][CH2:42][CH3:43]
Reactant: CCO
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Cl
Product: CCOC(=O)O[C@](C)(CI)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COC)NC(=O)[C@H](COC)NC(=O)c1cnc(C)s1

Procedure:
Prepared according to procedures described above, by reacting ethanol with the intermediate (2S,4S)-1-iodo-4-((S)-3-methoxy-2-((S)-3-methoxy-2-(2-methylthiazole-5-carboxamido)propanamido)propanamido)-2-methyl-3-oxo-5-phenylpentan-2-yl carbonochloridate. 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.28-7.16 (m, 5H), 7.08 (d, J=9.2 Hz, 1H), 6.96 (d, J=7.2 Hz, 1H), 6.84 (d, J=6 Hz, 1H), 5.44-5.40 (m, 1H). 4.71-4.66 (m, 1H), 4.48-4.44 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.84-3.79 (m, 2H). 3.75-3.72 (m, 1H), 3.62 (d, J=11.2 Hz, 1H), 3.55 (t, J=4.8 Hz, 1H), 3.45 (s, 3H), 3.41-3.38 (m, 1H), 3.28 (s, 3H), 3.19-3.14 (m, 1H), 2.89-2.83 (m, 1H), 2.74 (s, 3H), 1.51 (s, 3H), 1.35 (t, J=7.2 Hz, 3H); MS for C28H37IN4O9S m/z: 733 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[NH2:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:25]/[N:26]3[CH2:30][CH2:29][NH:28][C:27]3=[O:31])/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: NN1CCNC1=O
Product: C/C(=N\N1CCNC1=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 74 %

Procedure:
The title compound (18.0 mg, 66%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (20.0 mg, 0.06 mmol) and 1-amino-imidazolidin-2-one (28.2 mg, 0.19 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H), 8.93 (dd, 1H), 8.41 (d, 1H), 8.20 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 7.38 (s, 1H), 6.25 (s, 2H), 3.86 (t, 2H), 3.42 (t, 2H), 2.38 (s, 3H). LCMS (method A): [MH]+=401, tR=2.01 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[N:24][CH:25]=1)#[CH:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:19]=[CH:18]/[C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: C#Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2ccc(C)nc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (453 mg, 2.0 mmol; Example 2B) and 5-ethynyl-2-methylpyridine (937 mg, 8.0 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound as the minor isomer: 1H NMR (300 MHz, methanol-d4) δ ppm 2.05-2.19 (m, 4H), 2.41 (s, 3H), 2.53 (s, 3H), 3.00-3.14 (m, 2H), 3.17-3.28 (m, 2H), 3.39-3.47 (m, 1H), 4.22 (s, 2H), 6.74 (d, J=15 Hz, 1H), 7.03 (dd, J=8, 2 Hz, 1H), 7.12-7.19 (m, 1H), 7.29 (d, J=8 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.69 (d, J=14 Hz, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 8.51 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 344 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15](OCCC)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].O.[NH2:24][NH2:25].O>C(O)C.O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15]([NH:24][NH2:25])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1ccc(-c2ccc(OCCC)cc2)cc1
Reactant: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCOc1ccc(-c2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of propyl 4-(4′-propoxyphenyl)benzoate (20.00 g) in a mixture of ethanol (100 ml) and tetrahydrofuran (40 ml) was added hydrazine monohydrate (32.5 ml). The mixture was refluxed for 2 hours, during this period additional hydrazine monohydrate (32.5 ml) was added into the mixture. After cooling to room temperature, the reaction mixture was poured into water (1800 ml) and then the mixture was stirred for 30 minutes at room temperature. The resulting precipitate was filtered, washed with water, and dried to give the objective compound, 4-(4′-propoxyphenyl)-benzoyl hydrazine (17.63 g), as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][C:14]=1[CH:19]=O>>[Cl:1][C:2]1[C:3]2[C:10](=[CH:19][C:14]3[NH:15][C:16]([CH3:18])=[CH:17][C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Product: Cc1cc(C)c(C=C2C(=O)Nc3ncnc(Cl)c32)[nH]1
Yield: 44.5 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 eq.) was condensed with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (1 eq.) at room temperature to give (44.5%) of 4-chloro-5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [CH:1]([CH:3]=C)=O.C(O[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:13]([O:12][CH:8]([O:9][CH2:10][CH3:11])[CH:1]=[CH2:3])[CH3:14]
Reactant: C=CC=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=CC(OCC)OCC
Temperature: 5 °C
Yield: 48 %

Procedure:
After 10 ml of acrolein commercially available from Aldrich, Co. is dissolved in 50 ml of anhydroust ethanol, 19 ml of triethylorthoformate and p-toluene sulfonic acid are added to the solution, and the resulting mixture is allowed to reflux under a nitrogen atmosphere for 5 hours. After that, the resulting solution is cooled to a temperature of 5° C., extracted with diethyl ether, washed with 5% sodium bicarbonate (NaHCO3) aqueous solution, dried with anhydrous magnesium sulfate (MgSO4), and then evaporated under a reduced pressure to remove ethanol. Next, the material is fractionally distilled, thereby giving 8.4 g of 3,3-diethoxy-1-propene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14]O)([O-:3])=[O:2].C1(C)C=CC=CC=1.N1C=CC=CC=1.[Cl-:29]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][Cl:29])([O-:3])=[O:2]
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCl)c([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
20 g 2-(2,4-dinitrophenyl)ethanol (94 mmol) are dissolved in 120 ml abs. toluene and 4 ml pyridine. 34 g thidnyl chloride (21 ml, 282 mmol) in 20 ml abs. toluene are quickly added in a drop-wise manner. After 2 h under reflux, this is cooled and poured onto ice. This is mixed with 100 ml CH2Cl2 and the aqueous phase is extracted 2× each with 50 ml CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and rotary evaporated. 21.51 g (93 mmol, 98%) 2-(2,4-dinitrophenyl)ethyl chloride are obtained as a brown oil.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][CH:16]=[CH2:17])[C:10]=2[C:9](=[O:18])[NH:8][C:7]1=[O:19])[CH2:2][CH2:3][CH2:4][CH3:5].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][N:8]1[C:9](=[O:18])[C:10]2[N:11]([CH2:15][CH:16]=[CH2:17])[CH:12]=[N:13][C:14]=2[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1=[O:19]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Yield: 100 %

Procedure:
3-Pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20 g, 0.76 mmol), potassium carbonate (0.4 g, 2.9 mmol) and methyl iodide (0.5 ml, 4.9 mmol) were stirred and heated at 50° C. in DMF (5 ml) for 3 h. The solution was allowed to cool and separated between ethyl acetate and brine. The organics were isolated, dried (MgSO4) and concentrated to provide the title compound (0.21 g, 100%). m/z 277[MH+]
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([N:14]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCN
Product: CCN(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C

Procedure:
The product from Example 14A and ethylamine were processed as described in Example 7B to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](I)[CH3:28].O>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:27]([O:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]1[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]2=1)[CH3:28]
Reactant: CCI
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc2nc(N)c3nc4n(c3c2c1)[C@@H](C)COC4
Temperature: 75 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol) and ethyl iodide (346 mg, 2.03 mmol). After stirring overnight at 75° C., the light brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 101 mg of the title compound as an off-white solid, mp 187-188° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH3:20])[C:12](=[C:13]=[S:14])[C:11](=[C:15]=[S:16])[CH2:10][CH2:9][C:8]2=[CH:17][CH:18]=[O:19])[CH:2]=1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH3:20])[C:12](=[C:13]=[S:14])[C:11](=[C:15]=[S:16])[CH2:10][CH2:9][C:8]2=[CH:17][CH2:18][OH:19])[CH:2]=1
Reactant: CC1(c2cccnc2)C(=C=S)C(=C=S)CCC1=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(c2cccnc2)C(=C=S)C(=C=S)CCC1=CCO
Yield: 66.7 %

Procedure:
A solution of 2-(pyrid-3-yl)-2-methyldithiocarbonyl-1-formylmethylenecyclohexane (890 mg, 3 mmol) in methanol (20 ml) at 25° C. was treated with sodium borohydride (127 mg, 3.36 mmol). After 30 mins at 25° C. the solution was treated with ethyl acetate (50 ml) and water (20 ml) was added dropwise. The organic phase was removed and dried over magnesium sulphate. Concentration in vacuo yielded a crude oil. Purification over silica gel, eluting with ethyl acetate/n-hexane (7:3) afforded 2-(pyrid-3-yl)-2-methyldithiocarbonyl-1-(2-hydroxyethylidene)cyclohexane (590 mg, 2 mmol) as an orange solid, m.p. 139°-140° C.;
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1)[CH2:2][CH3:3].O.O.O.O.O.O.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:14].[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1)[CH2:2][CH3:3]
Reactant: C1CNCCN1
Reactant: CCCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: O
Product: CCCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Product: Cl
Yield: 16.4 %

Procedure:
A mixture of 1-propyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 0.95 g (3.3 millimole) and piperazine hexahydrate 10 g (50 millimole) was heated in a sealed tube at 125°-135° C. (inner temperature) for 22 hours. After cooling, the reaction mixture was evaporated under vacuum, and the residue was acidified with acetic acid and the insoluble matters were removed by filtration. The filtrate was neutralized with an aqueous solution of caustic soda, extracted with the use of CHCl3, washed with water, dried over anhydrous Na2SO4, and the solvent was evaporated off. The residue was dissolved in dilute hydrochloric acid, reprecipitated with the addition of ethanol. The precipitated crystals were collected by filtration, washed with ethanol and dried to obtain 0.2 g (16%) of 1-propyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride. Colorless powders.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([C:25](=[CH2:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:31][CH:25]([CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCNC(=O)OCc1ccccc1
Reactant: C=C(CCc1ccccc1)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CNCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A mixture of 20 g of 4-benzyloxycarbonylamino-1-butylamine, 21.04 g of ethyl α-(phenethyl)acrylate and 200 ml of ethanol was stirred at room temperature for 8 days and evaporated to dryness. The residue was dissolved in ethyl ether and the solution was extracted three times with 100 ml of 2N hydrochloric acid. The aqueous layer was basified with 2N sodium hydroxide and extracted three times with methylene chloride, dried over magnesium sulfate and evaporated to give the ethyl 2-(4-benzyloxycarbonylaminobutyl)aminomethyl-4-phenylbutyrate having signals in the NMR spectrum at δ=7.4, 7.25, and 5.1 ppm.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(=O)(O)[O-].[K+]>CO>[C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH:22][CH2:30][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=3)[CH:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(C(F)(F)F)cc1
Yield: 40.7 %

Procedure:
A methanol (7 ml) solution of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide (0.50 g), 4-(trifluoromethyl)benzyl bromide (0.418 g) and potassium bicarbonate (0.423 g) is stirred for 1 hour at 60° C. to give preliminarily purified N-benzenesulfonyl-4-acetylamino-3-[4-(trifluoromethyl)benzylamino]benzamide (0.30 g). This is dissolved in methanol. When it is left undisturbed crystals precipitated. The crystals are separated through filtration, dried and thus, 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole (0.160 g)is obtained.
Reaction SMILES: [C:1]1([P:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([OH:17])[CH3:16].N1C=CC=CC=1>CCOCC>[C:1]1([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:17][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOP(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of diphenylphosphinous chloride (135 mmol) in dry ether (120 mL) was treated dropwise at 5° C. with a solution of ethanol (200 mmol) and pyridine (134 mmol) in ether (120 mL). After addition was complete, the mixture was warmed to room temperature, filtered under argon, and the solid hydrochloride washed with ether. Evaporation of the solvent gave an oil which was purified by Kugelrohr distillation at 95° C. (0.1 mmHg). Yield: 119 mmol (88%); 1H NMR (CDCl3) δ7.6-7.2 (m, 10H), 3.95 (doublet of quartets, JH-H =7 Hz, JP-H =10 Hz, 2H), 1.30 (t, J=7 Hz, 3H).
Reaction SMILES: Cl.[C:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[NH:3][NH2:4].[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=O)[CH3:14].C(O)C>O>[N:19]1[CH:20]=[CH:21][C:16]([C:13](=[N:4][NH:3][C:2]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:5])[CH3:14])=[CH:17][CH:18]=1
Reactant: NNC(=O)Oc1ccccc1
Reactant: CC(=O)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=NNC(=O)Oc1ccccc1)c1ccncc1
Yield: 53.9 %

Procedure:
A solution of 5.66 gm (0.03 mole) of phenyl carbazate hydrochloride, 3.63 gm (0.03 mole) of 4-acetylpyridine and 50 ml of ethanol is refluxed 2 hr. The solution is cooled and evaporated to dryness in vacuo to give an oil. The oil is triturated with ethyl acetate-methanol to afford a solid. The solid is dissolved in 50 ml of water and treated with 50 ml water containing 5 gm sodium carbonate. A gummy solid separates which solidifies on standing. The crude product is collected and crystallized from ethyl acetate-Skellysolve B to yield 4.13 gm (54%) of the title compound having a melting point of 120.4° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3]C(Cl)=O)[CH3:2].[CH:7]1[C:17]2[C:16](=[C:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH:29]1C=CC=CC=1>>[CH:7]1[C:17]2[C:16](=[C:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:2][C:1](=[O:3])[CH3:29])[CH2:22][CH2:23]3)[C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: c1ccccc1
Reactant: CN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Reactant: CCOC(=O)Cl
Product: CC(=O)CCN1CCC(=C2c3ccccc3COc3ccccc32)CC1

Procedure:
A solution of 96 g of chloroformic acid ethyl ester in 100 cc of benzene is added dropwise to a solution of 64 g of 4-(6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)-1-methylpiperidine in 600 cc of benzene, and the mixture is heated in an oil bath of 100° for 4 hours. After cooling, the reaction mixture is filtered through diatomaceous earth, the filtrate is extracted with 2 N hydrochloric acid and water, dried over magnesium sulphate and completely concentrated at reduced pressure. The resulting urethane is split in a manner analogous to that described in Example 4 a), whereby crude 4-(6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)piperidine is obtained as yellow-brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.[C:15](=[S:17])=[S:16].Cl[CH2:19][C:20](=O)[CH3:21]>C(O)C>[OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][N:7]1[C:20]([CH3:21])=[CH:19][S:16][C:15]1=[S:17]
Reactant: S=C=S
Reactant: NCCSCCO
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc(=S)n1CCSCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In 500 ml of ethanol, 24.2 g of (2) and 24.7 ml of triethylamine were dissolved and cooled to 0° C. Thereto, 16.8 g of carbon disulfide was added dropwise. The resulting mixture was allowed to stand for 2 hours at a room temperature and further, for an additional 30 minutes at 50° C. to conduct the reaction. Then, the reaction mixture was cooled to 0° C. again. Thereto, 19.4 g of chloroacetone was added dropwise. The reaction was run by keeping the temperature of the reactionsystem at a room temperature for 1 hour and further, at 40° C. for an additional 2 hours. At the conclusion of the reaction, the solvent was removed by distillation under reduced pressure, and water was added to the residue. The reaction product was extracted with ethyl acetate, washed with water three times, and dried over anhydrous sodium sulfate. Upon the removal of ethyl acetate from the extract by distillation, (1) was obtained as an oily sub stance.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[C:11]([Cl:18])[N:10]=2)[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27](NC1CCN(C2C=C(C3N=CON=3)C=C(Cl)N=2)CC1)=[O:28]>>[C:15]([C:13]1[CH:12]=[C:11]([Cl:18])[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:27]([C:21]3[NH:22][C:23]([CH3:26])=[C:24]([Cl:25])[C:20]=3[Cl:19])=[O:28])[CH2:4][CH2:5]2)[CH:14]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1

Procedure:
The title compound was synthesized by an analogous method to Example 18 starting from 1-[2-(4-aminopiperidin-1-yl)-6-chloropyridin-4-yl]ethanone hydrochloride salt (Intermediate 197) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).