Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1.[CH2:10](O)[CH2:11][CH2:12][OH:13].O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:4][CH2:3]1
Reactant: OCCCO
Reactant: O=CC1CCC(Cl)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: ClC1CCC(C2OCCCO2)CC1

Procedure:
A solution of 10.62 g of 4-chlorocyclohexanecarboxalde-hyde in 150 ml of toluene is treated with 11.5 ml of 1,3-propanediol and 1 g of Amberlyst® 15 and heated to boiling for 2 hours on a water separator while stirring. The reaction mixture is treated with 2 ml of triethylamine and, after cooling, is filtered. The filtrate is washed three times with 30 ml of water, dried over sodium sulphate and concentrated. There is obtained 2-(4-chlorocyclohexyl)-1,3-dioxane.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[F:37])=[CH:25][CH:26]=1.O>CN(C)C=O>[F:37][C:28]1[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[C:22]([CH3:38])[C:21]([CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:15][CH:14]=2)=[CH:26][CH:25]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 359 mg (1.65 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 20.0 ml N,N-dimethylformamide was treated at 0° C. with 66 mg (1.65 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 500 mg (1.65 mmol) 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine were added and stirred continued at r. t. over night. After addition of 40 ml water, the precipitate was isolated, washed thoroughly with water and diisopropylether. The residue was dried at 40° C. to give 618 mg (77%) of the title compound as light brown powder.
Reaction SMILES: N1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:42]=[CH:41][C:32]5OC(F)(F)OC(F)(F)[C:31]=5[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])C=CN=C1.NCCCN1C=CN=C1.[CH3:52][N:53]1C2C(=CC(NC(NC3C=CC(OC4C=CN=C(C(N)=O)C=4)=CC=3)=O)=CC=2)[CH:55]=[N:54]1.FC1(F)OC2C=CC(NC(NC3C=CC(OC4C=CN=C(C(OC)=O)C=4)=CC=3)=O)=CC=2C(F)(F)O1>>[CH:8]1([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[C:31]5[C:32](=[CH:41][CH:42]=4)[N:54]([CH3:55])[N:53]=[CH:52]5)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCCn3ccnc3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: Cn1ncc2cc(NC(=O)Nc3ccc(Oc4ccnc(C(N)=O)c4)cc3)ccc21
Agent: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)cc2)ccn1
Agent: NCCCn1ccnc1
Product: Cn1ncc2cc(NC(=O)Nc3ccc(Oc4ccnc(C(=O)NC5CC5)c4)cc3)ccc21

Procedure:
The title compound was prepared in the same manner described for N-[3-(1H-imidazol-1-yl)propyl]-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}-amino)phenoxy]pyridine-2-carboxamide, substituting cyclopropylamine for 1-(3-aminopropyl)imidazole and 4-[4-({[(1-methyl-1H-indazol-5-yl)amino]-carbonyl}amino)-phenoxy]pyridine-2-carboxamide for methyl 4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxylate. 1H-NMR (MeOH-d4/CD2Cl2) δ 8.42 (d, J=5.5 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.45-7.57 (m, 5H), 7.08 (m, 2H), 7.02 (dd, J=5.5, 2.6 Hz, 1H), 4.04 (s, 3H), 2.84 (m, 1H), 0.81 (m, 2H), 0.65 (m, 2H); MS LC-MS [M+H]+=443.2, RT=2.51 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1C(O)=O.CN([CH:55]=[O:56])C>CCCCCC.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:55]([C:47]2[C:48]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[CH:45][CH:46]=2)=[O:56])[CH2:10][C@@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-2(S)-(2-hydroxyethyl)piperazine (0.479 g, 2.08 mmol) in DMF was added EDC.HCl (0.432 g, 2.25 mmol), HOBT (0.314 g, 2.05 mmol) and naphthalene-2-carboxylic acid (0.353 g, 2.05 mmol). Triethylamine was added to pH 7. The reaction was stirred overnight at room temperature. The DMF was removed in vacuo and the residue dissolved in 1:1 methanol-tetrahydrofuran and 5% sodium hydroxide added. The reaction was stirred several hours, the solvent evaporated and the residue partitioned between ethyl acetate and 5% sodium hydroxide. The organic phase was dried over magnesium sulfate and the crude product thus obtained chromatoraphed on silica gel with 50% ethyl acetate in hexane. The title compound was obtained as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].O>ClCCl>[S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)([O:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[Br:1])(=[O:21])=[O:20]
Reactant: OCCOc1ccccc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccccc2Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(2-Bromophenoxy)ethanol (17.4 g) was dissolved in dichloromethane (250 ml) and cooled to 0° C. Triethylamine (9.7 g) was added along with tosyl chloride (18.3 g). The mixture was stirred for 2 h, then added to water (500 ml). The organics were washed twice with 2N hydrochloric acid and dried. Separation was achieved using silica chromatography eluting with hexane/ethyl acetate mixtures. This gave 2-(2-bromophenoxy)ethyl tosylate (14.4 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:20][CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:30][CH3:31])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:43][CH:44]([F:46])[F:45])(=O)=O>C(O)C>[F:45][CH:44]([F:46])[CH2:43][N:20]1[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][O:23][C:16]2([CH2:15][CH2:14][N:13]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([O:30][CH3:31])[CH:7]=3)=[O:12])[CH2:18][CH2:17]2)[CH2:19]1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CNC(c2ccccc2)CO3)ccc1OC(C)C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)CN(CC(F)F)C(c2ccccc2)CO3)ccc1OC(C)C
Temperature: 80 °C
Yield: 25.6 %

Procedure:
To a solution of (4-isopropoxy-3-methoxy-phenyl)-(9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone (15 mg, 0.04 mmol) in ethanol (375 μL) was added NaHCO3 (12 mg, 0.14 mmol), followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (11 mg, 0.05 mmol). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was filtered and purified by Waters mass directed LC/MS: (1-99% ACN/H2O (5 mM HCl) to obtain [8-(2,2-difluoroethyl)-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone (5 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 7.45-7.36 (m, 5H), 6.98-6.83 (m, 3H), 5.25 (d, J=10.4 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 3.85 (s, 3H), 3.60 (d, J=10.9 Hz, 1H), 3.47-3.12 (m, 6H), 2.86-2.60 (m, 3H), 1.88-1.50 (m, 5H), 1.38 (d, J=6.1 Hz, 6H); ESI-MS m/z calc. 488.5. found 489.7 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CS(Cl)(=O)=O.CCN(CC)CC.O>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Fc1cccc(-c2cc3ccc(C(F)(F)F)cn3n2)c1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 84.2 %

Procedure:
To a suspension of 1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (10.0 g, 33.53 mmol) in DME (38 ml) was added MsCl (2.6 ml, 33.53 mmol) at 0° C. The suspension was stirred for 15-20 min and then Et3N (9.3 ml, 67.1 mmol) dissolved in DME (4 ml) was added dropwise at a rate to maintain the temperature ≦5° C. After the addition was complete, the suspension was warmed to room temperature and stirred for 1 hour. Additional Et3N (0.47 ml, 3.35 mmol) was added and the solution was stirred for 15 min at 30-35° C. The suspension was cooled to room temperature and filtered to remove the salts. The cake was washed with twice with DME (10 ml) and the filtrate was transferred to a clean reaction flask. To the filtrate was added FeCl2 (42 mg, 0.34 mmol) at room temperature. The solution was heated to 70° C. and stirred for 30 min. After cooling the solution to 40° C., H2O was added (80 ml). The resultant suspension was cooled to 0-5° C. and stirred for 30 min. The solid was isolated by filtration and partially dried via airflow. The solid was further dried under reduced pressure (20 in Hg Vacuum) at 50° C. to afford 7.91 g (84%) of the title compound as a beige solid.
Reaction SMILES: [CH:1]1([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]1([CH2:7][O:8][NH:9][S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
2-(cyclohexylmethoxy)-1H-isoindole-1,3(2H)-dione (11.8 mmol, 3.05 g) was combined with hydrazine (12.9 mmol, 0.41 mL) in anhydrous THF (25 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 48 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (9.5 mmol, 1.97 g) and diisopropylethylamine (11.6 mmol, 2.03 mL) was added. After stirring at room temperature for 18 hours, the reaction was concentrated to a solid residue and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The product was concentrated to a solid and purified by silica gel chromatography (2:1 hexanes/ethyl acetate) providing 2.55 g (80%) of a yellow solid. H1-NMR (CDCl3): δ 7.81 (2H,d), 6.97 (2H,d), 6.78 (1H,s), 3.85 (3H,s), 3.75 (2H,d), 1.65-1.55 (6H,m), 1.25-1.07 (3H,m), 0.93-0.85 (2H,m).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=O)C.C=O.[ClH:21]>O>[C:1]1([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH2:15][Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: Cl
Agent: C=O
Solvent: O
Product: ClCC=C(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 3.5 h
Yield: 99.7 %

Procedure:
A 300-ml reaction flask was charged with 54.13 g (0.3 mol) of 1,1-diphenylethylene (9a), 108.26 g of acetic acid and 13.51 g (0.45 mol) of paraformaldehyde, and 13.67 g (0.375 mol) of hydrogen chloride was blown in with stirring at 30° C. for 3.5 hours. The reaction temperature was kept at 30° C. by cooling because of weak heat development. The blowing-in of hydrogen chloride was stopped, and the solution was stirred at the same temperature for 2 hours, followed by standing overnight. The reaction solution was poured into 200 ml of water, followed by extraction with 200 ml of toluene. The resulting product was washed with water, washed with 2% soda ash, washed with water, dried over magnesium sulfate, and concentrated to obtain 68.42 g of a crude chloride. It was distilled in a Claisen flask equipped with a vigreux to obtain 57.51 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[O:28])=[C:22]([CH3:38])[C:21]=3[CH3:39])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:40][CH3:41])[C:2]1C=CC=CC=1.[H][H].CN(C)[CH:46]=[O:47]>C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[CH3:41][O:40][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][CH2:1][CH2:2][O:47][CH3:46])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[O:28])=[C:22]([CH3:38])[C:21]=1[CH3:39]
Reactant: COc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)c(C)c1C
Reactant: CN(C)C=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4OC)c(C)c3C)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylphenyl)-N′-(2-methoxyphenyl)urea (161 mg) was dissolved in N,N-dimethylformamide (4 ml) and triethylamine (1 ml), and palladium hydroxide (32 mg) was added to the solution. The mixture was stirred in a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through Celite and was washed with chloroform/methanol. The solvent was removed by distillation under the reduced pressure. A 110 mg portion of the residue (223 mg) was dissolved in N,N-dimethylformamide (1.5 ml), and potassium carbonate (23 mg), tetra-n-butylammonium iodide (5 mg), and 2-bromoethyl methyl ether (23 mg) were added to the solution. The mixture was stirred at 70° C. overnight. A saturated aqueous sodium hydroqencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/acetone (2/1) to give 89 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O>C(O)(=O)C>[Cl:23][CH2:16][C:15](=[O:17])[C:9](=[N:8][O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOCc1ccc(F)cc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(F)cc1)C(=O)CCl
Yield: 40.9 %

Procedure:
Ethyl 2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 64.0 g.) and sulfuryl chloride (35.6 g.) and acetic acid (70.0 ml.) were treated in a similar manner to that of Example A - (2) to give ethyl 4-chloro-2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 29.55 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].C(O)C>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 95.4 %

Procedure:
Using 10.0 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate, the reaction and after-treatment of Example 1 was repeated except that ethanol was used in lieu of methanol. The procedure provided 6.83 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 91%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Br[CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCCBr
Product: ClCCn1nnc2ccccc21
Yield: 35.8 %

Procedure:
1-(2-Chloroethyl)-1H-1,2,3-benzotriazole (164 mg, 36%) was prepared from benzotriazole (300 mg, 2.52 mmol) and 1-bromo-2-chloro ethane (397 mg, 2.77 mmol) according to the procedure of Example 291. The title compound was isolated as a yellow oil (48 mg, 98%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(2-chloroethyl)-1H-1,2,3-benzotriazole (44 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.69-2.20 (m, 4H), 2.39-2.45 (m, 1H), 2.61-2.68 (m, 1H), 2.72-2.81 (m, 1H), 2.84-3.01 (m, 2H), 3.03-3.12 (m, 2H), 3.20-3.27 (m, 1H), 3.49-3.60 (m, 1H), 3.74-3.84 (m, 1H), 4.06 (t, 1H, J=6.7 Hz), 4.76 (t, 1H, J=6.6 Hz), 4.96 (t, 1H, J=6.2 Hz), 6.61 (t, 1H, J=7.5 Hz), 6.82 (d, 1H, J=7 Hz), 6.95 (dd, 1H, J=1.1, 7.7 Hz), 7.34-7.62 (m, 3H), 8.08 (t, 1H, J=7.6 Hz) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:37]([OH:39])=O)[C:30]2[N:34]=[C:33]([CH3:35])[NH:32][C:31]=2[CH:36]=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:47][C:44]1[CH:45]=[CH:46][C:41]([NH:40][C:37]([C:29]2[C:30]3[N:34]=[C:33]([CH3:35])[NH:32][C:31]=3[CH:36]=[C:27]([O:26][CH3:25])[CH:28]=2)=[O:39])=[N:42][CH:43]=1
Reactant: COc1cc(C(=O)O)c2nc(C)[nH]c2c1
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(C)cn2)c2nc(C)[nH]c2c1
Temperature: 25 °C
Yield: 27 %

Procedure:
HATU (431 mg, 1.13 mmol) was added to a mixture of 6-methoxy-2-methyl-1H-benzoimidazole-4-carboxylic acid (350 mg, 1.0 mmol), 2-amino-5-picoline (134 mg, 1.24 mmol), and DIEA (0.359 mL, 2.06 mmol) in DMF (5 mL) while stirring at room temperature. The resulting mixture was stirred at room temperature under N2 atmosphere for 16 hours. The mixture was worked up with water and extracted into chloroform; the organic layer was dried over MgSO4, concentrated. The crude product was purified by flash silicagel chromatography (ISCO) eluting with CHCl3:MeOH (95:5) to gain 85 mg light brown color solid product in 27% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.68 (s, 1 H) 12.41 (s, 1 H) 8.27 (d, J=8.56 Hz, 1 H) 8.23 (s, 1 H) 7.68 (dd, J=8.56, 1.76 Hz, 1 H) 7.51 (d, J=2.27 Hz, 1 H) 7.23 (d, J=2.27 Hz, 1 H) 3.85 (s, 3 H) 2.61 (s, 3 H) 2.29 (s, 3 H). LRMS for C16H16N4O2 m/z 297 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:11][C:12](=[O:14])[CH:13]=1)=O.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)(=O)C>[CH:15]1([N:21]2[C:12](=[O:14])[CH:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]2=[O:11])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1C=C(c2ccccc2Cl)C(=O)O1
Reactant: NC1CCCCC1
Solvent: CC(=O)O
Product: O=C1C=C(c2ccccc2Cl)C(=O)N1C1CCCCC1
Yield: 52 %

Procedure:
To a solution of 2-(2-chlorophenyl)maleic anhydride (125.0 g) in acetic acid (1.2 1) is added cyclohexylamine (59.4 g) and the mixture is refluxed for 12 hours. The solvent is distilled off and the residue is dissolved in ethyl acetate (500 ml). This solution is successively washed with 5% hydrochloric acid (150 ml), sodium hydrogen carbonate solution (500 ml) and water (150 ml) and dried over magnesium sulfate. The solvent is distilled off and the residue is distilled off to give N-cyclohexyl-(2-chlorophenyl)maleimide (oil) (90.2 g), b.p. 171°-176° C./0.8 ton.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][OH:13]
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CO)cc1O
Product: COc1ccc(CO)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
121.1 mg (0.50 mmol) of 3-benzyloxy-4-methoxybenzaldehyde (7), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 74.0 mg (0.31 mmol) of 3-benzyloxy-4-methoxybenzyl alcohol (8) and 6.9 mg (0.05 mmol) of 3-hydroxy-4-methoxybenzyl alcohol (9). The yields were 61% and 9%, respectively. The reaction is expressed by the following scheme. 23.7 mg (0.10 mmol) of unreacted 3-benzyloxy-4-methoxybenzaldehyde (7) was recovered.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]([OH:54])[CH3:53])=[CH:48][CH:47]=1>C(Cl)Cl>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:27]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([CH:52]([OH:54])[CH3:53])=[CH:48][CH:47]=4)=[O:29])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.7 %

Procedure:
To a stirred mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) in methylene chloride at 0° C. was added triphosgene (0.25, 0.84 mmoles) and Et3N (3 mL). The reaction mixture was stirred for 20 minutes at 0° C. Then 1-(4-aminophenyl)ethanol (0.10 g, 0.73 mmoles) was added to the mixture. The reaction mixture was stirred for about 16 hours at room temperature. The solvent was removed. The residue was dissolved in DMSO and place at HPLC using acetonitrile buffer TFA to give 48 mg (24%) of [4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea. M+H 506.4.