Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1N=C2N=CN(C3SC(C(OC)=O)=C(O)C=3)C2=CC=1OC.[CH3:24][O:25][C:26]1[N:31]=[C:30]2[N:32]([C:35]3[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[C:37]([OH:44])[CH:36]=3)[CH:33]=[N:34][C:29]2=[CH:28][C:27]=1[O:45][CH3:46].C([O-])([O-])=O.[K+].[K+].Br[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]([F:64])([F:63])[F:62]>CN(C)C=O>[CH3:24][O:25][C:26]1[N:31]=[C:30]2[N:32]([C:35]3[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[C:37]([O:44][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:62])([F:63])[F:64])[CH:36]=3)[CH:33]=[N:34][C:29]2=[CH:28][C:27]=1[O:45][CH3:46]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)nc32)cc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: COC(=O)c1sc(-n2cnc3nc(OC)c(OC)cc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)nc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of an isomeric mixture of 1.76 g of methyl 5-(5,6-dimethoxy-1H-imidazo[4,5-b]pyridin-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(5,6-dimethoxy-3H-imidazo[4,5-b]pyridin-3-yl)-3-hydroxythiophene-2-carboxylate (example C7) in 20 ml anhydrous N,N-dimethylformamide were added 0.86 g K2CO3 and 1.51 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene under a nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature, poured into 200 ml of ice water and stirred for 1 h. The solid was filtered, dissolved in acetonitrile and the isomeric mixture was separated and purified by preparative HPLC to yield compound B4a and compound B4b. The structural assignment of compound B4a was unequivocally established by two-dimensional 1H NMR experiments (NOESY, COSY).
Reaction SMILES: [CH3:1][C:2]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:3][O:4][C:5](=[O:21])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH:15]=[CH:16][CH:17]([CH3:19])[CH3:18])=[O:9].CC(CCCC(C)CCC=C(C)C)=COC(=O)C.CC(CCC=C(C)C)CCOC(=O)CCC(Cl)=O.CC(C)([O-])C.[K+]>>[CH3:1][C:2]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])=[CH:3][O:4][C:5](=[O:21])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])=[O:9]
Reactant: CC(C)=CCCC(C)CCCC(C)=COC(=O)CCC(=O)OCCC(C)CC=CC(C)C
Agent: CC(=O)OC=C(C)CCCC(C)CCC=C(C)C
Agent: CC(C)(C)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)CCC(=O)Cl
Product: CC(C)=CCCC(C)CCCC(C)=COC(=O)CCC(=O)OCCC(C)CCC=C(C)C

Procedure:
According to the same procedure, succinic acid 3,7-dimethyl-oct-5-enyl ester 2,6,10-trimethyl-undeca-1,9-dienyl ester was prepared from acetic acid 2,6,10-trimethyl-undeca-1,9-dienyl ester, 3-chlorocarbonyl-propionic acid 3,7-dimethyl-oct-6-enyl ester and potassium tert-butoxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1.[N:16]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[N:17]1>>[CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:28][CH:27]=2)[CH:7]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: COC(=O)C(C)Cc1cccc(CN)c1
Product: COC(=O)C(C)Cc1cccc(CNCc2ccc(-n3cccn3)cc2)c1

Procedure:
The title compound of Step δ was prepared from 3-(3-aminomethyl-phenyl)-2-methyl-propionic acid methyl ester of Step C and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 1, Step A, except no base was used. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.66 (m, 3H), 7.41 (m, 2H), 7.24-7.02 (m, 4H), 6.45 (m, 1H), 3.81 (s, 2H), 3.77 (s, 2H), 3.61 (s, 3H), 3.01 (dd, 1H), 2.76-2.60 (m, 2H), 1.14 (d, 3H); MS 364 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.Cl[C:21]([O:23][CH3:24])=[O:22].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:21]([O:23][CH3:24])=[O:22])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Reactant: COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)SC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 83.7 %

Procedure:
In 20 ml of pyridine was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.5 g of methyl chloroformate was added to the solution with stirring with cooling at 5° to 10° C. over a period of 20 minutes. After stirring was effected at the same temperature for 2 hours and then at room temperature for 1 hour, the reaction solution was treated with water, and extracted with dichloromethane, followed by washing with dilute hydrochloric acid and water, successively, and drying over anhydrous sodium sulfate. The dichloromethane was distilled off under reduced pressure, and the residual, oily substance was purified by means of column chromatography with the use of silica gel (developing solvent of acetone-hexane), thereby producing 3.0 g (yield of 84%) of the subject compound in white crystals, m.p. 80°-81° C.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:12][C:11]1[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[S:2]
Reactant: CSC(=S)NN=Cc1nc(-c2ccccc2)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(-c2ccccc2)n2c(=S)[nH]ncc12

Procedure:
A mixture of 73.4 gm. of 3-[(5-methyl-2-phenyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester and 500 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product as purple crystals, m.p. 237.5°-239° C.
Reaction SMILES: [CH3:1][C@:2]12[C@H:60]3[CH2:61][C@H:58]([C:59]3([CH3:63])[CH3:62])[CH2:57][C@H:3]1[O:4][B:5]([C@@H:7]([NH:10][C:11]([C@H:13]1[N:17]3[C:18](=[O:44])[C:19]([N:22](C(OCC4C=CC=CC=4)=O)[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[CH:20][N:21]=[C:16]3[C@@:15]([CH2:46][C:47]([O:49]CC3C=CC=CC=3)=[O:48])([CH3:45])[CH2:14]1)=[O:12])[CH2:8][CH3:9])[O:6]2>CO.[Pd]>[CH3:1][C@:2]12[C@H:60]3[CH2:61][C@H:58]([C:59]3([CH3:62])[CH3:63])[CH2:57][C@H:3]1[O:4][B:5]([C@@H:7]([NH:10][C:11]([C@H:13]1[N:17]3[C:18](=[O:44])[C:19]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=4)=[CH:20][N:21]=[C:16]3[C@@:15]([CH2:46][C:47]([OH:49])=[O:48])([CH3:45])[CH2:14]1)=[O:12])[CH2:8][CH3:9])[O:6]2
Reactant: CC[C@H](NC(=O)[C@@H]1C[C@@](C)(CC(=O)OCc2ccccc2)c2ncc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OCc3ccccc3)c(=O)n21)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](NC(=O)[C@@H]1C[C@@](C)(CC(=O)O)c2ncc(NCc3cccc(C(F)(F)F)c3)c(=O)n21)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
To a solution of 117f (293 mg, 0.337 mmol) in 5 mL MeOH, was added 29 mg 10% Pd-C. The mixture was evacuated and flushed with H2 (3×), then was stirred under an atmosphere of H2 for 45 min. The mixture was filtered and concentrated in vacuo to afford 217 mg (100%) of 117g as a colorless glass. MS(ESI) 645.4 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[CH2:9][C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)[CH2:11][C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH3:24])[CH2:9][C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C[C@@H](CC(=O)O)c1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of 102 (632 mg, 1.756 mmol) in 4:1 THF/H2O (5 mL) was added 3M aq. LiOH (5.855 mL, 17.56 mmol). The reaction mixture was stirred at RT for 4 h. The aqueous solution was acidified with 2N HCl to ca. pH 2-3 and then twice extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated to afford 598 mg (98.46%) of (S)-4-(tert-butoxycarbonyl(methyl)amino)-3-(4-chloro-3-fluorophenyl)butanoic acid (104).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:18]3[C:13](=[CH:14][CH2:15][CH2:16][CH2:17]3)[N:12]2[CH:26]=1)([CH3:7])[CH3:6])C.[ClH:28]>>[ClH:28].[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:11]3[N:12]([CH:26]=[C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:27])=[O:3])[CH:10]=3)[C:13]3[C:18]=2[CH2:17][CH2:16][CH2:15][CH:14]=3)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)(C)Oc1cc2c(-c3ccncc3)c3c(n2c1)=CCCC3
Agent: Cl
Product: CC(C)(Oc1cc2c(-c3ccncc3)c3c(n2c1)=CCCC3)C(=O)O

Procedure:
The above compound was prepared from 2-[7,8dihydro9-(4-pyridyl)-6H-pyrrolo[1,2-a]indole-2-yloxy]-2-methyl-propanoic acid ethylester by alkaline hydrolysis using a procedure analogous to that of Example 66. When the aqueous alkaline solution was acidified with 2N hydrochloric acid, the hydrochloride precipitated, which was then recrystillzed from ethanol.
Reaction SMILES: [K:1].[C:2]1([S:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[CH:14]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].CO.CC(C)=O>[Pd].O>[K:1].[C:2]1([S:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[CH:14]=2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc([N+](=O)[O-])c(NCc2ccc(-c3ccccc3)cc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 14 h
Yield: 78.2 %

Procedure:
5% palladium/carbon (0.64 g) is added to a mixture of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-nitrobenzamide potassium salt (4.27 g), 20% potassium bicarbonate aqueous solution (10.7 g), and methanol (200 ml). The solution is then stirred for 14 hours at 35° C. under a hydrogen environment. The precipitated crystals are dissolved when a mixture solution of acetone and water (acetone/water=5/2, 400 ml) is added and its solids are separated through filtration. The filtrate is concentrated, the precipitated crystals are separated through filtration and are dried. Thus, N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide potassium salt (3.15 g) is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[CH2:21](Br)[C:22]#[CH:23]>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:23][C:22]#[CH:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCO
Reactant: C#CCBr
Product: C#CCOCCn1c(CCCC)nc2cnc3ccccc3c21
Yield: 70.5 %

Procedure:
Using the general method of Example 1 Part A, 2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (5.0 g, 18.56 mmol) was reacted with propargyl bromide (80% in toluene, 6.3 mL, 55.62 mmol) to provide 4.02 g of 2-butyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [CH2:1]([S:5]([OH:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].N1C=CC=C[CH:10]=1.C(S([O-])(=O)=O)CCC.[NH+]1C=CC=CC=1.S(OC)(OC)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([S:5]([O:8][CH3:10])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: c1ccncc1
Reactant: CCCCS(=O)(=O)O
Agent: CCCCS(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Product: CCCCS(=O)(=O)OC

Procedure:
After 1-butanesulfonic acid (10 g, 0.072 mol) was dissolved in methylene chloride (50 mL), pyridine (11 g, 0.14 mol) was added dropwise thereto, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under the reduced pressure to dryness to obtain a crude product containing pyridinium 1-butanesulfonate salt. To a suspension of this crude product (5 g, 0.023 mol) in cyclohexane (50 mL), dimethyl sulfate (15 g, 0.12 mol) was added, and the mixture was reacted at 80° C. for 2 hours. The resultant reaction liquid was condensed under the reduced pressure to obtain the desired product of methyl 1-butanesulfonate. Quantitative analysis by 1H-NMR showed a conversion rate of 77%.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([O:19][CH2:25][CH3:26])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
A solution of 40 g., of 3-phenyl-7-benzofuranacetic acid in 400 ml. of ethanol and 40 ml. of sulfuric acid is heated under reflux for four hours. The solution is partially concentrated under reduced pressure, poured onto ice and extracted with ether. The ether is washed, dried and concentrated and the residue distilled to give ethyl 3-phenyl-7-benzofuranacetate, b.p. 187°-189°/0.12 mm.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][C:18]([C:22](O)=[O:23])=[CH:17][C:16]=4[CH:25]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:26][N:27]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][C:18]([C:22]([NH:39][C:38]5[CH:40]=[CH:41][C:35]([CH2:34][N:27]([CH:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)[CH3:26])=[CH:36][CH:37]=5)=[O:23])=[CH:17][C:16]=4[CH:25]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(-n4ccnc4)cc3)ccc2OCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(-n5ccnc5)cc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
To a solution of 7—(4—(1-imidazolyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.13 g), 4—(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.11 g) and 1-hydroxybenzotriazole (0.07 g) in dimethylformamide (20 ml) was added 1-ethyl-3—(3-dimethylamino-propyl)carbodiimide hydrochloride (0.13 g) under ice-cooling. Under nitrogen atmosphere, the mixture was warmed to room temperature. To the mixture were added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.2 ml), and the mixture was stirred over night. The solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7—(4—(1-imidazolyl)phenyl)-N-(4—((N-tetra-hydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 153) (0.11 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(CC)CC)C.C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:27](=[O:28])[O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)Oc5ccccc5)c4c(c23)C1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3), in 5 mL of dichloromethane, 75 μL of phenyl chloroformate and 85 μL (2 molar equivalents) of triethylamine were added. The mixture was magnetically stirred at 20° C. during 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 94 mg (yield: 69%) of the desired product (formula below) as a red powder.
Reaction SMILES: CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:45][C:46]2[N:51]=[C:50]([C:52](O)=[O:53])[N:49]=[C:48]([O:55][CH2:56][CH2:57][OH:58])[C:47]=2[O:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=2)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[C:26]1([NH:25][C:52]([C:50]2[N:49]=[C:48]([O:55][CH2:56][CH2:57][OH:58])[C:47]([O:59][C:60]3[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=3)=[C:46]([NH:45][S:42]([C:39]3[CH:40]=[CH:41][C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=3)(=[O:43])=[O:44])[N:51]=2)=[O:53])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCO)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)Nc3ccccc3)nc2OCCO)c1

Procedure:
0.2 ml of Hunig base, 0.052 g of bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride and 0.01 ml of aniline were added to a solution of 0.053 g of 6-(4-tert.butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid in 5 ml of acetonitrile. After 3 hours the reaction mixture was evaporated and partitioned between ethyl acetate and water. The organic phase was dried and evaporated, and the residue purified over silica gel with chloroform. There was obtained 0.032 g of 6-(4-tert.butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid phenylamide, m.p. 143° C., MS: (M-H)- 591.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[CH:15]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:12]1[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[O:11]1[CH:15]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:12]1[CH:13]=[O:14]
Reactant: OCC1OC1c1ccc(Cl)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1OC1c1ccc(Cl)s1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.6 ml of dimethyl sulfoxide in 2 ml of dichloromethane is added with stirring, at -60° C., to a solution of 0.37 ml of oxalyl chloride in 10 ml of dichloromethane in a nitrogen atmosphere. After the mixture has been stirred for 5 minutes at -60° C. there is added thereto, over a period of 20 minutes, a solution of 0.7 g of (2RS,3SR)-2,3-epoxy-3-(5-chlorothiophen-2-yl)-propanol according to d) in 10 ml of dichloromethane. After a further 20 minutes at -60° C. 1.3 ml of triethylamine is added, the mixture is allowed to come to room temperature, washed with water, and dried over sodium sulfate. Filtration and concentration by evaporation yields the crude title compound in the form of a dark viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][C:60]([F:64])([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (110 mg, 0.27 mmol), 1,1′-(azodicarbonyl)dipiperdine (137 mg, 0.54 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.136 mL, 0.54 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.197 mL, 2.70 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 6 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (43.3 mg, 0.089 mmol, 33%) as colorless crystals.
Reaction SMILES: CC1C2N=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:14]([CH2:24][OH:25])=[CH:13][C:12]=3[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:10]C=2C=CC=1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](Cl)([O-])(=O)=O.CCOCC>C(Cl)Cl>[CH2:27]([O:26][C:12]1[CH:13]=[C:14]([CH2:24][OH:25])[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:11]=1[CH:9]=[O:10])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOc1cc(-c2nc3c(C)cccc3o2)c(OCCCCCC)cc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCOc1cc(CO)c(OCCCCCC)cc1C=O
Reaction time: 2 h

Procedure:
A solution of 2-(4-methylbenzoxazolyl)-5-(hydroxylmethyl)-1,4-bis(hexyloxy)benzene (1.99 g, 4.53 mmol) in CH2Cl2 (10 mL) was added dropwise to a stirred solution of freshly prepared pyridium chlorochromate (PCC) (1.46 g, 6.80 mmol) in CH2Cl2 (100 mL) at room temperature. Anhydrous Et2O (100 mL) was added, and the mixture was stirred for an additional 2 h. The reaction mixture was then directly transferred onto the top of a short silica gel column. The yellow and highly fluorescent product was then washed off the column with CH2Cl2, giving 2,5-bis(hexyloxy)-4-(hydroxymethyl)benzaldehyde in 86.9% (1.72 g). The product (mp. 48-50° C.) had the following spectral properties. 1H NMR (CDCl3, 300 MHz, δ): 10.53 (s, 1H, —CHO), 7.78 (s, 1H), 7.48 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.26 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 4.18 (t, J=6.6 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.68 (s, 3H), 1.87 (q, J=6.3 Hz, 4H), 1.54 (m, 4H), 1.35 (m, 8H), 0.90 (m, 6H). IR(KBr): 1684 cm−1, 1609.5 cm−1, 1534.6 cm−1.