Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(OCC)n1ccnc1
Temperature: 140 °C
Yield: 67 %

Procedure:
Mixture of imidazole (13.6 g), triethyl orthoformate (133 ml) and p-toluenesulfonic acid monohydrate (1.00 g) was stirred by heating at 140° C. for 2 hours. Reaction mixture was subjected to distillation under a reduced pressure, there was obtained N-(diethoxymethyl)imidazole (22.8 g, yield: 67.0%) as colorless oily product.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1cccnc1Br
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound was prepared by Method C using compound 12b and 2-bromo-3-methylpyridine. HRMS (ESI+): m/z=388.1471 [M+H]
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].O1CCOC[CH2:14]1.CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[Cl:12][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:14])[N:11]=[CH:10][CH:9]=1
Reactant: C1COCCO1
Reactant: COC(=O)c1c(Cl)ccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(Cl)ccnc1C
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of methyl 2,4-dichloronicotinate (10.0 g, 48.5 mmol) in a solvent mixture of 1,4-dioxane (400 mL) and water (40 mL) was added trimethylboroxine (6.79 mL, 48.5 mmol) followed by PdCl2(dppf)-CH2Cl2 adduct (1.982 g, 2.427 mmol) and cesium carbonate (31.6 g, 97 mmol). The reaction mixture was degassed with argon for 5 minutes. The reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate and the combined filtrate was concentrated under reduced pressure to afford the crude product which was purified by silica gel column chromatography (gradient of ethyl acetate and petroleum ether) to afford methyl 4-chloro-2-methylnicotinate (5.20 g, 28 mmol, 58% yield) as a yellow liquid. LC/MS (ESI) m/e 185.7 [(M+H)+, calcd for C8H8ClNO2 185.6]; LC/MS retention time (method G): tR=1.90 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:31])[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:31])[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)CSc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(SCC(=O)NN=C2C(=O)Nc3ccc(I)cc32)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 61 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-[(2-hydrazino-2-oxoethyl)thio]-3-nitrobenzenesulfonamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 24 mg of the title compound (61%) as a yellow solid in 99.3% purity by HPLC (Rt: 3.51, 4.17, gradient of 8 rnin, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:32][C:26]3[C:27](=[O:31])[NH:28][N:29]=[CH:30][C:25]=3[CH:24]=2)=[CH:19][CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(N)CCCCC1(C)N>O1CCOCC1.C(Cl)Cl.[Cu-]=O.CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:32][C:26]3[C:27](=[O:31])[N:28]([C:2]4[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])=[C:4]([O:14][CH3:15])[CH:3]=4)[N:29]=[CH:30][C:25]=3[CH:24]=2)=[CH:21][CH:22]=1
Reactant: COc1cc(Br)ccc1OCC(C)(C)O
Reactant: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Agent: O=[Cu-]
Agent: CC1(N)CCCCC1(C)N
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(-n2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Temperature: 130 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
A mixture of 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol (157 mg, 0.571 mmol), 2-(4-chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (150 mg, 0.571 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (24.36 mg, 0.171 mmol), K3PO4 (0.142 ml, 1.713 mmol) and cupric oxide (24.51 mg, 0.171 mmol) in dioxane (4 ml) was stirred at 130° C. under N2 in a sealed tube for 24 hours. Since LC-MS analysis revealed no product, another portion of cupric oxide (24.51 mg, 0.171 mmol) was added to the mixture which was then was stirred at 130° C. under N2 in a sealed tube for another 24 hours. Since LC-MS analysis indicated only 25% conversion to product, another equivalent of copper (I) oxide and dimethylcyclohexane-1,2-diamine was added. The mixture was stirred at 150° C. under N2 in a seal tube for 8 hours. After cooling to RT, LC-MS analysis showed the conversion was 45% to product. The mixture was diluted with CH2Cl2 (40 ml) prior to removal of the inorganic solid by filtration. The CH2Cl2 filtrate was washed with a solution of saturated NaHCO3 (3×40 ml), dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on two silica gel column (2×4.0 g) employing a 10 min gradient ranging from hexane to 100% ethyl acetate to elute partially pure product. After titration with MeOH, 2-(4-chlorophenyl)-6-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-one (101 mg, 0.221 mmol, 38.7% yield) was obtained as light brown solid. LC MS at t=2.52 min. (m+H=457) PHENOMENEX® S5 C18 4.6X30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CDCl3) 8 ppm 1.36 (s, 6H), 3.89 (d, J=3.78 Hz, 5H), 7.00 (d, J=8.56 Hz, 1H), 7.17-7.24 (m, 2H), 7.42-7.54 (m, 3H), 7.66 (d, J=8.31 Hz, 2H), 8.31 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5]C(C)=[CH:3]1.C[N+:12]1[CH:16]=[C:15]([C:17]([O-])=O)N(C)C=1.C#N>>[CH3:5][C:6]1([CH3:8])[CH2:7][C:15]([C:16]#[N:12])([CH3:17])[CH2:3][C:2](=[O:1])[CH2:9]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: Cn1c[n+](C)cc1C(=O)[O-]
Agent: C#N
Product: CC1(C)CC(=O)CC(C)(C#N)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
622 g (4.5 mol) of isophorone and 1.8 g (12.9 mmol) of 1,3-dimethylimidazolium-4-carboxylate were placed in a reaction vessel and a mixture of 207.3 g (1.5 mol) of isophorone and 81.0 g (3 mol) of hydrogen cyanide was added at 150° C. over a period of about 60 minutes. The mixture was subsequently stirred further for about 60 minutes at 150° C. After cooling, the HCN concentration was determined by titration. No free hydrocyanic acid could be detected (HCN conversion>99.9%). After addition of 2.0 g of 85% strength H3PO4, the reaction product was distilled at 0.1 hPa. This gave 486 g of 3-cyano-3,5,5-trimethylcyclohexanone (98.1% based on HCN used). The amount of distillation residue was only 3% by weight, based on isophorone used.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]([NH:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)[CH2:5][CH3:6])=[O:3].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:5]([C@H:4]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:13])[C:2]([NH2:1])=[O:3])[CH3:6]
Reactant: CC[C@H](NC(=O)CCCCl)C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Reaction time: 1 h
Yield: 60.7 %

Procedure:
6.2 g (0.03 mole) of (S)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide and 0.484 g (0.0015 mole) of tetrabutylammonium bromide are mixed in 45 ml of dichloromethane at 0° C. under a nitrogen atmosphere. 2.02 g (0.036 mole) of potassium hydroxide powder are added over 30 minutes, at such a rate that the temperature of the reaction mixture does not exceed +2° C. The mixture is then stirred for one hour, after which a further 0.1 g (0.0018 mole) of ground potassium hydroxide is added and stirring continued for 30 minutes at 0° C. The mixture is allowed to return to ambient temperature. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue obtained is recrystallized from 40 ml of ethyl acetate in the presence of 1.9 g of 0,4 nm molecular sieve. The latter is removed by hot filtration to give 3.10 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:53][CH2:52][C:49]2[CH:50]=[CH:51][C:46]([O:45][CH3:44])=[CH:47][CH:48]=2)=[O:10])[CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cc(Br)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a flask containing a 4-bromopicolinic acid (1.0 g) in DMF (10 mL) was added HATU (2.3 g) and N-ethyl-N-isopropylpropan-2-amine (1.0 mL) The mixture was stirred at about 25° C. for approximately 10 min followed by addition of (4-methoxyphenyl)methanamine (0.68 g). The reaction was then stirred at about 25° C. for about an additional 12 h. The reaction was basified to pH 10 with aqueous 1 N NaOH and washed three times with EtOAc. The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure to afford 4-bromo-N-(4-methoxybenzyl)picolinamide as a clear oil (1.2 g, 75%). LC/MS (Table 1, method f). Rt=1.73 min; MS m/z 322 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH:18]([OH:32])[CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=O)=[CH:23][CH:22]=4)[CH2:12]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[NH3:36]>CO>[Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH:18]([OH:32])[CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:36])=[O:30])=[CH:23][CH:22]=4)[CH2:12]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cc1ccc(OCC(O)CN2CCCC(Cn3c(=O)[nH]c4cc(Cl)c(Cl)cc43)C2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CN2CCCC(Cn3c(=O)[nH]c4cc(Cl)c(Cl)cc43)C2)cc1
Temperature: 110 °C
Yield: 25 %

Procedure:
A mixture of 11 parts of methyl 4-{3-[3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl)-1-piperidinyl]-2-hydroxypropoxy}benzeneacetate and 800 parts of methanol saturated with ammonia is stirred and heated in an autoclave at 110° C. and at a pressure of 85.7 lbs/sq. inch. The reaction mixture is cooled and evaporated. The residue is stirred in 4-methyl-2-pentanone. The product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone and a small amount of 2-propanol. The product is filtered off and dried, yielding 2.7 parts (25%) of 4-{3-[3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl)-1-piperidinyl]-2-hydroxypropoxy}benzeneacetamide; mp. 147.9° C.
Reaction SMILES: CO.[CH3:3][NH:4][CH3:5].[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19])(=[O:8])[CH3:7]>CO.O1CCCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([S:18](=[O:20])(=[O:19])[N:4]([CH3:5])[CH3:3])=[C:11]([CH:16]=1)[CH2:10][NH:9][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Step 1) To a solution of 2N dimethylamine methanol solution (7.51 ml) in methanol (15 ml) was added dropwise a suspension of 2-[(acetylamino)methyl]-4-chlorobenzenesulfonyl chloride (2.12 g) in tetrahydrofuran (5 ml) under ice-cooling. The mixture was allowed to warm to room temperature, and stirred for 3 hr. The reaction mixture was quenched with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-[5-chloro-2-(dimethylsulfamoyl)benzyl]acetamide (1.77 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:26]3[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=3)[N:20]=[CH:21][CH:22]=[CH:23]4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(O)c1ccc2ncccc2c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc2ncccc2c1
Yield: 9.9 %

Procedure:
Using the general method of Example 18, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.96 mmol) was coupled with 6-quinolinecarboxylic acid (0.34 g, 1.96 mmol) to provide 0.08 g of N6-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl) butyl]-6-quinolinecarboxamide as a tan powder, m.p. 122-127° C. (foaming). 1H NMR (300 MHz, DMSO-d6) δ 8.98 (m, 1H), 8.73 (t, J=5.4 Hz, 1H), 8.43 (m, 2H), 8.23 (s,1H), 8.13-8.03 (m, 3H), 7.60 (m, 2H), 7.40 (m, 1H), 7.20 (m, 1H), 6.58 (broad s, 2H), 4.66 (t, J=6.7 Hz, 2H), 3.37 (m, 2H), 1.96 (m, 2H), 1.64 (m, 2H); MS (EI) m/e 410.1847 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][C:8](=[O:13])[C:7]=1[CH2:14][CH3:15].[C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27]OC(=O)C)(=[O:22])[CH3:21].C[Si](C)(C)N[Si](C)(C)C.C[Si](Cl)(C)C.[Cl-].[Na]>C(#N)C.ClCCl>[C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][N:9]1[C:8](=[O:13])[C:7]([CH2:14][CH3:15])=[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:18]=[C:17]([CH3:19])[CH:16]=2)[NH:11][C:10]1=[O:12])(=[O:22])[CH3:21]
Reactant: CC(=O)OCCOCOC(C)=O
Reactant: CCc1c(Cc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Solvent: CC#N
Solvent: ClCCl
Product: CCc1c(Cc2cc(C)cc(C)c2)[nH]c(=O)n(COCCOC(C)=O)c1=O
Reaction time: 14 h
Yield: 92 %

Procedure:
6-(3,5-dimethylbenzyl)-5-ethyluracil (see the above Example 4-A) (516 mg, 2 mmol) and 1-acetoxy-2-acetoxymethoxyethane [A. Rosowski, S. H. Kim. M. Wick, J. Med. Chem. (1981) 24, 1177-81]) (704 mg, 4 mmol) were suspended, under nitrogen atmosphere, in acetonitrile (20 ml). It was added thereto HMDS (hexamethyldisilazane) (646 mg, 4 mmol) and TMSCl (chlorotrimethyl-silane) (435 mg, 4 mmol) and the mixture was then stirred for 10 mn. Then it was added dropwise thereto, over 10 mn, a solution of tinIV chloride (625 mg, 2.4 mmol) in acetonitrile (5 ml). After 14 h under stirring, it was added thereto dichloromethane (50 ml) and an aqueous saturated sodium hydrogenocarbonate solution (50 ml). The mixture was extracted with dichloromethane (3×50 ml). The organic phases, collected, were washed with a aqueous saturated sodium hydrogenocarbonate solution (25 ml), with water (25 ml), and then with an aqueous saturated sodium chloride solution. The organic phase was dried (sodium sulfate), concentrated, and then subjected to a flash column chromatography (petroleum ether/ethyl acetate 3:2) to give 1-(2-acetoxyethoxymethyl-6-(3,5-dimethylbenzyl)-5-ethyluracil (690 mg, 92%) in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(C)(CN)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CO)CNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-amino-2,2-dimethylpropanol (10 mg, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(3-hydroxy-2,2-dimethylpropyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([OH:8])[CH:6]2[CH2:9][CH:3]1[C:4](=[O:10])[NH:5]2.[CH:11]12CC(C=[CH:16]1)C(=O)N2.S(=O)(O)[O-].[Na+].C(OC=C)(=O)C>N1C=CC=CC=1.O.[Os](=O)(=O)(=O)=O.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[OH:1][CH:2]1[CH:7]([OH:8])[CH:6]2[CH2:9][CH:3]1[C:4](=[O:10])[N:5]2[CH:11]=[CH2:16]
Reactant: O=C1NC2CC1C(O)C2O
Reactant: O=C1NC2C=CC1C2
Agent: Cl[Pd]Cl
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Solvent: O
Solvent: c1ccncc1
Solvent: C=COC(C)=O
Product: C=CN1C(=O)C2CC1C(O)C2O

Procedure:
The intermediate 5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-one is made by stirring a solution of 2-azabicyclo[2.2.1]hept-5-en-3-one (1.00 g, 9.16 mmole) and osmium tetroxide (2.33 g, 9.16 mmole) in pyridine (35 ml) at room temperature for 2 hours. The osmate ester is cleaved by mixing the reaction solution with a solution of sodium bisulfite (4.2 g) in water (70 ml) and pyridine (50 ml). The product is extracted from the reaction solution with 3-150 ml portions of methylene chloride. Evaporation of the dried methylene chloride gives the crude dihydroxy bicyclic amide (intermediate). The intermediate is mixed with sodium tetrachloropalladate (30 mg, 0.10 mmole) and vinyl acetate (6 ml, 66 mmole). The mixture is then refluxed for 5 days. The crude product (Compound 7) is isolated by filtration to remove the catalyst and evaporation of the excess vinyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=1>C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.8 %

Procedure:
To a stirred solution of ethyl 4-[N′-(2,6-dichlorophenyl)ureido]phenylacetate (3.19 g, 8.69 mmol) in THF (70 ml), 0.25 N NaOH (70 ml) was added. After stirring at room temperature for 17 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[N′-(2,6-dichlorophenyl)ureido]phenylacetic acid (2.44 g, 82%) as colorless powder. mp 262–263° C. (dec.); 1H-NMR (DMSO-d6) δ 3.48 (s, 2H), 7.14 (d, J=8.3 Hz, 2H), 7.31 (t, J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 8.18 (s, 1H), 8.90 (s, 1H), 12.22 (br, 1H); MS (ESI) m/z 339 (M++1), 341 (M++3), 343 (M++5).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].OOS([O-])=O.[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>CN(C=O)C.O>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:30]1[C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(-c3ccc(F)cc3)n(CC(OC)OC)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (1.0 g, 3.9 mmol) from Step C of Example 13 in DMF (9 mL) and H2O (0.3 mL) were added oxone (1.6 g, 2.6 mmol) and 4-fluorobenzaldehyde (0.5 mL, 4.3 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 5% to 100% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-2-(4-fluorophenyl)-1H-benzo[d]imidazole-7-carboxylate (1.1 g, 79%): 1H NMR (500 MHz, CDCl3) δ7.97 (dd, J=8.0, 1.0 Hz, 1H), 7.80 (dd, J=8.0, 1.0 Hz, 1H), 7.73-7.70 (m, 2H), 7.32 (t, J=8.0 Hz, 1H), 7.24-7.20 (m, 2H), 4.72 (d, J=5.0 Hz, 2H), 4.24 (t, J=5.0 Hz, 1H), 3.94 (s, 3H), 3.38-3.33 (m, 1H), 3.19 (s, 6H); MS (ESI+) m/z 359 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:8]=2)[N:3]=1.[NH2:22][C@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:22][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[CH:8]=3)[N:3]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: COc1cccc(COc2ccc3nc(Cl)ccc3c2)c1
Reactant: N[C@@H]1CCc2ccccc21
Product: COc1cccc(COc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)c1
Temperature: 130 °C
Yield: 6.9 %

Procedure:
A stirred mixture of 2-chloro-6-(3-methoxy-benzyloxy)-quinoline (0.08 g, 0.4 mmol) and (R)-1-aminoindane (0.107 g, 1.00 mmol) was heated in a sealed tube for 20 h at 130° C. Purification by flash chromatography on silica gel (ethyl acetate in heptane, 0=>100%) yielded the title compound as a dark oil (11 mg, 10%), MS 397.5 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)[C:5]([F:16])=[CH:4][C:3]=1[NH-:17].[O:18]=[C:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32](O)=O)[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2>C(O)(=O)C>[F:16][C:5]1[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)=[CH:7][C:2]2[NH:1][C:32]([C:27]3[C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19](=[O:18])[C:31]=4[CH:30]=[CH:29][CH:28]=3)=[N:17][C:3]=2[CH:4]=1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Reactant: CN1CCCN(c2cc(N)c([NH-])cc2F)CC1
Solvent: CC(=O)O
Product: CN1CCCN(c2cc3[nH]c(-c4cccc5c4-c4ccccc4C5=O)nc3cc2F)CC1

Procedure:
The procedure used in Example 68 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 950 mg of [2-amino-5-fluoro-4-(4-methylperhydro-1,4-diazepin-1-yl)phenyl]-amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 15 ml of acetic acid. After purification by formation of a paste with diisopropyl ether, in this way we obtain 950 mg of 4-[5-fluoro-6-(4-methyl-perhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics: