Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([NH:44][C@H:45]3[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH2:46]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH2:46]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.2 %

Procedure:
6.5 ml of trifluoroacetic acid and 0.21 ml of trifluoromethanesulfonic acid were added to a suspension of 835 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (iii) above] in 1.3 ml of anisole, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was first washed with hexane to remove the anisole and then mixed with diethyl ether. The mixture was cooled to -78° C., and the solidified product was broken up and separated by decantation. Several repetitions of this procedure yielded 940 mg of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]([OH:7])=O.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:7])[NH:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:3][C:2]=1[Br:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Br
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)cc1Br
Temperature: 30 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of Intermediate 15 (100 g, 0.303 mol, 1.0 eq) and 4-aminopyridine (28.5 g, 0.303 mol, 1.0 eq) in DMA (1 L) was added Et3N (30.6 g, 0.303 mol, 1.0 eq), DMAP (3.7 g, 0.030 mol, 0.1 eq) and HATU (115.2 g, 0.303 mol, 1.0 eq). The reaction solution was stirred at 30° C. for 16 hrs. Solvent was evaporated under vacuum and the residue was solidified by adding DCM (600 ml) and H2O (600 ml) to give the title compound (86.1 g, 70% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]([CH3:30])([CH3:29])[CH2:15][N:16]([C:25](=[O:28])[CH2:26]Br)[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[Cl:24])([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>O1CCCC1.O>[C:7]([O:11][C:12]([N:13]1[CH2:26][C:25](=[O:28])[N:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[CH2:15][C:14]1([CH3:30])[CH3:29])=[O:31])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CN(C(=O)CBr)c1cc(F)ccc1Cl)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(F)ccc2Cl)CC1(C)C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
A solution of 2.2 g of potassium t-butoxide (19.9 mmol) in tetrahydrofuran (130 ml) was added to a solution of 5.8 g of {2-[(2-bromoacetyl)-(2-chloro-5-fluorophenyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (62b) (13.3 mmol) in tetrahydrofuran (130 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 30 minutes, and the mixture was stirred at the same temperature for 10 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture. The mixture was returned to room temperature and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=10/1) to obtain 2.79 g of the title compound (yield: 64%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.O>CS(C)=O.C(OCC)(=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cccc(Oc2nnc(Cc3ccncc3)c3ccccc23)c1

Procedure:
Under exclusion of air, 200 mg (0.78 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67A.1), 173 mg (1.25 mmol) K2CO3, and 120 mg (0.94 mmol) 3-chlorophenol (Fluka) are heated in 2 ml DMSO for 3 h to 90° C. The reaction mixture is distributed between 20 ml water and 20 ml ethyl acetate, and the aqueous phase separated and extracted with 2 portions of ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4), and concentrated by evaporation. The residue is dissolved in ≦15 ml THF, precipitated with hexane, and filtered. Title compound is obtained from the evaporated filtrate after chromatography (SiO2; ethyl acetate/CH3OH, 4:1): m.p.: 143-145° C.; HPLC: tRet(Grad20-100)=8.9; FAB MS (M+H)+=348.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:19]3[CH:20]=[CH:21][C:22]4[C:23]5[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][CH2:29][C:24]=5[N:25]([CH3:28])[C:26]=4[CH:27]=3)[C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=c1cc(OCc2ncc(F)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncc(F)cc5F)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 52.2 %

Procedure:
4-((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (206 mg, 0.544 mmol) and tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (100 mg, 0.418 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (117 mg, 50%) as a yellow oil; ESI MS m/z 537 [M+H]+;
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][OH:15].[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].ClC(O)C>C(Cl)Cl.O.C1COCC1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH2:14][OH:15])=[CH:11][CH:10]=1
Reactant: OCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCO)cc1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
Methyl 4-hydroxybenzoate (1.52 g, 10 mmol), 2-chloroethanol (960 mg, 12 mmol), potassium iodide (100 mg, 0.6 mmol) and cesium carbonate (4.56 g, 14 mmol) are combined with dry THF (50 mL) and the reaction mixture is stirred under reflux for 24 h. Additional chloroethanol (960 mg), cesium carbonate (4.56 g) and potassium iodide (100 mg) are added to the mixture and stirred under reflux for 24 h. The reaction mixture is cooled to room temperature and water and CH2Cl2 are added. The separated CH2Cl2 layer is dried over Na2SO4, filtered and evaporated. The crude product is purified using silica-gel column chromatography (hexane:EtOAc=3:1) to give the titled compound (862 mg, 44%). NMR (CDCl3): δ 8.02 (d, 2H, J=9.0 Hz), 6.97 (d, 2H, J=9.0 Hz), 4.17 (t, 2H, J=5.0 Hz), 4.03 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: OCCc1ccc(O)cc1
Product: C=CCOc1ccc(CCO)cc1
Yield: 77 %

Procedure:
The two-step synthetic procedure of Example 1 was repeated starting with 2-(4-hydroxyphenyl)ethyl alcohol. In this case 1.2 equivalents of allyl bromide was employed in the alkylation step and the intermediate 4-allyloxyphenethyl alcohol was obtained in 77% yield following vacuum distillation (104-112° C. at 0.2 torr). Esterification of the alcohol with methacrylic acid afforded 4-allyloxyphenethyl methacrylate (AOPMA) in 88% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][O-:16].[Na+].[OH-].[Na+]>CO.O>[CH3:15][O:16][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(SC)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (24.40 g, 104.9 mmol) in MeOH (125 mL) was added solid sodium methoxide (11.40 g, 211.0 mmol) at rt. The reaction mixture was stirred at rt for 5 h and then treated with NaOH (17.70 g, 315.5 mmol) in H2O (100 mL). It was then stirred at the same temperature for an additional 1 h. The reaction mixture was concentrated to half of the volume and then acidified to pH=4 with HCl (6N). The reaction was extracted with EtOAc (5×200 mL) and the organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated to yield the desired product as a white solid (19.28 g, 92%). MS (m/z): 201 (MH+). 1H NMR (DMSO-d6) δ: 8.72 (s, 1H), 3.98 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Br)ccc1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ccc2OCCN1Cc1ccccc1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a solution of N-benzyl-5-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (4.70 g, 13.3 mmol) in N,N-dimethylformamide (100 ml) was added under ice-cooling sodium hydride (60%, 691 mg, 17.3 mmol), and the mixture was stirred under ice-cooling for 1 hr, and poured into ice water. The mixture was extracted with ethyl acetate and the extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (4.20 g, 96.3%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[C:25]=[O:26]>C1COCC1>[CH3:22][CH:21]([CH3:23])[CH:16]([NH:15][C:13]([C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[O:26])=[CH:3][CH:4]=2)=[CH:9][N:10]=1)=[O:14])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)o1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(5-(4-aminophenyl)oxazole-2-carboxamido)-3-methylbutanoate (Intermediate 1, 150 mg) in THF (3 ml) was added 1-isocyanato-3-(trifluoromethyl)benzene (132 mg) and the mixture was stirred overnight at RT. The mixture was then concentrated, purified by column chromatography (EtOAc:Pet ether, 2:8) and crystallized in CHCl3/Pet ether to give the title compound. Yield: 210 mg (88%). 1HNMR (DMSO-d6, 300 MHz): δ 9.13 (s, 1H), 9.09 (s, 1H), 8.99 (d, 1H), 8.03 (d, 1H), 7.82 (s, 1H), 7.8 (d, 2H), 7.64 (d, 2H), 7.58 (dd, 1H), 7.55 (dd, 1H), 7.34 (m, 1H), 4.3, (m, 1H), 3.68 (s, 3H), 2.24 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 505 (M+1).
Reaction SMILES: [OH:1][C:2]1([C:15]([OH:17])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Cl.[CH3:19]O>>[CH3:19][O:16][C:15]([C:2]1([OH:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17]
Reactant: CO
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: Cl
Product: COC(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
9-Hydroxy-9H-fluorene-9-carboxylic acid (Aldrich Chemical, Inc.) (20.0 g, 88.4 mmol) was added to 100 mL methanol saturated with hydrogen chloride and mixture was stirred at reflux for 4 h. The crystalline material obtained on cooling was collected by filtration and washed with cold 1:1 ethyl acetate/hexane to provide after drying (1), 15.8 g (74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COCCN(C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
Amine preparation: A mixture of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (see preparation of 121) (300 mg) and 2-bromopropane (1.20 mL) in MeCN (3 mL) with potassium carbonate (192 mg) were heated at 60° C. in a sealed tube for 7 days. The reaction mixture was cooled down, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-[isopropyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as an oil (131 mg). Treatment of this compound with HCl in DCM/MeOH and basic wash with aqueous sodium bicarbonate yielded the desired amine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:14].[K+].O.Cl>CS(C)=O>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: [OH-]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-nitrobenzoic acid (100 g) in 800 ml dimethylsulfoxide was treated with 112 g powdered KOH with cooling, 170 ml anhydrous alcohol added and the mixture stirred 2 hours at 25° and then left overnight. The mixture was kept at 28° for about 8 hours, then overnight at 0°, warmed to room temperature and 3.5 liters of water added. The mixture was acidified with HCl, 1 kg NcCl added and extracted with ethyl acetate. The extract was washed with water, dried, 50 g KHCO3 in 500 ml water added, diluted to 2 liters, and the ethyl acetate blown off with a stream of nitrogen. The solution was acidified and filtered to give 56 g product, m.128-30°.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)(=O)[CH:2]=[CH2:3].[CH3:18][N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH2:1]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:22]1[CH2:23][CH2:24][CH2:25][N:19]([CH3:18])[CH2:20][CH2:21]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCn1c(Cl)nc2ccccc21
Reactant: CN1CCCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: C=CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Yield: 63.4 %

Procedure:
In the same manner as described in Example 1 using 1-[2-(alloyloxy)ethyl]-2-chlorobenzimidazole (4.00 g), N-methylhomopiperazine (4.00 g) and fumaric acid (2.58 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(allyloxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (3.85 g) as colorless needles, m.p. 144.5°-146.5° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[N:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH:24]([O:37][C:38]1[C:39]2[C:51](=[O:52])[N:50]([CH2:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH2:49][C:40]=2[C:41]([OH:48])=[C:42]2[C:47]=1[N:46]=[CH:45][CH:44]=[CH:43]2)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(C)=O.CCCCCC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:24]([O:37][C:38]1[C:39]2[C:51](=[O:52])[N:50]([CH2:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH2:49][C:40]=2[C:41]([O:48][S:20]([C:17]2[CH:18]=[N:19][C:14]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[C:42]2[C:47]=1[N:46]=[CH:45][CH:44]=[CH:43]2)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1c2c(c(O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1c2c(c(OS(=O)(=O)c3ccc(N4CCOCC4)nc3)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Triethylamine (50 μl), DMAP (catalytic amount) and 6-Morpholin-4-yl-pyridine-3-sulfonyl chloride (26.3 mg, 0.10 mmol) were added to 0.034 mmol 45. The reaction mixture was stirred at room temperature for 18 hours under an inert atmosphere. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 44=0.5, Rf 45=0, Rf 266=0.3) and LC/MS. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethylacetate/hexane—3/7) to afford 6-morpholin-4-yl-pyridine-3-sulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 266 (14.6 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.C(O[CH:23](N(C)C)[N:24]([CH3:26])[CH3:25])(C)(C)C>>[CH3:23][N:24]([CH3:26])[CH:25]=[C:11]1[C:10](=[O:15])[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(c2cccc(C(F)(F)F)c2)C1=O

Procedure:
2-(3-Trifluoromethyl-phenyl)-cyclohexanone (106 mg, 0.44 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a), to give crude title compound (132 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 298.0 [(M+H)+]
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:15])[C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.CO>CCOCC.O>[Si:1]([O:8][CH2:9][C@H:10]([CH3:15])[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: C[C@H](C=O)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
Methyl (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropionate (1.31 g; 5.6 mmol) was dissolved in anhydrous ether (18.5 ml), and a hexane solution (8.4 ml) of 1M diisobutylaluminum hydride was added dropwise thereto at -78° C. in 5 minutes in an argon stream. After stirring for 30 minutes, methanol (0.09 ml) and then water (0.84 ml) were added thereto, and the resultant mixture was allowed to stand at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture in gel was filtered, dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. Purification of the oily residue by silica gel column chromatography using a mixture of hexane and ethyl acetate (9:1) gave (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropanal (0.89 g, yield, 78%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[O:8]1CC[CH2:10][CH2:9]1>>[C:1]([CH:4]([C:9](=[O:8])[CH3:10])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(C(C)=O)C(C)=O

Procedure:
Gaseous acetyl fluoride is bubbled into a suspension of 30.0 g. (0.1 mole) of the thallous salt of acetylacetone in 150 ml. of dry tetrahydrofuran, under nitrogen, at a rate of 3.0 cc./minute for a total of 30 minutes. After filtration through Celite, the solution is concentrated and the residue distilled to give 13.5 g. (96%), b.p. 90°-95°/1.0 mm.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>C(#N)C>[CH2:11]([O:13][CH2:14][O:10][C:6]1[CH:5]=[C:4]([NH2:3])[CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: CCOCCl
Reactant: Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOCOc1cccc(N)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A dispersion of 12 g (274.9 mmol) of sodium hydride (55% in oil) was added portionwise at 0° C. to a solution of 20.0 g (183.3 mmol) of 3-aminophenol in 450 mL of dried acetonitrile. The mixture was then allowed to agitate at 0° C. for 3 hours. A solution of 25 g (210.8 mmol) of chloromethyl ethyl ether in 30 mL of acetonitrile was added dropwise, and the mixture was allowed to agitate overnight at room temperature. The reaction mixture was then filtered and the filter cake was washed with a small amount of acetone. The combined filtrates were evaporated. This gave 32.3 g of 3-ethoxymethoxyphenylamine. The resulting crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]NC(=O)CCC(N)=O>ClCCl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
The product from step (ii) (30 g) was dissolved in dry dichloromethane (200 ml). The solution was stirred at room temperature whilst N-bromosuccinamide (27 g) was added portionwise. The mixture was stirred at ambient temperature overnight. 20% (w/v)-Sodium sulfate (200 ml) was added and the separated aqueous phase extracted with dichloromethane. The combined organic phase was washed with saturated sodium hydrogen carbonate solution and brine. After concentration in vacuo, the residue was dissolved in ethyl acetate, washed with water, brine and dried. The solution was filtered through silica gel and concentrated in vacuo. The residue was triturated with diethyl ether and isohexane (1/1, 200 ml) then filtered to give the subtitle compound (26 g). The filtrate was concentrated in vacuo and the residue purified by column chromatography (ethyl acetate/isohexane) to give a further 2.5 g of product. The solids were combined to give the subtitle compound as a yellow solid. Yield 28.5 g. mp 148-50° C.