Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1OC(=O)c1ccccc1

Procedure:
To a cooled solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (8.0 parts) in dry pyridine (42 parts) was added benzoyl chloride (4.75 parts) at such a rate that the temperature did not exceed 10° C. After one hour the mixture was poured into a slight excess of dilute hydrochloric acid. The product was extracted with ether and the ethereal solution washed, dried with sodium sulphate and evaporated to give an oil which solidified on scratching. The solid was recrystallised from a mixture of benzene and light petroleum to give 2-benzoyloxy-2,3-dihydro-3, 3-dimethylbenzofuran-5-yl methanesulphonate (5.1 parts), melting point 102°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH:10]([CH3:17])[CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH:10]([CH3:17])[CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CC(O)C(C)CSc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CC(C)CSc1cccc(Cl)c1
Yield: 98.9 %

Procedure:
1.00 Gram of 6-(3-chlorophenylthio)-4-hydroxy-5-methyl-2-hexanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 1.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 1.05 g of 6-(3-chlorophenylthio)-5-methyl-3-hexen-2-one. (trans : cis =5.7 : 1) (purity: 88.6%). The yield was 98.9%.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35]I>CN(C)C=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:35][CH2:34][CH2:33][CH2:32][Cl:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3[nH]cnc23)cc1
Reactant: ClCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-1H-imidazo[4,5-c]quinolin-4-amine (20.0 g, 55.04 mmol), sodium hydride (3.3 g, 60% dispersion, 82.56 mmol), and anhydrous dimethyl formamide (275 mL) under a nitrogen atmosphere. After the reaction mixture had stirred at ambient temperature for 2 hours, 4-chloro-1-iodobutane (19.23 g, 88.06 mmol) was added and the resulting homogeneous solution was stirred at ambient temperature for 48 hours at which time the starting material was consumed. The solution was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid. The material was recrystallized from ethyl acetate and hexanes to give N,N-dibenzyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (20.7 g, 45.49 mmol) as white needles. MS (CI) for C28H27ClN4 m/z 455 (MH+), 365, 329, 239
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)CCC>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=Cc1cc2cccc(Cl)c2nc1-c1cnccn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.3 g, 10.18 mmol), 2-(tributylstannanyl)pyrazine (4.5 g, 12.2 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.4 g, 0.35 mmol) in 1,4-dioxane (25 mL) was degassed and the mixture was heated under nitrogen at 110° C. for 5 h. The mixture was allowed to cool to room temperature overnight and the solidified product was collected by filtration and washed repeatedly with ether. The filtrate was concentrated and left in a refrigerator for 2 h to give a second crop, which was filtered, washed with ether and combined with the bulk material to give the title compound (2.74 g, 99%) as a yellow crystalline solid. LCMS (ES+) 270 (M+H)+, RT 1.41 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:5]([CH3:16])[CH:4]=1.[Li]CCCC.[CH2:22]1[O:25][C@@H:23]1[CH3:24]>C1COCC1>[OH:25][CH:23]([CH3:24])[CH2:22][CH2:16][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1ccc(NC(=O)C(C)(C)C)c(C)c1
Reactant: C[C@@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)C(C)(C)C)c(CCC(C)O)c1
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To a stirred solution of the the product from Step A (3.00 g, 13.6 mmol) at 0° C. in anhydrous THF (50 mL) was added a solution of 2.5 M n-BuLi in hexanes (13.6 mL, 2.5 equiv.) over about 2 min under a nitrogen atmosphere. After 10 minutes a solution of (R)-propylene oxide (1.18 g, 1.5 eq) in anhydrous THF (5 mL) was added and the mixture was stirred for about 30 min. The reaction was quenched by the addition of ice-water. The THF was evaporated and the residue was extracted with ethyl acetate to give a viscous oil (4.03 g), which was used in next reaction without further purification: LC/MS (+APCI) m/z 280 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH:12]2[CH2:14][CH:13]2[CH3:15])[N:7]=[C:6]([N:23]([CH3:30])[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:41]([C@:48]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:51])[CH:49]=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[CH2:41]([C@:48]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:51])/[CH:49]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]([N:23]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:25])=[O:26])[CH3:30])[N:7]=[C:8]([N:10]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH:12]2[CH2:14][CH:13]2[CH3:15])[CH:9]=1)=[O:3])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(=O)c1cc(N(Cc2ccccc2)CC2CC2C)nc(N(C)S(=O)(=O)C(C)C)c1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CC1CN(Cc1ccccc1)c1cc(C(=O)/C=C/[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(C)S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of N-(4-acetyl-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylpropane-2-sulfonamide (100 mg, 0.23 mmol) from Step B in 1.5 mL dry THF was added lithium bis(trimethylsilyl)amide (244 μL, 0.49 mmol, 2M solution in THF), and the resulting mixture was allowed to stir for 15 min. To this mixture was added a solution of tert-butyl (1R) -1-benzyl-1-methyl-2-oxoethylcarbamate (61 mg, 0.23 mmol, prepared according to preparation of intermediate III up to step C) dissolved in 1 mL dry THF. The solution was allowed to slowly warm to rt and then allowed to stir for an additional 16 h, at which time it was quenched with a saturated solution of ammonium chloride (15 mL) and extracted with ethyl acetate (2×25 mL). The combined organics were dried over sodium sulfate and concentrated. Purification by reverse-phase chromatography afforded tert-butyl (1R,2E)-1-benzyl-4-{2-{benzyl[(2-methylcyclopropyl)methyl]amino}-6-[(isopropylsulfonyl)(methyl)amino]pyridin-4-yl}-1-methyl-4-oxobut-2-enylcarbamate, intermediate n, as an orange oil. LCMS [M+H]=675.3.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@H:7]1[C:10](=[O:11])[NH:9][C@@H:8]1[C:12]([OH:14])=[O:13])=[N+]=[N-]>CN(C=O)C.C(O)(=O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][C@H:7]1[C:10](=[O:11])[NH:9][C@@H:8]1[C:12]([OH:14])=[O:13]
Reactant: [N-]=[N+]=NCCC[C@H]1C(=O)N[C@@H]1C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: NCCC[C@H]1C(=O)N[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 146 (0.59 g, 1.0 eq.) in DMF (5 mL) and acetic acid (1 mL) was added 10% Pd/C (300 mg). The flask was evacuated and flushed with hydrogen. The reaction was then stirred at room temperature under an atmosphere of hydrogen for 16 hours. The reaction was then filtered through Celite and crude amine 147 was immediately used in the next step as a solution in DMF.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:53]1([C:57](Cl)=[O:58])[CH2:56][CH2:55][CH2:54]1>CC#N>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([N:45]([CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:57]([CH:53]3[CH2:56][CH2:55][CH2:54]3)=[O:58])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:43][CH2:42]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCc3ccccc3)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: O=C(Cl)C1CCC1
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(Cc3ccccc3)C(=O)C3CCC3)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example 134 using (3S,5R)-3-Benzylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and cyclobutanecarbonylchloride. MS: 557 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.34 min.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1)(=O)C.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[N:19]([CH:29]3[CH2:33][CH2:32][CH2:31][O:30]3)[C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1CCCO1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c(F)cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)c(=O)n1C1CCCO1
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
A 1.32 g quantity of N,O-bis(trimethylsiliyl)-acetamide was added with stirring to a suspension of 0.40 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 8 ml of dry dichloromethane at room temperature. To the mixture were added, after 4 hours, 0.32 g of 2-acetoxytetrahydrofuran and a solution of 0.1 ml of stannic chloride in 1.6 ml of dry dichloromethane. The mixture was stirred for 1.5 hours and neutralized with 0.64 ml of triethylamine and washed with water. The dichloromethane layer was concentrated and the residue was dissolved in 16 ml of methanol. To the solution was added 0.24 ml of acetic acid and the mixture was left to stand for 3 hours at 40° C. The solvent was distilled off and the residue was subjected to silica gel column chromatography to conduct a gradient elution using chloroform and mixtures of methanol (up to 4%) and chloroform, giving 0.3 g of the title compound in a yield of 77%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22](=O)[NH2:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]#[N:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(N)=O)c12
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C#N)c12
Temperature: 5 °C
Yield: 84.5 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carbamoyl-5-fluoro-1,2-benzisoxazole (0.25 g) in dimethylformamide (2.0 ml) was added phosphorus oxychloride (0.12 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.20 g, 87% yield) as a colorless powder.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:11][N:10]=[C:9]([NH2:12])[CH:8]=2)=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23].CN(C=O)C>O>[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:21]=1[C:22]([NH:24][C:25]([NH:12][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:2][CH:3]=2)[O:11][N:10]=1)=[O:26])=[O:23]
Reactant: Nc1cc(-c2ccc(-c3ccccc3)cc2)on1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cc(-c2ccc(-c3ccccc3)cc2)on1

Procedure:
5-(4-Biphenylyl)-3-aminoisoxazole (450 mg.) was mixed with excess 2,6-dichlorobenzoyl isocyanate in 50 ml. of DMF and the reaction mixture stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product separated by filtration and recrystallized from ethanol, m.p. 225°-227° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH:12]([N:15]1[CH2:18][CH:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)([CH3:14])[CH3:13].[OH-].[K+]>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:18][CH:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:16][NH:15][CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)N1CC(OCc2ccccc2)C1
Reactant: Oc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)NCC(COc1ccc2ccccc2c1)OCc1ccccc1
Temperature: 180 °C
Yield: 84 %

Procedure:
A mixture of 17.3 parts of β-naphthol, 20.5 parts of 1-(iso-propyl)-3-benzyloxyazetidine, and 1.1 parts of potassium hydroxide was heated under nitrogen gas at 180° C. for 8 hours with agitation. The reaction mixture was cooled and dissolved in 100 parts of ether. The solution was washed with 50 parts of 2 N-sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate. Ether was distilled off and the residue was subjected to distillation to yield 29.3 parts of 1-(β-naphthoxy)-2-benzyloxy-3-(iso-propylamino)-propane boiling at 185°-190° C. under 1 mm Hg. The yield was 84%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:11][C:2]([CH3:1])=[CH:3][C:4]=12
Reactant: Cc1cc2c(O)ccnc2[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of 2-methyl-1H-pyrrolo[2,3-b]pyridin-4-ol (90 mg, TFA salt, 0.34 mmol), 3,4-difluoronitrobenzene (0.05 mL) and potassium carbonate (100 mg, 0.72 mmol) in DMF (1 mL) was stirred at 50° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to afford the crude product, which was purified by preparative HPLC to give the title compound (45 mg, 46%). 1H NMR (CD3OD) δ 8.25 (dd, 2H, J=10.4, 2.6 Hz), 8.12 (m, 1H), 8.04 (d, 1H, J=5.5 Hz), 7.30 (t, 1H, J=8.3 Hz), 6.67 (d, 1H, J=5.5 Hz), 5.95 (s, 1H), 2.41 (s, 3H); MS(ESI+) m/z 288 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5](Cl)[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:21]3[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Clc1nccc2sc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nccc3sc(Br)cc23)CC1
Yield: 24.2 %

Procedure:
The same procedure above intermediate was used starting from 2-bromo-4-chlorothieno[3,2-c]pyridine (7.5 g, 30.45 mmol), K2CO3 (6.7 g, 33.5 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (21.0 g, 152.2 mmol) in DMSO (30 mL). Purification by flash chromatography 3.04 g of the title compound (Yield 25%). HPLC purity 92%; 1H NMR (270 MHz, CDCl3) δ 1.38 (s, 4.5H), 1.43 (s, 4.5H), 1.96-2.11 (m, 2H), 3.36-3.41 (m, 1H), 3.46-3.51 (m, 1H), 3.65-3.87 (m, 6H), 7.02-7.04 (m, 1H), 7.40-7.42 (m, 1H), 7.94 (d, J=5.4 Hz, 1H). m/z=411.97 (M+H).
Reaction SMILES: Cl.[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>>[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:26])[NH2:27])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)C3CCCC3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([Li])CCC.[Cl-:14].[Cl-].[Cl-].[CH3:17][C:18]1[C:22]([Ti+3:24])([CH3:23])[C:21]([CH3:25])=[C:20]([CH3:26])[C:19]=1[CH3:27]>C1(C)C=CC=CC=1>[Cl-:14].[Cl-:14].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][Ti+2:24][C:22]1([CH3:23])[C:18]([CH3:17])=[C:19]([CH3:27])[C:20]([CH3:26])=[C:21]1[CH3:25]
Reactant: CC1=C(C)C(C)([Ti+3])C(C)=C1C
Reactant: Cc1ccccc1O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti+2]Oc2ccccc2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 165.1 %

Procedure:
0.86 g (5.1 mmol) of 2-methylphenol (Aldrich, 99%) was dissolved in 40 ml of toluene, and 2.4 ml of butyllithium (2.5 M hexane solution) was slowly added dropwise thereto. The mixture solution was allowed to react at room temperature for 12 hours, and a solution of (pentamethylcyclopentadienyl)titanium(IV) trichloride (1.64 g, 5.5 mmol) in 10 ml of toluene was slowly added dropwise to the reaction solution at 0° C. The reaction solution was stirred at room temperature for 12 hours, filtered, treated to remove volatile material, and recrystallized with a mixed solution of toluene and hexane at −35° C., thus obtaining 1.64 g of a red solid. The cyclic voltammogram of the catalyst thus prepared is shown in FIG. 2.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[CH2:18][C:19]([N:21]([CH3:32])[N:22]=[C:23]([N:29]([CH3:31])[CH3:30])[C:24](OCC)=[O:25])=[O:20])[CH3:8]>C1COCC1.O>[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[C:18]1[C:19](=[O:20])[N:21]([CH3:32])[N:22]=[C:23]([N:29]([CH3:31])[CH3:30])[C:24]=1[OH:25])[CH3:8]
Reactant: CCOC(=O)C(=NN(C)C(=O)Cc1c(CC)cc(C)cc1CC)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(N(C)C)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a solution of potassium t-butoxide (380 mg, 3.38 mmol) in dry THF (10 ml) was slowly added a solution of ethyl 2-[2-(2,6-diethyl-4-methylphenyl)acetyl-2-methylhydrazono]-2-dimethylaminoacetate (Compound (II-2)) (280 mg, 0.840 mmol) in dry THF (3 ml) dropwise. The mixture was stirred at room temperature for 15 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was washed with hexane, filtered, and dried to give 230 mg of Compound (I-1-2).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:3]1[C:19]([O-:21])=[O:20].CO.Cl>O>[CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:3]1[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)C(=CC1C(C(=O)[O-])C1(C)C)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C(=CC1C(C(=O)O)C1(C)C)OC(C)(C)C
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A mixture of 590 mg Sof the product of Step B, 20 ml of methanol, 10 ml of acetane and 20 ml of aqueous N hydrochloric acid was stirred at 20° C. for 6 hours and was poured into water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 4-6 hexane-ethyl acetate mixture to obtain 364 mg of (1R,transΔZ) 2,2-dimethyl-3-[2-tert.-butoxy-2-tert.-butoxycarbonyl-ethenyl]-cyclopropane-carboxylic acid melting at 85° C.