Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:45]=[C:44]([CH3:46])[C:43]([O:47]CC4C=CC=CC=4)=[C:42]([CH3:55])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:56]=[CH:57][CH:58]=[CH:59][C:4]=2[NH:3]1.[H][H]>CCO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:45]=[C:44]([CH3:46])[C:43]([OH:47])=[C:42]([CH3:55])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:56]=[CH:57][CH:58]=[CH:59][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
2.00 g (2.47 mmol) of (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 25 mL EtOH were combined with 200 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac. The residue was reacted further without any purification by chromatography.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.O>C1COCC1>[CH:1]1([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][N:9]=[C:10]3[NH:11][C:17]2=[O:18])[CH2:3][CH2:2]1
Reactant: Nc1nccnc1NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2nccnc2n1C1CC1
Yield: 71.2 %

Procedure:
To a solution of N2-cyclopropylpyrazine-2,3-diamine (0.6690 g, 4.45 mmol) in THF (22.27 ml) at 50° C. was added CDI (2.89 g, 17.82 mmol, Fluka). The reaction was allowed to stir for 1½ h. The reaction flask was place in an ice bath until the temperature reached 0° C. The flask was raised and water (5 mL) was added dropwise to quench. (Note: if exothermic reaction was detected then flask was placed back into ice bath until it stopped.) The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 1% to 8% MeOH in CH2Cl2, to provide 1 the title compound (0.5578 g, 3.17 mmol, 71.1% yield). LCMS showed product peak at 0.999 min (m+1=177.1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.07 (m, 4 H) 2.87-3.00 (m, 1 H) 7.84-7.89 (m, 1 H) 7.89-7.94 (m, 1 H) 11.87 (s, 1 H)
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[CH:21]1([CH2:24][C@@H:25](OS(C(F)(F)F)(=O)=O)[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:23][CH2:22]1>COCCOC.ClCCl>[CH:21]1([CH2:24][C@@H:25]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:2]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:1]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H](CC1CC1)OS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)[C@@H](CC1CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 3.8 g of benzyl tert-butyl malonate in 50 ml of 1,2-dimethoxyethane was treated with 0.504 g of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred at room temperature for 30 minutes and then cooled to 0°. A solution of 5.37 g of benzyl 3-cyclopropyl-2(R)-trifluoromethylsulphonyloxypropionate in 20 ml of dichloromethane was added dropwise at 0°. The mixture was stirred at 0° for 2 hours and then left to warm to room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated to give 6.54 g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-2(R),3(R,S),3-propane-tricarboxylate as a 1:1 mixture of diastereoisomers in the form of an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]1[CH2:15][O:14]1)[CH:7]=[C:6]2[C:16]1[N:28]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:19]2=[N:20][CH:21]=[C:22]3[CH:26]=[N:25][N:24]([CH3:27])[C:23]3=[C:18]2[CH:17]=1.[CH3:39][NH:40][CH3:41]>CN(C=O)C>[CH3:39][N:40]([CH3:41])[CH2:15][CH:13]([OH:14])[CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([C:16]2[N:28]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:19]3=[N:20][CH:21]=[C:22]4[CH:26]=[N:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[CH:7]1
Reactant: CNC
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC1CO1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC(O)CN(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.8 %

Procedure:
In a flask, a mixture of 7-(5-methoxy-1-(oxiran-2-ylmethyl)-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.212 mmol) in DMF (5 mL) and dimethylamine (0.054 mL, 1.061 mmol) was stirred for about 17 h at rt. Additional dimethylamine (0.054 mL, 1.061 mmol) was added and the mixture was heated to about 50° C. for about 5 h, then at rt for about 17 h. The mixture was concentrated in vacuo to provide 1-(dimethylamino)-3-(5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-1-yl)propan-2-ol (0.120 g, 99%): LC/MS (Table 2, Method c) Rt=1.29 min; MS m/z 573 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:11][C:12]1[C:13]([CH3:18])=[N:14][NH:15][C:16]=1[CH3:17]>CN(C)C=O>[C:3]([N:15]1[C:16]([CH3:17])=[C:12]([O:11][C:10]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:8]([Cl:7])[CH:9]=2)[C:13]([CH3:18])=[N:14]1)(=[O:5])[CH3:4]
Reactant: Cc1n[nH]c(C)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1nc(C)c(Oc2cc(Cl)cc(Cl)c2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 684 mg, 17.1 mmol) was added to a stirred solution of acetyl chloride (1.21 ml, 17.1 mmol) and the pyrazole of Example 53 (4.00 g, 15.6 mmol) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 hour and then quenched by the addition of water (100 ml). The aqueous extracted was with ether (2×50 ml). The combined organic phases were washed with water (30 ml) and brine (30 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ether (90:10, by volume) to provide the title compound (3.0 g) as a white solid, m.p.<60° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Iodo-4-methylaniline (2.42 g, 10.4 mmol) was dissolved in DCM (20.00 mL) and triethylamine (TEA) (1.70 mL, 12.2 mmol) was added and the resulting mixture was cooled to 0° C. To the mixture was added dropwise 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1.60 mL, 10.5 mmol) and the resulting mixture was stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water sat. Na2CO3, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The reaction product was used in the next reaction without purification. 1H NMR (CDCl3): δ □ 8.98 (d, 1H), 7.78 (s, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.23 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=424 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH2:10])=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].Cl.N[OH:13]>COCCO>[CH3:1][N:2]1[C:9]([NH:10][OH:13])=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: COCCO
Product: Cn1c(NO)cc(=O)[nH]c1=O
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A mixture of 2 g of 1-methyl-6-aminouracil, 2 g of hydroxylamine hydrochloride and 30 ml of methyl-cellosolve is boiled for 2 hours, after which the insolubles are filtered off. The filtrate is concentrated to dryness and tritulated with water. The resultant crystals are recovered by filtration and recrystallized from ethanol. By the above procedure is obtained 1.5 g of the captioned compound as pale-yellow crystals, melting point: 247°-250° C. (decomp.).
Reaction SMILES: [CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][C:5]1[CH:40]=[CH:39][C:8]([C:9]([C:11]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]([C:23](=O)[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:25]=3)=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=O)=[CH:7][CH:6]=1)[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:36]([CH:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:17]2[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:41][CH2:42][CH2:43][CH3:44])=[CH:40][CH:39]=3)=[CH:19][C:18]=2[C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1)[CH3:37]
Reactant: [H][H]
Reactant: CCCCC(CC)Cc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CC(CC)CCCC)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CC(CC)CCCC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture containing 20.0 grams of 2,5-bis(4-(2-ethylhexyl)benzoyl)terephthalic acid in 1500 mL of THF and 2.9 grams of 10% palladium on carbon (as a catalyst) was heated to 65° C. in an atmosphere of hydrogen at 275 kPa for 17 hours. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-Bis(4-(2-ethylhexyl)benzyl)terephthalic acid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)[CH:8]1[O:10][CH2:9]1.C(N(CC)CC)C>CCOCC>[C:1]([O:6][CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: c1coc(COCC2CO2)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(O)COCc1ccco1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of methacrylic acid (10 g), furfuryl glycidyl ether (15 g) and triethylamine (0.3 g) was heated to 100° C. for 2 hours then to 105° C. for an additional 2 hours. GC analysis showed 96% conversion. The mixture was taken up into ether, washed with water, followed by saturated sodium bicarbonate, dried with MgSO4 filtered and rotary evaporated to provide 23.7 g of a faintly yellow oil (94.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL). Pyridine (1.5 mL) was added followed by 2,2-dimethylpropanoyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2,2-dimethylpropanamide (27 mg, 0.064 mmol). 1H NMR (CDCl3-d) δ 1.35 (s, 9H), 2.09 (m, 4H), 3.66 (m, 2H), 3.96 (s, 3H), 4.13(m, 2H), 4.97 (m, 1H), 5.46(bs, 2H), 6.98 (s, 1H), 7.04 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 8.29 (s, 1H), 8.49 (d, J=8.2 Hz, 1H). LC/MS: MH+=424.
Reaction SMILES: [CH:1]([C:4]1[O:5][C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:7][C:8]=1[CH:9]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])([CH3:3])[CH3:2].[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39]>>[CH:1]([C:4]1[O:5][C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=2)=[CH:7][C:8]=1[CH:9]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:20])=[CH:17][CH:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCNC
Reactant: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C(C)C
Product: CC(C)CC(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C(C)C
Yield: 22.8 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methylbutoxy)benzoic acid (170 mg) as well as ethyl 3-(methylamino)propanoate (58 mg) to give the title compound (46 mg, 23%) as a white crystal.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.C([O:12][C:13](=[O:43])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:42])C>>[Cl:29][C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([O:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][C:36]=2[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:26]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:43])=[O:12])=[C:17]([CH3:42])[CH:18]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1cncnc1
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3-c3cncnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using pyrimidine-5-boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester to afford about 31 mg (22%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C27H20O4F3N2Cl 528, found 529 (M+1, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:14])=[C:4]([NH2:15])[CH:3]=1.[C:16](=S)=[S:17].[OH-].[K+].[K+].[Br-]>O.C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][C:5]2[N:14]=[C:16]([SH:17])[NH:15][C:4]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(N2CCNCC2)cc1N
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1cc2[nH]c(S)nc2cc1N1CCNCC1
Yield: 81.2 %

Procedure:
6-Fluoro-5-(piperazin-1-yl)-2-mercapto-1H-benzimidazole (4.3 g, 80%) was prepared by an analogous procedure as described in preparation 1 (step 5) using the diamine (4.5 g, 0.021 mol) (obtained in step 2 above), carbon disulfide (1.9 g, 0.025 mol), potassium hydroxide (1.4 g, 0.025 mol), ethanol (25 mL) and water (5 mL). mp 100-10 1 ° C.; IR (KBr) 3133, 1482 cm-1 ; 1H NMR (DMSO-d6) δ 2.25 (s, 1H, SH), 2.90 (m, 4H, N(CH2)2), 4.10 (brs, 1H, NH), 4.48 (m, 4H, N(CH2)2), 6.80 (d, J=8.4 Hz, 1H), 7.00 (d, J=12.3 Hz, 1H), 12.30 (brs, 1H, NH); Mass (m/z) 252 (M+.).
Reaction SMILES: [C:1]1([Mg]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C@@:14]12[C:22](=[O:23])[CH2:21][C@@H:17]([C:18]1([CH3:20])[CH3:19])[CH2:16][CH2:15]2>C1COCC1>[C:1]1([C:22]2([OH:23])[CH2:21][CH:17]3[C:18]([CH3:19])([CH3:20])[C@:14]2([CH3:13])[CH2:15][CH2:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1cccc2ccccc12
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2
Solvent: C1CCOC1
Product: CC1(C)C2CC[C@]1(C)C(O)(c1cccc3ccccc13)C2

Procedure:
The resulting THF solution of 1-naphthylmagnesium bromide was cooled to room temperature. Then, a THF (200 ml) solution of (-)-camphor (50 g, 0.328 mol) was added thereto, and the whole was heated under reflux for 72 hours. The reaction was terminated by cooling with ice-water and adding saturated ammonium chloride aq solution. Then, the organic layer was filtered off, and the solid residue was treated with 10% hydrochloric acid and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate and, after filtration, concentrated to give 121 g of a crude (1S)-2-(1-naphthyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol as an oil.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
5.0 mL of methylene chloride, 0.056 mL of triethylamine and 51 mg of 4-methoxybenzoyl chloride were added sequentially to 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature, and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufacture by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(4-methoxybenzamido)-4-phenoxybenzoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)[CH3:18]
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CC(C)=O)cc1
Temperature: 90 °C
Yield: 100.4 %

Procedure:
1-(4-hydroxyphenyl)propan-2-one (500 mg, 3.33 mmol), ethyl 2-bromoacetate (0.37 mL, 3.34 mmol) and potassium carbonate (575 mg, 4.16 mmol) were dissolved in acetonitrile (7 mL) in a sealed tube under argon atmosphere. The reaction mixture was heated to 90° C. for 3.5 hours. The solids were filtered and washed with additional acetonitrile and the filtrate was concentrated under reduced pressure to give the title compound (790 mg, 100% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg]Br.C(OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][C:17]2=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a solution of 4-(2-methoxycarbonyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 12.0 mmol) in anhydrous THF (75 mL) was slowly added a solution of methyl magnesium bromide in diethyl ether (3 M, 6 mL, 18 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h, then allowed to warm to RT and stirring was continued for 72 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc and an aqueous solution of ammonium chloride. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (598 mg, 20%). To a solution of 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (595 mg, 2.34 mmol) in DCM (6 mL) was added TFA (2 mL). The resulting mixture was stirred at RT for 1.5 h, then concentrated in vacuo. The resultant residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (325 mg, 90%).
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2([CH3:11])[CH3:10])[C:3]1=[CH:12][O:13][C:14](=[O:16])[CH3:15].O=[C:18]1N2C(CCOC2(C)C)C1>CN(C)C(=O)C>[O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2([CH3:10])[CH3:11])[C:3]1=[C:12]([O:13][C:14](=[O:16])[CH3:15])[CH3:18]
Reactant: CC(=O)OC=C1C(=O)N2C1CCOC2(C)C
Reactant: CC1(C)OCCC2CC(=O)N21
Solvent: CC(=O)N(C)C
Product: CC(=O)OC(C)=C1C(=O)N2C1CCOC2(C)C

Procedure:
Following the procedure described for the preparation of 8-oxo-7-acetoxymethylene-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane and using N,N-dimethylacetamide instead of N,N-dimethylformamide one obtains 8-oxo-7-(1'-acetoxyethylidene)-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([S:8]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O.O>[CH:11]1([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:16])=[O:3])(=[O:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a solution of 5.4 g (21.7 mmol) of 2-cyclopentanesulfonyl-2-methyl-propionic acid ethyl ester in THF/water (4/1, 60 mL) are added 2.3 g (56.6 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 18 h. The reaction is further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer is cooled in an ice bath and then acidified with 2M aqueous HCl solution to pH 2. The acidic aqueous layer is extracted with 2-propanol/chloroform (1/4, 100 mL). The combined organic extracts are washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure affords 4.34 g of 2-cyclopentanesulfonyl-2-methyl-propionic acid. Yield: 92%, ES-MS: m/z 221 [M+H]
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](=[O:26])[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC1

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-N5-(tert-butyloxycarbonyl)-ornithine and pyrrolidine, the expected product is obtained according to the procedure described in Step A of Example 3.