Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H](C=O)CCSC.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23]CC)=O)[CH2:14][CH2:13]1)[CH2:10][CH3:11].Cl.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[F:42])[C:36]([NH2:38])=[NH:37]>CO.Cl>[OH:23][C:21]1[C:20]([CH2:19][CH2:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([CH2:9][CH2:10][CH3:11])[CH2:17][CH2:16]2)=[C:26]([OH:28])[N:37]=[C:36]([C:35]2[CH:39]=[CH:40][C:41]([F:42])=[C:33]([F:32])[CH:34]=2)[N:38]=1
Reactant: N=C(N)c1ccc(F)c(F)c1
Reactant: CCC[C@H]1CC[C@H](CCC(C(=O)OCC)C(=O)OCC)CC1
Agent: CSCC[C@H](N)C=O
Agent: Cl
Solvent: CO
Product: CCC[C@H]1CC[C@H](CCc2c(O)nc(-c3ccc(F)c(F)c3)nc2O)CC1
Yield: 94.2 %

Procedure:
Metal sodium (0.3 g) was dissolved in anhydrous methanol (100 m(), followed by adding diethyl 2-(trans-4'-propylcyclohexyl)ethylmalonate (3.2 g) and 3,4-difluorobenzamidine hydrochloride (1.9 g) with stirring, reacting the mixture under reflux for 10 hours, thereafter cooling the reaction solution, pouring it in 6N HCl (100 ml) and ice (300 g), filtering off deposited yellow crystals, washing with water and drying crystals to obtain 4,6-dihydroxy-5-[2'-(trans-4"-propylcyclohexyl)ethyl]-2-(3,4-difluorophenyl)pyrimidine (3.5 g).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]([OH:24])=[C:19]([C:21]([NH2:23])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.C[O-].[Na+].C(OC(C)C)(C)C>CO>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:17][C:18]([OH:24])=[C:19]([C:21]([NH2:23])=[O:22])[N:20]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)c1nc(-c2ccc(OC(=O)c3ccccc3)cc2)[nH]c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: NC(=O)c1nc(-c2ccc(O)cc2)[nH]c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a chilled suspension of 2-(4-benzoyloxyphenyl)-5-hydroxyimidazole-4-carboxamide (323 mg) in anhydrous methanol (20 ml) was added sodium methoxide (216 mg). After stirring for 5 minutes at 0°-5° C. and 15 minutes at room temperature, N-hydrochloric acid aqueous solution (4 ml) and isopropylether (30 ml) were added. The precipitated crystal was separated by filtration, washed with isopropylether and dried under vacuum to give 2-(4-hydroxyphenyl)-5-hydroxy-1H-imidazole-4-carboxamide (190 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.O>O1CCCC1>[CH2:12]([C:7]1[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=2)[N:8]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(N)cc23)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(NS(C)(=O)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of tert-butyl [6-amino-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.21 g, 0.5 mmol) in tetrahydrofuran (10 ml) were added dropwise methanesulfonyl chloride (0.05 ml, 0.6 mmol) and triethylamine (0.08 ml, 0.6 mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-[(methylsulfonyl)amino]-3-quinolinyl]methylcarbamate (0.21 g, yield 84%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16](COCC[Si](C)(C)C)[CH:17]=[CH:18][C:11]=12.Cl[C:28]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:31]=[C:30]([NH2:41])[N:29]=1.Cl.[OH-].[Na+]>O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:31]=[C:30]([NH2:41])[N:29]=[C:28]([NH:8][C:6]3[CH:5]=[CH:4][C:3]([NH:9][C:10]4[CH:15]=[CH:14][N:13]=[C:12]5[NH:16][CH:17]=[CH:18][C:11]=45)=[C:2]([F:1])[CH:7]=3)[CH:33]=2)=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Nc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccc(F)cc2)n1

Procedure:
100 mg (0.27 mmol) of 2-fluoro-N1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 63 mg (0.28 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine are suspended in 3 ml of water. 39 μl (0.40 mmol) of a 37% strength hydrochloric acid solution are then added, and the mixture is heated under reflux overnight. After addition of a further 39 μl (0.40 mmol) of a 37% strength hydrochloric acid solution, the mixture is again reacted under reflux overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off, washed with a little water and then dissolved in DMSO and purified by preparative RP-HPLC.
Reaction SMILES: [C:1]([O:4]C1C=C(Cl)C(OC2C=CC(NC(=O)C(C)C)=C(Br)C=2)=C(Cl)C=1C)(=[O:3])[CH3:2].C[Sn](C)(C)C.C(O[C:37]1[CH:42]=[C:41]([Cl:43])[C:40]([O:44][C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:56])[CH:53]([CH3:55])[CH3:54])=[C:47]([CH3:57])[CH:46]=2)=[C:39]([Cl:58])[C:38]=1C)(=O)C>[Cu]=O.CN(C)C=O>[Cl:43][C:41]1[CH:42]=[C:37]([CH2:2][C:1]([OH:4])=[O:3])[CH:38]=[C:39]([Cl:58])[C:40]=1[O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:56])[CH:53]([CH3:55])[CH3:54])=[C:47]([CH3:57])[CH:46]=1
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(Br)c2)c(Cl)c1C
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(C)c2)c(Cl)c1C
Agent: O=[Cu]
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)ccc1NC(=O)C(C)C
Yield: 88 %

Procedure:
Methyl[3,5-dichloro-4-(3-bromo-4-isobutyramidophenoxy)phenyl] acetate (100 mg) was reacted with tetramethyltin (40 mg), dichloro(1,2-bis(diphenylphosphino)butane)palladium(II), copper(II) oxide (16 mg) and dimethylformamide (3 mL) using the method described in Example 3. This gave 20 mg (23%) of methyl(3,5-dichloro-4-[4-isobutyr-amido-3-methylphenoxy]phenyl) acetate, which was hydrolyzed using the method described in Example 1(i), to give 17 mg (88%) of 3,5-dichloro-4-(4-isobutyramido-3-methyl-phenoxy)phenylacetic acid, m/z 396.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Cl:30])(=[O:29])[CH3:28]>ClCCl>[C:27]([Cl:30])(=[O:29])[CH3:28].[C:27]([O:19][CH2:18][CH2:17][CH2:16][NH:15][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:29])[CH3:28]
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reaction time: 0.08 h

Procedure:
To a round-bottomed flask containing 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (88.15 g) was added dichloromethane (DCM, 600 mL) followed by triethylamine (38 mL, 270.8 mmol) and the solution was stirred for 5 minutes. In a separate flask a solution of acetyl chloride (14.4 mL, 202.5 mmol) in dichloromethane (300 mL) was prepared. The acetyl chloride solution was added to the reaction mixture in a dropwise fashion. The reaction was stirred at ambient temperature for 4 h. Additional acetyl chloride (2.8 mL in DCM (50 mL)) was added and the reaction mixture was stirred at ambient temperature overnight. At this time additional acetyl chloride (1.4 mL in dichloromethane (25 mL)) was added and the reaction was stirred at ambient temperature for 1 h. Additional dichloromethane (200 mL) was then added and the reaction was transferred to a separatory funnel. The organic layer was washed with water (2×800 mL) and brine (1×800 mL). The organic layer was separated, dried (MgSO4), filtered, and the solvent evaporated to afford 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propyl acetate (60.8 g) as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[CH2:7][OH:8].[H-].[Na+].C([Li])CCC.[F:18][CH:19]([F:30])[CH:20]=[N:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:19]([F:30])[F:18])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: COc1ccc(N=CC(F)F)cc1
Reactant: OCc1cc(Cl)ccc1I
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A solution of 5-chloro-2-iodobenzylalcohol (0.948 g, 3.53 mmol) in dry THF (27 mL) was added, rinsing with dry THF, to a stirred suspension of NaH (0.155 g, 3.89 mmol) in dry THF (9 mL) at 0° C. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 2.97 mL, 7 mmol) was added dropwise over 5 minutes. After a further 10 min, a solution of N-(2,2-difluoroethylidene)-N-(4-methoxyphenyl)amine (0.654 g, 3.53 mmol) in dry THF (9 mL) was added. After 1 h the mixture was quenched with excess saturated aqueous NH4Cl at −78° C. then was stirred at ambient temperature for 15 min. The solution was partitioned between EtOAc and brine. The EtOAc layer was dried (Na2SO4) and evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-30% ethyl acetate/hexanes gradient) to give (5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}phenyl)methanol (0.439 g) as an oil: MS 328.4 (M+1); 1H NMR (CDCl3, 400 MHz) δ 2.00 (br s, 1H), 3.70 (s, 3H), 4.14 (br s, 1H), 4.82 (m, 2H), 5.02 (m, 1H), 6.08 (dt, J=3.0 Hz, 56.0 Hz, 1H), 6.57 (d, J=9.0 Hz, 2H), 6.71 (d, J=9.0 Hz), 2H), 7.29 (dd, J=2.2 and 8.4 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:51]=1)[CH:45]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:51]=1)[CH2:45][NH:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(C=O)cc2OCCCCOCc2ccccc2)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(CNc3nc4ccccc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2OCCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (0.11 g) and 3-(4-benzyloxybutoxy)-4-(3-methanesulfonylphenyl)benzaldehyde (0.24 g) were suspended in tetrahydrofuran (5 mL). To the reaction mixture was added sodium triacetoxyborohydride (0.12 g), and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction mixture, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 mL). To the mixture was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give 2-[3-(4-benzyloxybutoxy)-4-(3-methanesulfonylphenyl)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.16 g). The obtained compound was dissolved in methanol (2 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at 40° C. under a hydrogen atmosphere for 24 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.04 g).
Reaction SMILES: C[O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO>[F:19][C:15]1[CH:14]=[C:13](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:20])=[O:2])[CH:18]=[CH:17][CH:16]=1
Reactant: CCCCC/C(=C\C=C\C(=O)OC)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC/C(=C\C=C\C(=O)O)c1cccc(F)c1
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
As described in Example 99, (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid methyl ester (5.54 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 45 minutes the reaction was worked up in the usual way and the crude acid crystallized from hexane to yield 3.85 g of (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid, mp 84°-85.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[Br:19]N1C(=O)CCC1=O.O.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[C:17]([OH:18])=[CH:16][C:15]([Br:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1c(O)cc(Br)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: -15 °C
Yield: 83.3 %

Procedure:
2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (5.27 g) was dissolved in 60 ml of N,N-dimethylformamide and the solution was stirred at −15° C. N-Bromosuccinimide (3.56 g) was added thereto by dividing into four with an interval of 5 minutes each and the mixture was stirred at −15° C. for 1.5 hours. Then more 0.36 g of N-bromosuccinimide was added thereto, the mixture was stirred at −15° C. for 2 hours, then 120 ml of water and 120 ml of ethyl acetate were added thereto and the mixture was stirred at room temperature for 10 minutes. The resulting precipitate was filtered through Celite and an organic layer in the filtrate was collected while an aqueous layer was further extracted with ethyl acetate. Active carbon powder (2.6 g) was added to the resulting organic layer and the mixture was stirred for 15 minutes and filtered through Celite. The filtrate was washed with water and dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo and the residue was dried to give 5.70 g of 2-amino-5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[N+:32]([O-:34])=[O:33])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:35])=[O:5])[S:12][CH:13]=3)=[C:20]([N+:32]([O-:34])=[O:33])[CH:21]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2[N+](=O)[O-])cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2[N+](=O)[O-])cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
2-[(4-{2-[(4′-Fluoro-3-nitrobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (300 mg) obtained in Example 97-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (167 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH2:7][CH3:8])[S:4][C:3]=1[CH2:9][CH3:10].[Li]CCCC.CN([CH:19]=[O:20])C>CCOCC>[CH2:9]([C:3]1[S:4][C:5]([CH2:7][CH3:8])=[CH:6][C:2]=1[CH:19]=[O:20])[CH3:10]
Reactant: CCc1cc(Br)c(CC)s1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1cc(C=O)c(CC)s1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-2,5-diethyl thiophene, C6, (9.1 g, 41 mmol) in 100 mL of dry Et2O cooled to -78° C. was added n-BuLi (26.2 mL, 42 mmol) dropwise. The bath temperature was allowed to rise to -20° C. and DMF (6.3 mL, 82 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with NH4Cl (aq) and extracted with Et2O. The organic layer washed twice with water and brine and then dried (MgSO4). After evaporation of solvent, the crude product was purified on flash silica gel (98:2 hexane/Et2O) to afford 2,5-diethylthiophene-3-carboxaldehyde, D6, as a light yellow oil (5.0 g, 72%). 1H NMR (CDCl3) supported the assigned structure. ##STR51##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].[H-].[Na+].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:22].O>CN(C=O)C>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:12]([C:4]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:35][CH:36]=1)#[N:22]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC(=O)Nc1c(OC)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1c(OC)cccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a solution of N-(2-methoxy-6-nitrophenyl)valeramide (3.2 g) in DMF (15 ml) was added, under ice-cooling, sodium hydride (60% oil, 0.61 g). The mixture was stirred for 20 minutes and then there was added 4-(2-cyanophenyl)benzyl bromide (3.5 g), followed by stirring for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to give a yellow oil (5.8 g, quantitatively).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: C1COCCN1
Solvent: O
Product: Clc1nccnc1N1CCOCC1

Procedure:
149 g of 2,3-dichloropyrazine, 300 g of morpholine and 400 ml of water are stirred for 16 hours at 40° C. The reaction mixture is then extracted by shaking with ether. The ether extracts are washed with water until neutral, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a waterpump vacuum. 2-Chloro-3-morpholinyl-pyrazine, boiling point 162°-165° C./15 mm Hg, is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][O:61][C:62]1[CH:69]=[CH:68][C:65]([CH2:66][NH2:67])=[CH:64][CH:63]=1.Cl>C1COCC1>[CH3:60][O:61][C:62]1[CH:69]=[CH:68][C:65]([CH2:66][NH:67][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])=[CH:64][CH:63]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (2.50 g, 11.5 mmol), HOBT-H2O (1.76 g, 11.5 mmol) and DIEA (6.01 mL, 34.5 mmol) in THF (50 mL) was cooled to 0° C. HBTU (3.23 g, 13.8 mmol) was added and the mixture stirred at 0° C. for 30 minutes prior to addition of 4-methoxy-benzylamine (2.25 mL, 17.3 mmol). The reaction mixture was allowed to warm slowly to ambient temperature while stirring over 48 hours. The reaction mixture was poured into 10% HCl and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification of the crude material by column chromatography, eluting with 1.5-3% MeOH/dichloromethane afforded (S)-tert-butyl 1-(4-methoxybenzylamino)-3-methyl-1-oxobutan-2-ylcarbamate as a light yellow solid, 2.70 g (70%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7](C(C)=C)[C:6]1=[O:17].Cl>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:17]
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCCCl
Yield: 90 %

Procedure:
A solution of 13 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 6 parts of a hydrochloric acid solution and 40 parts of ethanol is stirred for 2 hours at room temperature. The reaction mixture is evaporated and the solid residue is crystallized from 2-propanol, yielding 9.5 parts (90%) of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 115° C.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C@@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)[OH:11].[CH3:23][C:24]1[CH:25]=[C:26]([S:35](Cl)(=[O:37])=[O:36])[CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[N:33][N:32]=[N:31]1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)[CH2:9][N:3]1[CH2:4][C@@H:5]2[CH2:8][C@H:2]1[CH2:7][N:6]2[S:35]([C:26]1[CH:27]=[CH:28][C:29]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[C:24]([CH3:23])[CH:25]=1)(=[O:37])=[O:36]
Reactant: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3)ccc2c1COC2=O
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1-n1cnnn1
Agent: Cl
Product: Cc1cc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C[C@H](O)c2ccc3c(c2C)COC3=O)ccc1-n1cnnn1

Procedure:
5-((R)-1-Hydroxy-2-((1S,4S)-5-(3-methyl-4-(1H-tetrazol-1-yl)phenylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 3 starting from 5-((R)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 14) and commercially available 3-methyl-4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].O[C@:6]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][C@@H:10]([CH:12]=[CH2:13])[C@H:9]([OH:14])[C@H:8]([OH:15])[CH2:7]1.C(N(CC)CC)C>ClCCl>[CH:12]([C@H:10]1[C@@H:9]2[O:14][S:1](=[O:2])[O:15][C@@H:8]2[CH:7]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1)=[CH2:13]
Reactant: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](O)[C@H]1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@H]2OS(=O)O[C@@H]12
Reaction time: 0.5 h

Procedure:
Thionyl chloride can be added dropwise to a 0° C. solution of Example 17F and triethylamine in dichloromethane. After stirring for 30 minutes, the reaction mixture can be washed with saturated NaHCO3 solution, and brine, dried (MgSO4) filtered and concentrated to afford the crude desired product.