Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCN=C=NCC.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:26]3[C@H:22]([CH2:23][NH:24][CH2:25]3)[C@@H:21]([OH:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:34][N:35]([CH3:50])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:50][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([N:24]1[CH2:23][C@H:22]2[C@H:26]([C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][CH2:20][C@@H:21]2[OH:27])[CH2:25]1)=[O:48]
Reactant: CN(C)CCCOc1ccccc1CC(=O)O
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)CCCOc1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
0,766 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is added to a solution, cooled to 10° C., of 1 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol, 0.97 g of 2-(3-dimethylaminopropoxy)phenylacetic acid and 0.05 g of 1-hydroxybenzotriazole in 50 cm3 of dichloromethane. The reaction mixture is stirred for 90 minutes 20° C. and then washed twice with 50 cm3 of water and with 50 cm3 of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 2.9 cm, height 23 cm), eluting under a nitrogen pressure of 0.7 bar with 1,2-dichloroethane and methanol mixtures (1 liter at 90/10 by volume and 1.5 liters at 70/30 by volume) and collecting fractions of 25 cm3. Fractions 10 to 84 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.1 g of (3aR,4S,7aR)-2-{[2-(3-dimethylaminopropoxy)phenyl]-acetyl}-7,7-diphenyl-4-perhydroisoindolol in the form of a cream-colored meringue.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2)=[O:29]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccc(Cl)c(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) in acetonitrile (10 mL), was added 3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N,N-diisopropyl ethylamine (0.54 mL, 3.3 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.60 min (99.6%); mp, 271-273° C.; 1HNMR (DMSO-d6) 2.17-2.22 (m, 1H, CHH), 2.58-2.90 (m, 6H, CHCH2, CH3), 4.97-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.34-8.17 (m, 6H, Ar), 9.14 (t, J=5 Hz, 1H, CH2NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.80, 23.29, 30.60, 42.30, 56.52, 117.66, 124.17, 125.56, 127.58, 129.28, 130.76, 131.31, 133.97, 134.11, 134.56, 140.39, 148.50, 154.86, 161.06, 164.10, 169.53, 172.62. LCMS MH=473, 475; Anal Calcd For C22H18N4O4Cl2+0.1 CH2Cl2: C, 55.09; H, 3.81; N, 11.63; Cl, 16.19. Found: C, 54.88; H, 3.60; N, 11.46; Cl, 16.38.
Reaction SMILES: [ClH:1].Cl.C[O:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:31](=[NH:33])[NH2:32])[CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)=[O:6].[OH-].[Na+].Cl>CO>[ClH:1].[ClH:1].[C:31]([N:27]1[CH2:26][CH2:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH:16]3[CH2:15][CH2:14][N:13]([C:12]4[CH:11]=[CH:10][N:9]=[CH:8][C:7]=4[C:5]([OH:6])=[O:4])[CH2:18][CH2:17]3)=[CH:22][CH:23]=2)[CH2:28]1)(=[NH:32])[NH2:33]
Reactant: COC(=O)c1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=N)N)CC3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)N1CCc2ccc(OCC3CCN(c4ccncc4C(=O)O)CC3)cc2C1
Yield: 71.8 %

Procedure:
To a solution of 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester dihydrochloride (43 mg) in methanol (0.2 ml) was added 1N aqueous sodium hydroxide solution (0.1 ml), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the reaction mixture was neutralized with 1N-hydrochloric acid and the solvent was evaporated. The obtained residue was purified by reverse phase preparative thin layer chromatography (40% aqueous acetonitrile, 1% trifluoroacetic acid) and the obtained residue was treated with hydrogen chloride-ethanol solution and dried under reduced pressure to give the title compound (15 mg).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a cold (−78° C.), stirred solution of (4R)-4-benzyl-1,3-oxazolidin-2-one (4.17 g, 23.53 mmol) in THF (100 mL) under nitrogen atmosphere was added n-BuLi (9.5 mL, 23.75 mmol) dropwise via syringe over 10 min. After stirring for 10 min, a solution of 2-phenylacetyl chloride (3.2 mL, 24.20 mmol) in THF (20 mL) was added via cannula over 10 min. After the addition was complete, the reaction mixture was placed in an ice-water bath and was stirred at 0° C. for 1 hr, then removed from the ice bath. To the reaction mixture was added aqueous saturated NH4Cl and was extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent hexanes/EtOAc, REDISEP® SiO2 120 g). Concentration of appropriate fractions provided Preparation 4E (6.19 g, 89%) as a colorless viscous oil: 1H NMR (400 MHz, CDCl3) δ 7.32-7.39 (4H, m), 7.21-7.32 (4H, m), 7.10-7.17 (2H, m), 4.67 (1H, dddd, J=10.29, 6.34, 3.45, 3.26 Hz), 4.30 (2H, q, J=15.56 Hz), 4.15-4.22 (2H, m), 3.26 (1H, dd, J=13.30, 3.26 Hz), 2.76 (1H, dd).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.C(OCC)(=O)C>O>[CH:17]1[CH:16]=[CH:15][C:14]([N:7]([C:1]2[CH:2]=[CH:3][C:4]([Br:20])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
First, 25 g (100 mmol) of triphenylamine, 18 g (100 mmol) of N-bromosuccinimide, and 400 mL of ethyl acetate were put in a 1000-mL Erlenmeyer flask, and the mixture was stirred at room temperature in the air for 18 hours. After the reaction was terminated, the mixture was washed with a saturated sodium carbonate aqueous solution twice to obtain an organic layer and a water layer. Then, the water layer was extracted twice with ethyl acetate, and the extract was combined with the organic layer and washed with a saturated saline solution. The solution was dried with magnesium sulfate and filtered naturally, and the filtrate was concentrated. An obtained colorless solid was recrystallized with ethyl acetate-hexane; thus, 22 g of a colorless powdered solid of 4-bromotriphenylamine was obtained (yield: 66%).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.[C:24]([O:28][CH2:29]Cl)(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:23][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[S:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]2[N:15]([CH2:29][O:28][C:24]([CH2:25][CH3:26])=[O:27])[N:16]=[N:17][N:18]=2)=[CH:12][C:11]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Reactant: CCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)OCn1nnnc1-c1cc(S(N)(=O)=O)c(Cl)cc1NCc1cccs1

Procedure:
In similar manner to Example 12, azosemide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in DMF to yield 2-chloro-5-[1-(ethylcarbonyloxymethyl)-1H-tetrazol-5-yl]-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].Cl[C:9]1[C:10]([F:45])=[C:11]([C@@H:15]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:44])[NH:31][CH:32]([CH2:36][C@H:37]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38]3)[CH2:33][NH:34][CH3:35])[CH2:25]2)[O:16][CH2:17][CH2:18][NH:19][C:20](=[O:23])[O:21][CH3:22])[CH:12]=[CH:13][CH:14]=1>CO.[Pd]>[F:45][C:10]1[CH:9]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@H:15]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:44])[NH:31][CH:32]([CH2:36][C@H:37]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38]2)[CH2:33][NH:34][CH3:35])[CH2:25]1)[O:16][CH2:17][CH2:18][NH:19][C:20](=[O:23])[O:21][CH3:22].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CNCC(C[C@H]1CCCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2F)C1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNCC(C[C@H]1CCCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((1R)-(3-chloro-2-fluorophenyl)((3R)-1-(1-(methylamino)-3-((R)-oxepan-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate TFA salt (12 mg, 0.018 mmol) in MeOH (5 mL) was added HCO2NH4 (1.2 g) and 10% Pd/C (50 mg). The mixture was stirred for 1 h at rt. The catalyst was filtered off and concentrated, the residue was purified on preparative HPLC to give methyl 2-((1R)-(2-fluorophenyl)((3R)-1-(1-(methylamino)-3-((R)-oxepan-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate as a TFA salt (1.84 mg, 16%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C@@H:7]([C@@H:11]1[CH2:15][CH2:14][CH2:13][O:12]1)[CH2:8][CH:9]=[CH2:10])C.C[C@@H]1C[C@H]1C(OCC=O)CC=C>>[O:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C@H:7]([O:6][CH2:5][CH:4]=[O:3])[CH2:8][CH:9]=[CH2:10]
Reactant: C=CC[C@@H](OCC(OCC)OCC)[C@@H]1CCCO1
Agent: C=CCC(OCC=O)[C@@H]1C[C@H]1C
Product: C=CC[C@@H](OCC=O)[C@@H]1CCCO1

Procedure:
(2S)-2-[(1R)-1-(2,2-Diethoxyethoxyl)but-3-en-1-yl]tetrahydrofuran (C95) was converted to the product using the method described for the synthesis of ({1-[(1R,2R)-2-methylcyclopropyl]but-3-en-1-yl}oxy)acetaldehyde (C83) in Example 20. The resulting product was used in the next step without further purification. Yield: 6 g, ≦33 mmol, ≦35%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11]O)[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3]1
Reactant: CC1(C)CC(=NO)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(N)c2ccccc21
Reaction time: 8 h
Yield: 99.8 %

Procedure:
3,3-Dimethylindan-1-one oxime (1.22 g, 6.96 mmol) was dissolved in MeOH (20.0 mL) and palladium (10 weight percent on carbon, 50% water wet, 148 mg) was added. The reaction was placed under an atmosphere of hydrogen and was stirred overnight. The mixture was then filtered through Celite, washed through with MeOH and the filtrates concentrated in vacuo to afford the product as a grey oil (1.12 g, 100%). LC/MS: Rt=1.04 min, ES+ 162 (AA standard).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8]2([S:14][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:7][N:6]1[C:15](=[O:40])[CH:16]([NH:21][C:22](=[O:39])[CH:23]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:4].[Li+].[OH-]>C1COCC1.O>[CH:33]1([CH:23]([NH:24][C:25]([C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[C:22]([NH:21][CH:16]([C:17]([CH3:19])([CH3:20])[CH3:18])[C:15]([N:6]2[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][C:8]3([S:10][CH2:11][CH2:12][CH2:13][S:14]3)[CH2:7]2)=[O:40])=[O:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)C1CC2(CN1C(=O)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)SCCCS2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(=O)N1CC2(CC1C(=O)O)SCCCS2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ester 33 (50 mg) in THF-water (400 uL-100 uL) was treated with LiOH (7 mg) and the mixture stirred for 3 hours at room temperature. The mixture was evaporated, diluted with EtOAc, washed with 1.0N HCl and brine then dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2-[2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-6,10-dithia-2-aza-spiro[4.5]decane-3-carboxylic acid 34 as a white solid which was used in the next step without further purification. Mass Spec. MH+=578.0, MH−=576.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[N+:29]([O-])([O-:31])=[O:30].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[N+:29]([O-:31])=[O:30]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cccc2c1CCCC(=O)N2C
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
To a solution of 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-1) (538 mg, 2.62 mmol) in acetonitrile brought to 0° C. in an ice bath was added 1.8 mL TFAA (2.7 g, 13.1 mmol), followed by KNO3 (320 mg, 3.14 mmol). After approximately 5 minutes, the reaction was allowed to warm to room temperature. Conversion of starting material to product was monitored by LC/MS. Upon completion, the reaction was cooled to 0° C. in an ice bath and quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 was achieved. The aqueous mixture was extracted 3× with EtOAc and the organic layers were washed with brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-2) as an orange solid (530 mg, 82%). By NMR, the product showed a 4:1 mixture of nitration products, 80% of which was the desired product. By TLC, the products appeared inseparable, so the material was taken on for reduction crude. Data for Major Isomer: 1H-NMR (CDCl3) δ 7.83 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.37 (s, 3H), 2.87 (br m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.24 (m, 2H); LC/MS (ESI-pos) m/z 251.03 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH2:12][CH2:13][OH:14])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:14][CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][O:10][C:18]([CH3:20])([CH3:19])[N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1[C@@H](CCCO)COC1(C)C

Procedure:
A solution of tert-butyl[(2S)-1,5-dihydroxypentan-2-yl]carbamate (9.45 g), 2,2-dimethoxypropane (48 mL) and p-toluenesulfonic acid monohydrate (0.41 g) in chloroform (100 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the solvent was distilled off under reduced pressure. Ethyl acetate was added thereto, and the resulting mixture was washed with water and brine, followed by drying over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=10:1-0:100) to afford tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.05 g).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[C:48]([C:52]1[NH:56][N:55]=[C:54]([CH2:57][NH2:58])[CH:53]=1)([CH3:51])([CH3:50])[CH3:49]>>[C:48]([C:52]1[NH:56][N:55]=[C:54]([CH2:57][NH:58][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:42])[CH:53]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: CC(C)(C)c1cc(CN)n[nH]1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc(C(C)(C)C)[nH]n1
Yield: 41 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-tert-butyl-1H-pyrazol-3-yl)methanamine, the title compound was obtained as a colorless solid in 41% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 2H), 6.42 (t, J=5.4 Hz, 1H), 6.10 (s, 1H), 6.05 (s, 1H), 4.55 (d, J=5.4 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2 H), 2.49 (s, 3H), 1.32 (s, 9H); MS (ES+) m/z 470.2 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCOCC>C(Cl)Cl>[CH2:47]([O:46][CH2:45][N:28]1[C:29](=[O:30])[C:31]([CH3:32])=[CH:33][N:25]([C@@H:23]2[O:24][C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C@@H:21]([OH:34])[CH2:22]2)[C:26]1=[O:27])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: ClCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)n(COCc2ccccc2)c1=O
Reaction time: 14 h
Yield: 88 %

Procedure:
To a stirred solution of 2 (117.0 g, 243.8 mmol) and Hunig's base (diisopropylethylamine, 63.0 g, 487.5 mmol) in CH2Cl2 (400 mL) at 23° C. was added a solution of benzyl chloromethyl ether (40.7 g, 260.0 mmol) over a 15 min. period. The resultant mixture was maintained at 23° C. and stirred for 14 h. Ether (1 L) was added to the mixture and the ethereal solution was washed with 10% aqueous HCl (1×100 mL) and H2O (200 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/AcOEt 40:1 then 10:1) to yield 128.9 g (88%) of 3 as a white solid. Rf(CH2Cl2/AcOEt 10:1) 0.31. 1H-NMR (CDCl3): 1.10 (s, 9H, C-Me3), 1.65 (s, 3H, 5-Me), 2.16 (m, 1H, 2′-Hβ), 2.41 (m, 1H, 2′-Hβ), 2.53 (br s, 1H 3′-OH), 3.84 (d, 1H, J=8.8 Hz, 5′-CHH), 3.98 (d, 1H, J=8.8 Hz, 5′-CHH), 4.01 (s, 1H, 4′-H), 6.64 (br s, 1H, 3′-H), 4.70 (s, 2H, OCH2Ph), 5.50 (s, 2H, NCH2O), 6.41 (dd, 1H, J=8.0, 5.8 Hz, 1′-H), 7.20-7.50 (m, 13H, aromatic-H), 7.65-7.69 (m, 3H, 6-H and aromatic-H). 13C-NMR (CDCl3): 12.86 (−5-CH3), 19.45 (+, C-Me3), 27.09 (−, C-Me3), 41.16 (+, 2′-C), 64.25 (+, 5′-C), 70.70 (+, O—C—Ph), 71.97 (−, 4′-C), 72.29 (+, N—C—C), 85.51 (−, 3′-C), 87.20 (−, 1′-C), 110.47 (+, 5-C), 127.72, 128.08, 128.36 (−, aromatic-C), 130.25 (−, 6-C), 132.42, 133.00 (+, aromatic-C) 134.39, 135.37, 135.62 (−, aromatic-C), 137.95 (+, aromatic-C), 151.01 (+, 2-C), 163.68 (+, 4-C).
Reaction SMILES: [Li][CH:2](CC)C.C1CCCCC1.CN(CCN(C)C)C.[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])[C:25]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])([CH3:23])[CH3:22].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])[C:25]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([CH3:2])[C:26]=1[C:27]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[O:28])([CH3:23])[CH3:22]
Reactant: CCN(CC)C(=O)c1cccc(F)c1[Si](C)(C)C(C)(C)C
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCCCC1
Solvent: CI
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1c(C)ccc(F)c1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
1.3M s-BuLi in cyclohexane (1.8 mL, 2.3 mmol) was added dropwise with stirring to THF (20 mL) and TMEDA (0.32 g, 2.76 mmol), cooled to −78° C. under nitrogen. To this mixture was added dropwise the compound of Example 9 (0.6 g, 2 mmol), dissolved in a minimum amount of THF. After stirring for 10 min, MeI (0.98 g, 6.9 mmol) was injected. The mixture was stirred for 1 h; 15 mL of 25% citric acid was added and the mixture extracted with ether 3 times. The ether extracts were combined and washed twice with water, dried (MgSO4), and concentrated. The crude product was purified by RC, eluting with 3:7 ethyl acetate/hexanes. The title compound was obtained as a light yellow oil in a 31% yield.
Reaction SMILES: C[O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2nc3c(OC)cccc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc3c(O)cccc3s2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33.4 %

Procedure:
The methyl 4-(4-methoxybenzothiazol-2-yl)benzoate (11.3 g) obtained in Example 3 (3) was dissolved in 200 ml of dichloromethane, and a solution of 9.5 g of boron tribromide in 80 ml of dichloromethane was added dropwise to the solution. The mixture was stirred at room temperature for 2.5 hours, then poured into 300 ml of ice water, extracted with chloroform three times, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluted with chloroform), and the solvent was evaporated under reduced pressure. The residue was washed with a small amount of chloroform, and recrystallized from ethyl acetate to give 3.6 g of methyl 4-(4-hydroxybenzothiazol-2-yl)benzoate. mp 215°-219.0° C.