Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C.O>C1COCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[B:16]([OH:19])[OH:17]
Reactant: COc1cccc(OC)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1,3-Dimethoxybenzene (4 g) was dissolved in freshly distilled THF (10 mL). This solution was cooled to −78° C. and n-BuLi (24 mL, 1.6 M solution in hexanes) was added dropwise to the cold solution. The mixture was stirred at −78° C. for 1 h, then warmed to room temperature and stirred for 1 h. The resulting mixture was cooled again to −78° C. and (MeO)3B (6.7 mL) was added. The mixture was allowed to warm to room temperature and stirred overnight. Water (10 mL) was added, and the mixture was stirred for 0.5 h, acidified to pH 4 with acetic acid and extracted with EtOAc. The extract was dried (MgSO4) and evaporated to give 2,6-dimethoxybenzeneboronic acid, which was used without further purification.
Reaction SMILES: [C:1]1([Te:7][CH2:8][CH2:9][CH:10]2[NH:14]C(=O)N[C:11]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+]>>[NH2:14][CH:10]([CH2:9][CH2:8][Te:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]([OH:16])=[O:17]
Reactant: [OH-]
Reactant: O=C1NC(=O)C(CC[Te]c2ccccc2)N1
Agent: *C(F)(F)C(*)(F)F
Agent: [Na+]
Product: NC(CC[Te]c1ccccc1)C(=O)O

Procedure:
Reactor produced 123mTe (65.5 mg, 26.3 mCi) was combined with 188.5 mg of carrier Te powder. This material was stirred in tetrahydrofuran (5 ml) to which was added phenyl magnesium chloride (4 mmole) in the same solvent (2 ml). The mixture was stirred rapidly and refluxed but the reaction did not commence as indicated by the absence of the orange-colored product. After the addition of a small crystal of benzoyl peroxide, reaction began immediately. The orange-colored solution was refluxed 1 minute and the reaction flask flushed with O2 and cooled in an ice bath. After warming to room temperature, the solution was stirred 30 minutes, filtered, and the orange-colored filtrate diluted with benzene to a final volume of 25 ml. Aliquots of this solution were counted. The 123mTe-labeled diphenyl ditelluride contained 9.22 mCi of radioactivity. The benzene solution was diluted to 50 ml with methanol and the 123mTe-labeled diphenyl ditelluride reduced with NaBH4 in the manner described in Example IV. To this mixture was added 208 mg, 1 mmole of 5-(beta-bromo ethyl)hydantoin prepared as in Example XI. The mixture was poured into water and extracted with benzene to remove diphenyl ditelluride and other non-polar material. The aqueous layer was acidified to pH 1-2 with 6 N HCl and extracted thoroughly with ether. The combined organic extracts were washed well with water, dried over anhydrous sodium sulfate and the solvent removed in vacuo to give 2.2 mCi of 123mTe-labeled 5-(beta[phenyl telluro]ethyl)hydantoin. This hydantoin is dissolved in 1 N NaOH (2 ml) and heated in a polytetrafluoroethylene-lined bomb by heating at about 165°-167° C. for one hour. Upon cooling, the solution is extracted with benzene and 1 N HCl is added to adjust the pH to 7-8, to provide 123mTe-labeled DL-alpha-amino-gamma-(phenyl telluro)butyric acid.
Reaction SMILES: C([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:11][CH:10]([C:26]([O:28][CH3:29])=[O:27])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[O:11]1[C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:13][NH:8][CH2:9][CH:10]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 65 °C
Yield: 74 %

Procedure:
A mixture of 9-tert-butyl 2-methyl 4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (670 mg, 1.66 mmol), ammonium formate (623 mg, 9.936 mmol) and palladium, 10 wt. % on activated carbon (353 mg, 3.31 mmol) in EtOH (5 mL) was heated at 65° C. for 50 minutes. The reaction mixture was cooled to room temperature, filtered and partitioned between EtOAc/1M aq. NaOH. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 9-tert-butyl 2-methyl 1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate as a foam (386 mg, 74%). ESI-MS m/z calc. 314.2. found 315.5 (M+1)+; Retention time: 0.99 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH:22]=O)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:24]=[C:25]1[N:29]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:28][CH2:27][O:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:33]2[CH2:32][CH2:31][CH:30]([N:29]3[CH2:28][CH2:27][O:26][C:25]3=[O:24])[CH2:35][CH2:34]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C1OCCN1C1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(CCN1CCC(N2CCOC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl
Reaction time: 0.08 h
Yield: 138.5 %

Procedure:
N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.823 g) in methanol (4 mL) was added to a solution of 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine (0.600 g) and acetic acid (0.20 mL) in methanol (8 mL). After 5 minutes, sodium cyanoborohydride (0.220 g) in methanol (4 mL) was added in a single portion. After being stirred for 3 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as eluent. The resulting material was dissolved in dichloromethane, precipitated as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound as a white solid (0.88 g); MS: m/z=504(M+1); Analysis for C26H31Cl2N3O3.1.20 HCl: Calculated: C, 56.96; H, 5.92; N, 7.66; Found: C, 57.02; H, 6.05; N, 7.62.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(NC2CCNCC2)cc1
Yield: 67.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(4-fluorophenyl)amino]-1-piperidinecarboxylate (D1) (1.6 g) in 2M HCl (5 ml) and 1,4-dioxane (20 ml) was heated at 60° C. for 24 h. On cooling, the solution was diluted with water, basified with 2M NaOH solution and extracted with EtOAc (×3). The combined organics were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (0.71 g). δH (CDCl3, 250 MHz) 6.88 (2H, t), 6.54 (2H, dd), 3.30 (1H, m), 3.20 (2H, m), 2.70 (2H, m), 2.05 (2H, m), 1.69 (2H, br), 1.29 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O)C.C(=O)([O-])O.[Na+]>O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 82 °C
Yield: 91.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), ethanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 82° C., and sodium hydrogencarbonate was added thereto so as to adjust the pH of the mixture at 9.0-9.3. Seven hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 67.6 g of p-cyanobenzoic acid (yield 92%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[OH:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1>C(O)(=O)C.C(Cl)Cl>[C:21]([C:17]1[CH:18]=[CH:19][C:20]([C:9]2([OH:13])[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[C:15]([OH:14])[CH:16]=1)(=[O:23])[CH3:22]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CC(=O)c1cccc(O)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 110 °C
Yield: 79.4 %

Procedure:
To a solution of ninhydrin (1.00 g, 5.61 mmol) in acetic acid (20 ml) was added 1-(3-hydroxy-phenyl)-ethanone (0.76 g, 5.61 mmol), followed by heating for 3 hrs at 110° C. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (White, 1.32 g, 79%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1nccc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nccc2ccc(-c3ccc4[nH]ccc4c3)cc12
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A mixture of 7-bromo-1-chloroisoquinoline (0.50 g, 2.1 mmol), 5-indoleboronic acid (0.40 g, 2.5 mmol), tetrakis(triphenylphosphene)palladium (0.035 g, 0.08 mmol), potassium carbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) was stirred while purging the headspace with argon for 30 min. The mixture was then brought to reflux for 16 h before being allowed to cool to RT. The mixture was filtered through a bed of silica gel, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, until refractive changes were no longer seen at the organic-aqueous interface), and ammonium chloride (20 mL, sat.). The organic layer was then adsorbed onto silica gel and flash-chromatographed (ethyl acetate/hexanes) to afford 0.14 g (25%) of a yellow solid. MS (ESI): calculated for C17H11ClN2, 278.1. found 301.0 [M+Na]+. 1H NMR (300 MHz, DMSO-d6) δ 6.56-6.58 (m, 1H), 7.44 (t, J=2.77 Hz, 1H), 7.57-7.59 (m, 2H), 7.93 (m, 1H), 8.04 (s, 1H), 8.13-8.20 (m, 1H), 8.27-8.31 (m, 2H), 8.43 (m, 1H), 11.25 (brs, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:12])[N:8]([CH3:11])[CH2:9][CH:10]=1.CO.[NH2:16][O:17][K].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[OH:17][NH:16][C:3](=[O:2])[CH2:4][CH2:5][C:6]1[C:7](=[O:12])[N:8]([CH3:11])[CH2:9][CH:10]=1
Reactant: COC(=O)CCC1=CCN(C)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN1CC=C(CCC(=O)NO)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
18 mg of 3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester (2g) prepared by the above Step 2 was dissolved in methanol solution (0.1 mmol) and then 1.7 M methanolic suspension solution containing NH2OK (0.09 ml, 0.15 mmol) was added thereto at 0° C. and the resulting mixture was stirred for 1 hr at room temperature. The resulting mixture was neutralized with 0.03 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and methanol (5:2) as an eluant to give 11 mg of N-hydroxy-3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionamide (2h) (yield: 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.C(N(C(C)C)CC)(C)C.[CH3:50][C:51]([CH3:65])([CH3:64])[CH2:52][NH:53][CH2:54][C:55]([N:58]1[CH:62]=[C:61]([NH2:63])[N:60]=[CH:59]1)([CH3:57])[CH3:56]>CN(C=O)C.C(Cl)Cl>[CH3:50][C:51]([CH3:65])([CH3:64])[CH2:52][NH:53][CH2:54][C:55]([N:58]1[CH:62]=[C:61]([NH:63][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:60]=[CH:59]1)([CH3:56])[CH3:57]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC(C)(C)CNCC(C)(C)n1cnc(N)c1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CNCC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (1 equiv) derived from diasteromer #1 above, TPTU (1 equiv), diisopropylethylamine (2 equiv) in DMF followed by 1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine (2 equiv) in methylene chloride. The reaction is stirred overnight at rt, quenched with aq. sodium bicarbonate, and extracted with methylene chloride. The solvent is dried, concentrated, and purified by silica gel chromatography to afford diastereomer #1 of the title compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C[O:21][C:22](=[O:51])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:40]=3Br)[CH:33]=2)=[CH:27][C:26]=1[CH3:50]>>[CH3:50][C:26]1[CH:27]=[C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:41][C:40]=3[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[CH:33]=2)[CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][C:22]([OH:51])=[O:21]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-tributylstannyl pyridine and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 29 mg (14%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H22NO4F3 493, found 494 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4C=CC=[CH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1.C[N:29]1[C:33](CO)=[N:32]C=N1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:23]([CH3:24])[N:29]=[CH:33][N:32]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Reactant: Cn1ncnc1CO
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncnn4C)nn23)on1

Procedure:
The title-compound was prepared from the product of Example 120 part a and 2-methyl-1,2,4-triazole-3-methanol (prepared using the conditions of Itoh and Okongi, EP-A-42120) following the procedure given for Example 98, 1H NMR (400 MHz, CDCl3) δ 2.43 (3H, s, CH3), 4.16 (3H, s, CH3), 5.82 (2H, s, CH2), 7.07 (1H, s, Ar—H), 7.84 (1H, m, Ar—H), 7.95-8.04 (2H, m, 2 of Ar—H), 8.21 (1H, d, J=8.0 Hz, Ar—H), 8.62 (1H, d, J=8.0 Hz, Ar—H); MS(ES30) m/e 363 [MH]+; Anal. Found. C, 56.12; H, 3.90; N, 30.74. C17H14N8O2 requires C, 56.35; H, 3.89; N, 30.92%.
Reaction SMILES: [CH2:1](C1(CC)C2C=C(C=O)C=CC=2C2C1=CC(Br)=CC=2)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O>O>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:1]1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2scnc2c1
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (49.35 g., 0.15 mol.), 2-aminothiophenol (20 ml. 0.187 mol., 1,25 eq.), and DMSO (110 ml) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 ml.) filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g., were then reslurried in hot ethanol, (600 ml), cooled and filtered to get the product benzothiazole, 45.69 g., m.p. 133.6-135° C. An additional 6.6 g., m.p. 134.6-135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery was 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Anal. Calculated for C24H20BrNS: C, 66.37; H, 4.64; Br, 18.40; N, 3.23; S, 7.37%. Found: C, 66.46; H, 4.52; Br, 18.54; N, 3.14; S, 7.19%.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[C:16]([C:24](=[N:26][OH:27])[NH2:25])[C:17](=[O:23])[NH:18]3)[CH:10]=[CH:11][CH:12]=1>CN(C=O)C>[CH3:1][C:2]1[O:27][N:26]=[C:24]([C:16]2[C:17](=[O:23])[NH:18][C:19]3[C:14]([CH:15]=2)=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=2)[N:22]=[CH:21][CH:20]=3)[N:25]=1
Reactant: CC(=O)O
Reactant: COc1cccc(-c2nccc3[nH]c(=O)c(C(N)=NO)cc23)c1
Solvent: CN(C)C=O
Product: COc1cccc(-c2nccc3[nH]c(=O)c(-c4noc(C)n4)cc23)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a solution of acetic acid (0.90 g) in DMF (100 ml) was added N,N′-carbonyldiimidazole (2.43 g) and the mixture was stirred at 70° C. for 3 hours. To the solution was added 1,2-dihydro-5-(3-methoxyphenyl)-2-oxo-1,6-naphthyridin-3-amidoxime (3.10 g) prepared in the same manner as described in Example 1(1), and the mixture was stirred at 70° C. for 2 hours and further at 130° C. for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue, and the precipitated crystals were separated by filtration and washed with water, isopropanol and diisopropyl ether in this order and then dried. The resulting crystals were subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1). The resulting crystals were recrystallized from chloroform-ethanol to give the title compound (2.22 g) as colorless crystals. M.p. 286-288° C. Hydrochloride of the title compound, M.p. 281-282° C. (recrystallized from ethanol).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:12][C:3]([NH2:2])([CH3:13])[CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[CH:7][CH:6]=1
Reactant: CC(C)(N)Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(N)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
A solution of 4-(2-amino-2-methylpropyl)aniline hydrochloride salt (1.0 g, 4.98 mmol) in anhydrous DMF (30 mL) was treated with benzenesulfonyl chloride (880 mg, 4.98 mmol). The solution was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was washed twice with hexane. The insoluble material was dissolved in water and extracted twice with ethyl ether to remove any remaining neutral impurities. The aqueous layer was separated and basified with excess 1N sodium hydroxide. Upon standing, a crystalline solid soon precipitated. The solid was collected, and dried under vacuum at 60° C. to provide 570 mg (38%) of the desired product as a white crystalline solid. Mp 180–181° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH3:9])[C@@H:3]([OH:7])[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCOCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([NH:1][C@@H:2]([CH2:8][CH3:9])[C@@H:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: CC[C@H](N)[C@@H](O)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
0.759 g (5.70 mmol) of (2R, 3S)-3-amino-2-hydroxypentanoic acid were admixed with a solution of 1.199 g (14.28 mmol) of sodium hydrogen carbonate in 20 ml of water, and with 20 ml of dioxane. The resulting mixture was cooled with ice. To this solution was dropwise added a solution of 1.623 g (6.27 mmol) of 9-fluorenylmethyl chloroformate in 10 ml of dioxane under cooling with ice for 30 minutes. After the completion of the addition, the reaction mixture was stirred at room temperature for 2 hours, diluted with 100 ml of water, and successively washed with 150 ml of ether and 75 ml of ether. To the aqueous layer were added 2.8 ml of 6N hydrochloric acid to adjust to pH 1.5. Then the aqueous layer was extracted three times with 50 ml of ethyl acetate. The oil layer was washed with 50 ml of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and distilled to remove the solvent therefrom, so that 1.622 g of crude (2R, 3S)-3-(9-fluorenylmethoxycarbonyl)amino-2-hydroxypentanoic acid were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[O:6][CH2:7][C:8](=[O:13])[CH2:9][N+:10]([O-])=O.[ClH:19].[H][H]>[Pd].CO>[ClH:19].[NH2:10][CH2:9][C:8](=[O:13])[CH2:7][O:6][C:5]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(OCC(=O)C[N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(OCC(=O)CN)cc1OC

Procedure:
To a MeOH (7 ml) solution of the compound (0.660 g) obtained in Example 19-(2), 10% Pd—C (0.330 g) and an aqueous solution of 1N HCl (14 ml) were added and the mixture was stirred at room temperature for 5 hours in a hydrogen gas atmosphere. The insoluble matter was filtered off and the filtrate was concentrated to give the titled compound (0.715 g, brown amorphous.)
Reaction SMILES: [N:1]1([C:7](=O)[CH2:8][C@@H:9]([NH2:18])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.B.CO>C1COCC1>[N:1]1([CH2:7][CH2:8][C@@H:9]([NH2:18])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N[C@@H](CSc1ccccc1)CC(=O)N1CCOCC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: N[C@H](CCN1CCOCC1)CSc1ccccc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
A solution of EXAMPLE 21E (6.00 g, 21.4 mmol) in THF (80 mL) was heated to 55° C. and treated dropwise with a solution of 1M borane in THF (85 mL, 85.0 mmol) over a 1 hour period. The resulting reaction mixture was stirred at 55° C. for 18 hours, cooled to 0° C., treated dropwise with methanol (10 mL), treated with 150 mL additional methanol, and concentrated. The crude residue was dissolved in methanol (70 mL), treated with methanolic HCl (100 mL), and heated to reflux for 24 hours. The mixture was allowed to cool to room temperature, concentrated, diluted with 2M NaOH (200 mL), and extracted with ethyl acetate (3×250 mL). The combined extracts were washed with 1M NaOH and brine, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography eluting with 5% triethylamine/10% methanol/0% acetonitrile/ethyl acetate to provide the desired product (3.45 g, 73%).