Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:20])[NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@H:11]([OH:13])[CH2:12][NH:8]2)=[O:20])[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)NC1CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCC1)[C@@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 463 mg (2S,4S)-2-Cyclobutylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 8 ml dichloromethane were added 1.2 ml TFA. After 5 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 463 mg.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Li]CCCC.CCCCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[CH3:10][C:9]1([CH3:11])[C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:14]=[CH:13][C:5]=2[NH:6][C:7](=[O:12])[O:8]1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2 g, 7.8 mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane (10 M, 2.4 mL, 24 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, a slurry was obtained and treated with triisopropyl borate (6.5 mL, 28 mmol). The reaction solution was slowly warmed to ambient temperature and quenched with IN aqueous hydrochloric acid solution (60 mL). Ethyl acetate (100 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×60 mL). The combined organic layer was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (ethyl acetate:hexane/2:1) to afford (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid as a white solid (1.4 g, 81%): mp 249–250° C.; 1H-NMR (DMSO-d6) δ 10.21 (s, 1H, D2O exchangeable), 7.90–7.95 (br s, 2H, D2O exchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8 Hz), 1.61 (s, 6H); MS (ESI) m/z 222([M+H]+, 87%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([C:37](=[O:39])[CH3:38])[CH2:8][C:7]=2[CH:29]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 18 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.071 g, 0.18 mmol) and triethylamine (0.048 ml, 0.35 mmol) in dichloromethane was added acetyl chloride (0.013 ml, 0.18 mmol) at room temperature. Stirring for 18 h was followed by partitioning between 1 M aqueous sodium hydroxide solution (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.039 g, 54%) as white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[CH:6]=[CH:5]1>N1C=CC=CC=1>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[N:2][OH:3])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc2cc[nH]c2c1
Reaction time: 1 h
Yield: 11.6 %

Procedure:
Hydroxylamine hydrochloride (0.574 g) was added portionwise to a solution of 1H-indole-6-carbaldehyde (1 g) in pyridine (5 ml) are RT. The resulting solution was heated to reflux and stirred at that temperature for 1 hour. The solvent was evaporated. The residue was diluted with ethyl acetate (50 mL) and the resulting solution was washed with aqueous hydrochloric acid (0.5 M, 40 mL). The organic fraction was separated and dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford a brown oily solid. The residue was triturated with ether/hexane to afford 1H-indole-6-carbaldehyde oxime (D11) as a pink solid (128 mg). Solid was precipated out from the filtrate. The solid was collected to give another batch of 1H-indole-6-carbaldehyde oxime (D11) (818 mg). δH (DMSO-d6, 400 MHz): 6.44 (1H, m), 7.24 (1H, dd), 7.32 (1H, m), 7.55 (1H, dd), 7.57 (1H, s), 8.19 (1H, s), 10.88 (1H, s), 11.25 (1H, br s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[K+].[C:8](=[S:10])=[S:9].[CH3:11]I>C(O)C.O>[C:3]([CH2:2][NH:1][C:8](=[S:10])[S:9][CH3:11])([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: S=C=S
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=S)NCC(=O)O
Reaction time: 3 h

Procedure:
Glycine (60 g., 0.8 mol.) was added to a cooled (5°-10°) solution of 89.6 g. (1.6 mol.) of potassium hydroxide in 200 ml. of water. After complete dissolution 60.8 g. (0.8 mol.) of carbon disulfide was added and the reaction mixture was stirred at 25° for three hours. A solution of 113.6 g. (0.8 mol.) of methyl iodide in 200 ml. of ethanol was added while maintaining the temperature at 25°-30°. The reaction mixture was stirred for two hours at 25°, then concentrated in vacuo and the remaining aqueous phase was basicified to pH 8.0 with aqueous sodium carbonate and extracted with ether. The aqueous phase was acidified to pH 2.5 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was concentrated in vacuo and the residue recrystallized from toluene to give methyl carboxymethyldithiocarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].S(=O)(=O)(O)O.[NH4+].[OH-].C(Cl)Cl.[CH2:33](O)[CH3:34]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH2:33][CH3:34])=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:20])[F:21]
Reactant: O=C(O)Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)acetic acid (3 g, 5.61 mmol) in ethanol (30 mL) was added sulfuric acid (8 mL, 150 mmol) in ethanol (30 mL). The reaction mixture was stirred at 80° C. for 2 hr. Then 30 mL of 25% aqueous NH4OH solution and 50 mL CH2Cl2 were added to the reaction mixture. The organic layer was separated and dried over Na2SO4, and concentrated under reduced pressure to provide ethyl 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)acetate (2 g, 79%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.C=[O:18].ClC[CH2:21][Cl:22]>>[C:2](=[O:18])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:3][CH2:21][Cl:22]
Reactant: ClCCCl
Reactant: C=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(OCCl)Oc1ccccc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Phenyl chloroformate (9.0 g, 57.5 mmol) was dissolved in 1,2-dichloroethane (50 ml) and pyridine (0.22 g, 2.8 mmol) was added dropwise to the stirred solution. In another reactor, paraformaldehyde (7.0 g, 233.1 mmol) was heated with a heat gun to generate the gaseous monomer. The formaldehyde gas was bubbled into the first reactor through a tube with the outlet below the surface of the liquid. Stirred at 65° C. for 3 hours. Washed three times with water, dried (MgSO4) and concentrated. Distillation (Bp. 64°-67° C. 5×10-4 mbar) yielded 2.7 g product. The product was further purified by flash chromatography (Silikagel 60, petroleum ether/ethyl acetate 95: 5). Yield: 2.1 g. 1H-NMR (CDCl3): delta=5.78 (CH2); 7.18-7.41 ppm (phenyl).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=2)[CH2:20]1)([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.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCOCC3)co2)C1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (1.00 g, 2.29 mmol) (obtained as described in Reference Example 70(8)) in toluene (50 ml) was added a solution of 0.67 M morpholine-trimethylaluminium in toluene (6.87 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred in an oil bath (80° C.) for 4 hours. After checking the completion of the reaction, to the reaction mixture were added 10% aqueous acetic acid (50 ml) and ethyl acetate (100 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (400 mg, yield 36%) as a pale brown solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:31])[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NN2CCNCC2=O)CC1
Yield: 87.7 %

Procedure:
A solution of 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone (3.19 g) and 10% Pd/C (0.64 g) in methanol (50 ml) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off, and the reaction mixture was concentrated to obtain 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone (1.93 g) as a colorless oil.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:31]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:13][C:12]=1[F:31]
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)c(F)c2)CC1
Product: Fc1cc(C2CCN(CCCc3onc4c3CCCCC4)CC2)ccc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4N=CN[CH:34]=4)=[O:29])=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C(C1C[CH2:47][C:46](=[O:49])[CH2:45]1)(O)=O.[NH4+].[OH-].[C:52]([C:56]([OH:58])=[O:57])([F:55])([F:54])[F:53]>C(Cl)(Cl)Cl.CO>[F:53][C:52]([F:55])([F:54])[C:56]([OH:58])=[O:57].[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([CH:30]4[CH2:34][CH2:47][C:46](=[O:49])[CH2:45]4)=[O:29])=[CH:25][CH:26]=3)=[CH:13][CH:12]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1c[nH]cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1CCC(C(=O)Nc2ccc(-c3sc4ccccc4c3Cc3ccc(OCCN4CCCC4)cc3)cc2)C1
Yield: 98 %

Procedure:
By essentially following the conditions described in Example 1, Part F, the free base of the title compound was prepared as a foam from 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Example 16; Part D) and 3-carboxycyclopentanone in 98% yield following radial chromatography (SiO2; 1% then 2% then 5% MeOH in CHCl3 sat'd with NH4OH). The solid was taken up in 5 mL of MeOH and was treated with 1.2 eq of CF3CO2H. The solution was concentrated in vacuo to give the title compound.
Reaction SMILES: [OH-].[K+].Br[CH2:4][CH:5]1[CH2:7][C:6]1([F:9])[F:8].[SH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>CO>[F:8][C:6]1([F:9])[CH2:7][CH:5]1[CH2:4][S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCS
Reactant: FC1(F)CC1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSCC1CC1(F)F
Temperature: 65 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Powdered potassium hydroxide (423 mg, 7.54 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (657 mg, 3.84 mmol) were sequentially added to a stirred solution of 3-mercaptopropanoic acid (400 mg, 3.77 mmol) in methanol (2 mL) at room temperature. The resulting white suspension was stirred at 65° C. for 3 hours and quenched with aqueous hydrochloric acid (1 N) and diluted with ethyl acetate. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title molecule as a colorless oil (652 mg, 84%): IR (thin film) 3025, 2927, 2665, 2569, 1696 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.85 (t, J=7.0 Hz, 2H), 2.82-2.56 (m, 4H), 1.88-1.72 (m, 1H), 1.53 (dddd, J=12.3, 11.2, 7.8, 4.5 Hz, 1H), 1.09 (dtd, J=13.1, 7.6, 3.7 Hz, 1H); ESIMS m/z 195 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH:15]([OH:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:14]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20])[O:25][CH2:10][C:9]1=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CN(Cc1ccccc1)C(=O)CCl)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of N-benzyl-N-[(2RS,3RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,4-dichlorophenyl)-3-hydroxybutyl]-2-chloroacetamide (44.7 g) in THF (450 ml) was added sodium methoxide (5.46 g) at 0° C. The mixture was stirred at room temperature for 2 hr, water was added, and methanol was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (10%-50%)) to give the title compound (40.6 g) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:71])[CH:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([N:68]5[CH2:69][CH2:70][C@H:66]([N:65]([CH3:71])[CH3:64])[CH2:67]5)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CN(C)C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a stirred solution of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid (70 mg; 0.16 mmol) in DMF (5 ml) was added HATU (103 mg; 0.27 mmol), DIPEA (50 μl; 0.27 mmol) and (S)-(+3-(dimethylamino)pyrrolidine (50 μl; 0.38 mmol). The reaction mixture was stirred at r.t. for 4 h upon which time it was diluted with EtOAc (20 ml) and washed successively with satd. NaHCO3 (20 ml) and brine (2×20 ml). The organic layer was dried (Na2SO4), concentrated and purified by prep. LCMS to give 420 as an off-white solid (50 mg; 58%). δH (400 MHz, CDCl3) 1.77-1.92 (br m, 1H), 2.06-2.17 (m, 1H), 2.24 (br s, 3H), 2.35 (br s, 3H), 2.60-2.83 (m, 1H), 3.16 (br s, 2H), 3.29-3.98 (m, 4H), 4.33 (br s, 2H), 6.94-7.20 (m, 4H), 7.32-7.39 (m, 1H), 7.50-7.60 (m, 1H), 7.77 (s, 1H), 8.11 (s, [M+H]+: 522
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-])=O)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCO.CCOC(C)=O.[Pt]=O>[NH2:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:38])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Yield: 60.4 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{2-[(3-nitrobenzyl)oxy]ethoxy}hexyl)-1,3-oxazolidin-2-one (0.10 g) in EtOH (3 ml) and EtOAc (3 ml) was hydrogenated for 19.5 h over platinum oxide (0.020 g). The mixture was filtered through celite, and the solvent evaporated in vacuo to give a residue which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (8:2) followed by solvent evaporation in vacuo gave the title compound (0.057 g). LCMS RT=3.43 min, ES+ve 499 (MH)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7]([C:9]1[C:18]([Cl:19])=[CH:17][C:16]2[C:11](=[C:12]([CH:20]=O)[CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8])[CH3:5].C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH2:4]([O:6][C:7]([C:9]1[C:18]([Cl:19])=[CH:17][C:16]2[C:11](=[C:12]([CH2:20][N:2]([CH3:3])[CH3:1])[CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cc2c(C=O)cccc2cc1Cl
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(CN(C)C)cccc2cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
A solution of dimethylamine (5.6 M in EtOH, 0.36 ml, 2.0 mmol, 1.5 equiv) was added to a solution of 3-chloro-8-formyl-naphthalene-2-carboxylic acid ethyl ester (350 mg, 1.33 mmol) in THF (6.5 ml). After stirring at room temperature for 16 hours, a solution of sodium cyanoborohydride (101 mg, 1.6 mmol, 1.2 equiv) in MeOH (3.0 ml) and acetic acid (0.38 ml, 6.7 mmol, 5.0 equiv) were added, and the reaction mixture was stirred at room temperature for 3 hours. After dilution with water (75 ml), the mixture was extracted with CH2Cl2 (total of 400 ml). The combined organic layers were washed with concentrated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 1:2) to afford the title compound (133 mg, 34%) as a mixture of regioisomers, which could be separated for analytical purposes. 3-Chloro-8-dimethylaminomethyl-naphthalene-2-carboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3): δ=8.72 (s, 1H), 8.08 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.61-7.55 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 3.97 (br s, 2H), 2.33 (s, 6H), 1.40 (t, J=7.1 Hz, 3H). MS (ES+): 292 (M+H)+. 3-Chloro-5-dimethylaminomethyl-naphthalene-2-carboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3): δ=8.39 (s, 1H), 8.35 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7,57-7.50 (m, 2H), 4.41 (q, J=7.1 Hz, 2H), 3.81 (s, 2H), 2.24 (s, 6H), 1.40 (t, J=7.1 Hz, 3H). MS (ES+): 292 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1)([OH:3])=[O:2].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1)([O:3][CH2:15][CH3:16])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)CCCCCC1=CCCC1=O

Procedure:
A solution of 1.309 g. (0.00668 mole) of 2-(5-carboxypentyl)-2-cyclopentenone (Example 52) and 90 mg. of p-toluenesulfonic acid in 150 ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO4), and evaporated to give 1.371 g. of a light yellow oil.