Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([NH:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])=[O:14]>CN(C)C=O.C(OCC)(=O)C>[F:26][C:12]([F:11])([F:25])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([N:22]([CH3:23])[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:19]=[CH:18][C:17]=1[F:24])=[O:14]
Reactant: CNc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A solution of 2-chloro-5-nitropyridine (201 mg, 1.27 mmol) and 2,2,2-trifluoro-N-[2-fluoro-5-(methylamino)phenyl]acetamide (300 mg, 1.27 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 140° C. for 22 hr. The reaction mixture was cooled to room temperature, suspended in ethyl acetate (5 mL), washed with saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 ml), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to give the title compound (221 mg, 49%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].O1CCOC1CCCCCCCCOC1C=C(C=CC=1)C=O>>[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[OH:25])[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: O=Cc1cccc(OCc2cccc(CC3OCCO3)c2)c1
Agent: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Product: OC(c1cccc(F)c1)c1cccc(OCc2cccc(CC3OCCO3)c2)c1

Procedure:
The title compound was prepared as described in Example 10 Step 2 with 3-fluorophenylmagnesium bromide and 3-((3-((1,3-dioxolan-2-yl)methyl)benzyl)oxy)-benzaldehyde replacing 2-thienylmagnesium bromide and 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde, respectively.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15][C:16](OCC1C=CC=CC=1)=[O:17])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:46][CH:47]([CH3:61])[CH2:48][CH2:49][C:50]([NH:52][C@H:53](C(O)=O)[CH2:54][C:55](=[O:57])[NH2:56])=[O:51]>[Pd]>[C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15][C:16](=[O:17])[C@H:53]([CH2:54][C:55](=[O:57])[NH2:56])[NH:52][C:50](=[O:51])[CH2:49][CH2:48][CH:47]([CH3:46])[CH3:61])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)CCC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)CCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)CN1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 27.8 %

Procedure:
0.71 g (1.52 mmol) of N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-proline tert.butyl ester was hydrogenated in the presence of 0.58 g (3.05 mmol) of toluene-4-sulphonic acid over 5% palladium-on-carbon and the product was coupled with 0.35 g (1.52 mmol) of N-(4-methylvaleryl)-L-asparagine in an analogous manner to that described in Example 1. The crude product was purified by chromatography on silica gel using isopropanol in ethyl acetate (5%-8% gradient) for the elution. There was obtained 0.23 g of N-[[N-[N-(4-methylvaleryl)-L-asparaginyl]-L-phenylalanyl]methyl]-L-proline tert.butyl ester as a solid; MS: m/e 545 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([OH:16])=[CH:7][C:8]([CH:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:16][C:6]1[C:5]2[C:17]3[C:18]([C:2]([CH3:1])([CH3:23])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH3:11])[CH:7]=1)=[CH:19][CH:20]=[N:21][CH:22]=3)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CC1CC1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(C)CC2CC2)cc2c1-c1cnccc1C(C)(C)O2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(3-cyclopropyl-2-propyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(3-cyclopropyl-2-propyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: N1C(C)=CC=CC=1C.[SH:9][CH:10]([CH3:14])[CH:11]([OH:13])[CH3:12].FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[C:24]([Si:21]([CH3:23])([CH3:22])[O:13][CH:11]([CH3:12])[CH:10]([SH:9])[CH3:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(O)C(C)S
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(S)C(C)O[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2,6-lutidine (163 μl) was added to a solution of 3-mercapto-2-butanol (68 mg) in DCM (5 ml) and the mixture was cooled down to −20° C. Tert-butyldimethylsilyl trifluoromethanesulfonate (163 μl) was slowly added and it was stirred 1 h at −20° C. Another 163 μl of the silyl reagent was added and the mixture was allowed to warm to RT and stirred one might at RT. The mixture was evaporated off and used without purification and characterization.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:20]#[C:21][CH3:22])[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:42][N+:43]1[CH:48]=[CH:47][C:46]([CH:49]([O:53][CH2:54][CH3:55])[O:50][CH2:51][CH3:52])=[CH:45][CH:44]=1>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:22])=[N:42][N:43]3[CH:48]=[CH:47][C:46]([CH:49]([O:50][CH2:51][CH3:52])[O:53][CH2:54][CH3:55])=[CH:45][C:44]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1
Reactant: CC#Cc1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Reactant: CCOC(OCC)c1cc[n+](N)cc1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccn2nc(C)c(-c3nc(Br)c(-c4ncn(COCC[Si](C)(C)C)n4)s3)c2c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.5 %

Procedure:
To a mixture of 3-(4-bromo-2-prop-1-yn-1-yl-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole [Prepared as described in Example 14 (4.37 g, 10.9 mmol)] and potassium carbonate (3.00 g, 21.7 mmol) in dry N,N-dimethylformamide (20.0 mL) was added a solution of 1-amino-4-(diethoxymethyl)pyridinium 2,4,6-trimethylbenzenesulfonate (6.37 g, 15.6 mmol) in dry N,N-dimethylformamide (20.0 mL) over 10 min. The resulting dark brown solution was stirred at rt for 40 hours. The mixture was added to ˜250 mL of ice water with stirring, then was extracted with EtOAc (100 mL×5) until the aqueous layer turned into a clear solution. The combined EtOAc extracts were washed with water, brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography on silica gel, using EtOAc/hexane (0/100 to 50/50) as an eluant to give a solid product (4.56 g, 70.2%). LCMS: (FA) ES+ 593, 595. 1H NMR (400 MHz, CDCl3) δ: 8.46 (d, J=2.01 Hz, 1H), 8.40-8.42 (d, J=7.28 Hz, 1H), 8.32 (s, 2H), 7.05-7.08 (dd, J=2.01, 7.03 Hz, 1H), 5.57 (s, 2113.68-3.77 (m, 4H), 3.58-3.63 (m, 2H), 2.75 (s, 3H), 1.28-1.32 (m, 6H), 0.95-1.00 (m, 2H), 0.02 (s, 9H)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:25][OH:26]>>[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:25][O:26][C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cccc(F)c1F
Product: CC(C)N1c2cc(OCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH3:24][N:25]([CH3:30])[S:26]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:23])[CH2:15][CH2:14]1)(=[O:28])=[O:27]
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and dimethylsulfamoyl chloride
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:19][S:20](Cl)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:26]1[C:31]2[S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:30]=2[CH2:29][CH2:28][NH:27]1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:19][S:20]([N:27]1[CH2:28][CH2:29][C:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32][C:31]=2[CH2:26]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: c1ccc2c3c(sc2c1)CNCC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CS(=O)(=O)N1CCc2c(sc3ccccc23)C1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
4-(R)-Benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (370 mg) was added to a solution of 1,2,3,4-tetrahydro-benzo[4,5]thieno[2,3-c]pyridine hydrochloride (230 mg) and triethylamine (0.30 ml) in dichloromethane (20 ml) and the reaction stirred at room temperature for 18 h. The mixture was washed with water (30 ml) and brine (20 ml), dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound (180 mg) in crude form.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][NH:9][CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)C.[OH-].[K+].Cl>CCOCC>[ClH:1].[ClH:1].[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:10]([NH:9][CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1CC(NCC1CCCCC1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Nc1ccccc1CC(NCC1CCCCC1)c1ccccc1
Reaction time: 2 h

Procedure:
7.0 g of N-Cyclohexylmethyl-2-nitro-α-phenylphenethylamine hydrochloride is treated with 200 ml of warm 95% ethanol containing 2.07 of potassium hydroxide for 15 minutes, after which the mixture is filtered and placed in a Paar flask containing 0.35 g of 10% palladium on charcoal. The mixture is hydrogenated at 50 psia for 2 hours. After removal of the catalyst, the ethanol is evaporated and the resulting biphasic mixture is poured onto 200 ml of water. The aqueous mixture is extracted with methylene chloride (2×200 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride is evaporated giving a colorless oil. The oil is dissolved in 100 ml of ether. Ethereal hydrogen chloride (200 ml) is a added and the salt precipitates from solution. The hydrochloride salt is collected as a gummy powder, which is recrystallized from i-propanol to provide crystals, mp 205° C. dec, 2-amino-N-cyclohexylmethyl-α-phenylphenethylamine dihydrochloride.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]1([N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[N:25][N:24]4[C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:31]=5)=[CH:28][N:29]=[C:23]4[CH:22]=3)[CH:18]=[N:17]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)#[N:3].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)Cl>[C:2]([CH2:4][C:5]1([N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[N:25][N:24]4[C:27]([C:30]5[CH:31]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:43])([F:44])[F:42])=[O:38])[CH:33]=[CH:34][CH:35]=5)=[CH:28][N:29]=[C:23]4[CH:22]=3)[CH:18]=[N:17]2)[CH2:6][NH:7][CH2:8]1)#[N:3]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl in 1,4-dioxane (4.0 N, 2 mL) was added to a mixture of tert-butyl 3-(cyanomethyl)-3-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.55 g, 0.92 mmol) in methylene chloride (10.0 mL). The reaction mixture was stirred at r.t. for 1 h. The mixture was adjusted to pH=8 with aqueous Na2CO3, and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH (with 5% NH3.H2O) in DCM (0-15%) to afford the desired product. LCMS (M+H)+: m/z=496.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:29])[C@@H:12]([NH:21]C(OC(C)(C)C)=O)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:29])[C@@H:12]([NH2:21])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
2-((2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (0.65 g, 1.54 mmol) was mixed in dichloromethane (5 mL) in an ice-bath. Trifluoroacetic acid (5 mL) was added and the solution was stirred for 2 hours. The reaction mixture was evaporated and the residue was precipitated with ether. The mixture was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave 2-((2S,3S)-2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (0.35 g, 71%).
Reaction SMILES: [C:1]1([C@:7]23[NH:14][C@H:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9][C@H:8]3[O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[CH2:23]([N:14]1[C@@H:11]2[CH2:12][CH2:13][C@@:7]1([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:8]([O:15][Si:16]([CH2:19][CH3:20])([CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:9][CH2:10]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC[Si](CC)(CC)O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of (1R,2R,5R)-1-phenyl-2-triethylsilyloxy-8-azabicyclo[3.2.1]octane (Description 51; 100 mg, 0.315 mmol), benzyl bromide (0.5 ml), potassium carbonate (380 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 30 minutes. The reaction mixture was treated with diethyl ether, washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (107 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[N+:19]([CH:10]1[CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]1([CH3:13])[CH3:12])([O-:21])=[O:20]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC([N+](=O)[O-])C(C)(C)c2ccccc21
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (20.0 g, 106.2 mmole) in 85 ml of acetic anhydride at 0° C. was treated with 12.2 mL of acetic acid followed by 11.1 mL of nitric acid (70%) and was allowed to warm to room temperature. After 24 hours the reaction mixture was poured onto 300 mL ice-water and extracted with three 150 mL portions of ether. The combined organic extracts were washed with four 100 mL portions of 15% aqueous sodium hydroxide solution, two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated in vacuo, giving 23.93 g (97%) of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) as a pale yellow solid.
Reaction SMILES: CC([N:5]=[C:6]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:8][CH3:9])(C)C.C[O:22][CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25](OC)=O>COCCOCCOC>[CH2:8]([C:7]1[CH:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:22])[NH:5][C:6]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH2:15][CH2:14][CH2:13]2)[CH3:9]
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(c1)CCCN2C
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: COCCOCCOC
Product: CCc1cc(C(=O)OC)c(=O)[nH]c1-c1ccc2c(c1)CCCN2C
Temperature: 160 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
To a suspension of 2-methyl-N-(1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butylidene)propan-2-amine (1.96 g, ca. 7.2 mmol) in diglyme (7 mL) was added dimethyl 2-(methoxymethylene)malonate (2.12 g, 12.2 mmol, 1.7 eq). The reaction was stirred at 160° C. for 3 h then was cooled to room temperature. The precipitate was collected by filtration then washed with Et2O to afford the title compound (402 mg, ca. 1.23 mmol) which was carried over to next step without further purification.
Reaction SMILES: [K+].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:16]([O-:18])=[O:17].[K+].C1C2C(=CC(C(O)=O)=CC=2)C=CC=1C([O-])=O.C1(C(O)=O)C=CC=CC=1>O>[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:16]([OH:18])=[O:17]
Reactant: O=C([O-])c1ccc2cc(C(=O)[O-])ccc2c1
Agent: O=C(O)c1ccccc1
Agent: O=C([O-])c1ccc2cc(C(=O)O)ccc2c1
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc2cc(C(=O)O)ccc2c1

Procedure:
reacting at least one of 2,6-naphthalenedicarboxylic acid dipotassium salt and 2,6-naphthalenedicarboxylic acid monopotassium salt with a benzenecarboxylic acid of the formula ##STR6## wherein m is an integer from 1 to 6, n is an integer from 0 to 5, and m+ n is 1 to 6, in the presence of water at a temperature of 0°-200° C. to yield solid 2,6-naphthalenedicarboxylic acid and an aqueous solution of a benzenecarboxylic acid potassium salt of the formula ##STR7## b) separating the solid 2,6-naphthalenedicarboxylic acid from the aqueous solution; c) recovering the benzenecarboxylic acid potassium salt from the aqueous solution; d) reacting the benzenecarboxylic acid potassium salt with naphthalene to yield 2,6-naphthalenedicarboxylic acid dipotassium salt; and e) recycling the 2,6-naphthalene-dicarboxylic acid dipotassium salt to step a).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]2[O:15][C@@H:11]([CH2:12][CH2:13]2)[C@@H:10]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1C=CC=CC=1.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>O1CCOCC1>[C:16]([C@H:10]1[C@H:11]2[O:15][C@H:14]([CH2:13][CH2:12]2)[C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:18])[NH2:19]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(=O)O)[C@@H]2CC[C@H]1O2
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(N)=O)[C@@H]2CC[C@H]1O2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
(1S,2R,3S,4R)-3-(tert-butoxycarbonylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (13) (44 mg, 0.17 mmol) was taken in dioxane when pyridine (1.7 eq) was added followed by addition of BOC2O. The reaction mixture was stirred at rt for 40 min when NH4CO3 (38 mg, 0.49 mmol) was added and the reaction mixture was stirred at rt for 15 h when TLC confirmed formation of product. The reaction mixture was concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford the desired product (43 mg, 95%) as a yellow oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[C:23]([CH3:30])[CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:45]2[C:44](=[O:46])[CH2:43][C:42]([CH3:48])([CH3:47])[CH2:41][C:40]=2[O:39][C:38]2[CH2:37][C:36]([CH3:50])([CH3:49])[CH2:35][C:34](=[O:51])[C:33]1=2.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:28])[CH:24]=[C:23]([CH3:30])[CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:33]2[C:34](=[O:51])[CH2:35][C:36]([CH3:49])([CH3:50])[CH2:37][C:38]=2[O:39][C:40]2[CH2:41][C:42]([CH3:48])([CH3:47])[CH2:43][C:44](=[O:46])[C:45]1=2
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(-c2cc(C)cc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C)cc(C(=O)NS(C)(=O)=O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
1,1′-Carbonyldiimidazole (99.5 mg, 0.61 mmol) was added to a solution of the 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]-4-methylpyridine-2-carboxylic acid produced in Example 32-3 (250 mg, 0.47 mmol) in DMF (5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 1 hour and 30 minutes. Thereafter, methanesulfonamide (58.4 mg, 0.61 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 ml, 0.61 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, an aqueous solution of citric acid (454 mg, 2.36 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). The solid thus obtained was washed with diethyl ether, followed by collection by filtration and drying, to obtain the title compound (230 mg, yield: 80%).
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[CH:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:26][C:25]1[CH:20]=[CH:21][C:22]([OH:27])=[CH:23][CH:24]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Reactant: Nc1ccc(O)cc1
Product: CC(C)OC(=O)C(C(=O)Nc1ccc(O)cc1)=C1SCS1

Procedure:
Following the procedure of Example 18, the titled compound was prepared as a white solid (66%) from isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and p-aminophenol.