Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:13])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1.C(N(CC)CC)C.[C:27]1([N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[F:19][C:2]([F:18])([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:13][C:34]([N:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:35])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(OC(=O)N(c2ccccc2)c2ccccc2)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2 g (0.0069 mol) of methyl 2,6-bis(trifluoromethyl)-4-hydroxy-3-pyridinecarboxylate (example 4 of U.S. Pat. No. 4,655,816) in 20 mL of acetonitrile was added 0.7 g of triethylamine. A solution of 1.6 g (0.0069 mol) of diphenylcarbamyl chloride in 20 mL of acetonitrile was added to the above mixture and the resulting mixture was stirred at room temperature over the weekend. The precipitate formed was filtered off and the filtrate was concentrated in vacuo. The residue was slurried with ether. The insoluble material was filtered. The ether filtrate was concentrated and the residue was recrystallized from cyclohexane to give a white solid, mp 114-116° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)[S:5][C:6]=1[C:7]#[N:8].[F-:26].[Cs+]>CS(C)=O.CCOC(C)=O>[C:7]([C:6]1[S:5][C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:3][C:2]=1[F:26])#[N:8]
Reactant: [F-]
Reactant: CC(C)n1cc(-c2cc(Cl)c(C#N)s2)c2ccc(NS(C)(=O)=O)cc21
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2cc(F)c(C#N)s2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 21 °C
Yield: 3.5 %

Procedure:
Heat a mixture of N-[3-(4-Chloro-5-cyano-thiophen-2-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (Example 118) (0.15 g, 0.381 mmol) and CsF (0.324 g, 2.13 mmol) in DMSO (5 ml) at 150° C. for 6 hours under N2. Cool the mixture to 21° C. and dilute with EtOAc. Wash the mixture with water, brine, and dried over MgSO4. Filter the material and concentrate to dryness. Purify the crude product by reverse phase chromatography to yield 5 mg of the title compound. MS: 378.0 (MH+)
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1[C:42](=[O:43])CCC1=O>CO.C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:43][CH3:42])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenyl-acetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole) in 40 ml of methanol and 60 ml of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2X) and dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (m.p. 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl 3) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H), 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic H and N-H); u.v. (CHCl3) λmax 264 nm (ε=9726).
Reaction SMILES: Cl.[CH2:2]([N:6]([CH2:11][CH2:12][CH2:13]Cl)[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CCC(C)=O>O>[CH2:2]([N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCN(CCCC)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 90.9 %

Procedure:
9.69 g of dibutylamino propylchloride HCl salt (IV) (0.04 mol, 1 eq), 5 g of 4-hydroxybenzaldehyde (III) (0.04 mol, 1 eq), 17 g of potassium carbonate (0.12 mol, 3 eq) and 30 mL of MEK are added to the reaction flask. The suspension is heated to 80° C. and it is stirred for 10 hours at this temperature. Then the mixture is cooled to room temperature, 40 mL of water is added and the brown solution is stirred for 30 min. After phase separation the organic phase is washed with 15 mL of water and the solvent is evaporated to obtain 10.6 g of compound (V) as a yellowish-brown solid (89%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:11]=1.Br[CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:34][CH2:33][CH2:32][N:17]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:12]=2[CH:11]=1)=[O:30]
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCCO2
Temperature: 60 °C
Yield: 89.9 %

Procedure:
Potassium carbonate (818 mg, 5.92 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 1.00 g, 2.69 mmol) and 1,3-dibromopropane (597 mg, 2.96 mmol) in N,N-dimethylformamide (17 mL), and the suspension was heated at 60° C. for 5 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 9-(5-chloro-2-methoxybenzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylic acid methyl ester (996 mg, 90%). White solid, MS (ISP)=412.1 (M+H)+.
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:6]2[C:13]([I:14])=[CH:12][N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=2[N:8]=[CH:9][N:10]=1>CO.O>[I:14][C:13]1[C:6]2[C:5]([NH2:3])=[N:10][CH:9]=[N:8][C:7]=2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=1
Reactant: N
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(I)c2c(N)ncnc21
Temperature: 120 °C
Reaction time: 1 h

Procedure:
An 8 N ammonia methanol solution (120 ml) was added to the 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (20.0 g) obtained in Step 1, and the mixture was stirred in a microwave reactor at 120° C. for 1 hour. After being cooled, the reaction mixture was diluted with methanol (65 ml) and water (185 ml). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (15.2 g) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][CH2:26][OH:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]([CH3:23])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:27][CH2:26][CH2:25][CH2:24][O:22]1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A mixture of N-benzyl-N-methyl-2,3-dioxoindoline-5-sulfonamide (2.88 g, 7.8 mmol), 1,3-propane-diol (1.43 mL, 19.5 mmol, 2.5 eq) and para toluene-sulfonic acid hydrate (0.296 g, 1.56 mmol, 0.2 eq) in benzene (135 mL) was refluxed with a Dean Stark Trap for 3.5 hours and stirred at room temperature overnight. The reaction was washed with NaHCO3 (2×), water (2×) and brine (2×) and concentrated. The crude product was purified on Biotage KP silica gel eluting with a step gradient of 35/65 to 45/55 Pet. ether/EtOAc to give the title compound as a bright yellow solid (1.33 g, 44% yield). NMR (300 MHz, DMSO-d6): consistent.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:9]([CH2:25][CH2:26][CH3:27])[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:47])[C:35]([O:45][CH3:46])([CH3:44])[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[CH3:32].C([O-])([O-])=O.[K+].[K+]>CCO.O>[CH2:31]([O:33][C:34](=[O:47])[C:35]([O:45][CH3:46])([CH3:44])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:14][CH2:13][CH2:12][C:10]2[N:9]([CH2:25][CH2:26][CH3:27])[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=3)[CH:11]=2)=[CH:39][CH:38]=1)[CH3:32]
Reactant: CCCn1c(CCOS(=O)(=O)c2ccc(C)cc2)cn(Cc2ccc(C)cc2)c1=O
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCn1c(CCOc2ccc(CC(C)(OC)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Temperature: 75 °C
Yield: 43.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester (0.079 g, 0.184 mmol), 3-(4-hydroxy-phenyl)-2-methoxy-2-methyl-propionic acid ethyl ester (0.038 g, 0.169 mmol) and K2CO3 (0.047 g, 0.340 mmol) in EtOH (8 mL) was heated at 75° C. under N2 for 16 h. The reaction mixture was cooled to room temperature and quenched with aqueous 1 N HCl (1 mL). The solvent was removed in vacuo to give a residue that was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using a 2:1 hexanes:acetone to afford 0.036 g (44%) 2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][NH:16][CH3:17]>CO>[CH3:15][N:16]([CH3:17])[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: CNC
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A suspension of 2.3 g 5-chlorosulfonyl-2-oxindole in 10 mL 2M dimethylamine in methanol was stirred at room temperature for 4 hours at which time a white solid formed. The precipitate was collected by vacuum filtration, washed with 5 mL of 1N sodium hydroxide and 5 mL of 1N hydrochloric acid and dried under vacuum at 40° C. overnight to give 1.9 g (79% yield) of 5-dimethylaminosulfonyl-2-oxindole.
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C@H:5]([OH:18])[CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O.C(OC(=O)C[C@H](O)CI)C.C(OC(=O)CC1CO1)C.C(O)(=O)[C@H](CC(O)=O)O.[CH2:48]([NH2:51])[C:49]#[CH:50]>>[OH:18][C@@H:5]1[CH2:6][N:51]([CH2:48][C:49]#[CH:50])[C:3](=[O:19])[CH2:4]1
Reactant: COC(=O)C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCN
Agent: CCOC(=O)CC1CO1
Agent: CCOC(=O)C[C@H](O)CI
Agent: O=C(O)C[C@H](O)C(=O)O
Product: C#CCN1C[C@@H](O)CC1=O

Procedure:
In accordance with Scheme I, (S)-3-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxy]butanoic acid methyl ester 2, (S)-3-hydroxy-4-iodobutanoic acid ethyl ester 3 and (S)=oxiraneacetic acid ethyl ester 4 are prepared from (S)-malic acid 1 using previously described methods [S. Saito et. al. Chem. Lett. 1389, (1984) and M. Larcheveque et. al. Tetrahedron Lett. 1781, 28 (1987)]. The esters 2, 3 and 4 are individually reacted with propargylamine in an alcohol solvent at temperatures ranging from room temperature to the reflux temperature of the solvent, preferably in the presence of an alkali metal carbonate, to produce (S)-4-hydroxy-1-(2-propynyl)-2-pyrrolidinone 5. Compound 5 is then reacted with an aryl or a (C1 -C6) carboxylic acid anhydride such as acetic anhydride in the presence of pyridine and preferably dimethylaminopyridine in an ether or a chlorohydrocarbon solvent, such as dichloromethane, to give the intermediate of general formula 6, for example, (S)-4-(acetyloxy)-1-(2-propynyl)- 2-pyrrolidinone.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2)[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OC(O)C)C>[CH2:1]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][CH2:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:35][CH:34]=3)[CH2:25][CH2:26]1)[CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCc1c(C)c2ccc(O)cc2[nH]c1=O
Agent: CCOC(C)O
Product: CCCCc1c(C)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2[nH]c1=O
Yield: 57.5 %

Procedure:
In a manner analogous to that described in Example 1, 3-n-butyl-4-methyl-7-hydroxy-2-oxo-1,2-dihydroquinoline is reacted with 3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propyl chloride in ethoxyethanol. There is obtained 3-n-butyl-4-methyl-7-{3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline in a yield of 57.5% of theory; m.p. 148°-149° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:34])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCCCCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and heptane-1,7-diamine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J=1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d, J=7.6 Hz, 1 H), 7.74-7.68 (m, 2 H), 7.61-7.56 (m, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J=4.80 Hz, 2 H), 3.31 (d, J=1.60 Hz, 2 H), 2.94 (m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 6 H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[CH:17][N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[CH:17][N:18]=[C:13]2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Product: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Yield: 92 %

Procedure:
25.5 g. of 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one (0.1 mol.) are refluxed in 100 ml. of phosphorus oxychloride for 12 hours. After this time, the excess phosphorus oxychloride is distilled off in vacuo, the residue is treated with dry acetone and filtered off. 25 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidine are obtained, yield 92%; m.p. 196°-197°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:9][C:10]1[N:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:15]([Br:1])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(-c2ccco2)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)c(-c2ccco2)nc1N
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
N-Bromosuccinimide (3.5 g, 19.7 mmol) was added to a solution (60 ml) of 2-amino-6-(2-furyl)nicotinonitrile (4.0 g, 21.6 mmol) in N,N-dimethylformamide in a nitrogen atmosphere at 1 to 2° C., followed by stirring as it was. After 30 minutes, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of potassium carbonate. The organic layer was washed with an aqueous saturated solution of potassium carbonate and an aqueous saturated solution of ammonium chloride, then dried over anhydrous sodium sulfate and concentrated. Methanol was added to the residue, and the resulting solid was collected by filtration and washed with methanol, to give the title compound (3.02 g, 53%) as a brown solid.
Reaction SMILES: F[B-](F)(F)F.[C:6]([C:9]1[CH:10]=[C:11]([N+:23]([O-:25])=[O:24])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([N+]#N)[CH:14]=1)([OH:8])=[O:7].C(OC(=O)C)(=[O:28])C>C(O)(=O)C>[OH:28][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([N+:23]([O-:25])=[O:24])[C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([OH:8])=[O:7]
Reactant: N#[N+]c1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
5-Carboxy-3-nitro-2phenylbenzenediazonium tetrafluoroborate (110 g ) is added in portions to a stirred and refluxing mixture of acetic anhydride (275 ml) and acetic acid (275 ml). The mixture is refluxed for a further 4-5 hours and is then poured into ice-water (about 4 liters). The mixture is left for 20 hours, and the precipitated crude 3-acetoxy-5-nitro-4-phenylbenzoic acid is collected by filtration, washed with water and dried. It is saponified by heating with 4 N sodium hydroxide (250 ml) for 30 minutes; the resulting solution is left at 5° C for about 20 hours and is then filtered. The filtrate is acidified with 4 N hydrochloric acid to precipitate 3-hydroxy-5-nitro-4-phenylbenzoic acid. It is collected by filtration, washed with water and dried. After recrystallization from aqueous methanol, the acid is obtained with a melting point of 213°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=O.O=S(Cl)Cl.[C:19]([O:27]C)(=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=O>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:25][O:24][C:22]1[C:9]2[C:5](=[C:4]([CH3:14])[C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH:6]=[C:20]([C:19]([OH:27])=[O:26])[CH:21]=1
Reactant: COC(=O)CCC(=O)OC
Reactant: COc1ccc(C(=O)O)c(C)c1OC
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O=S(Cl)Cl
Product: COc1cc2c(OC)cc(C(=O)O)cc2c(C)c1OC

Procedure:
4,6,7-Trimethoxy-8-methyl-2-naphthoic acid (7) is prepared in six steps according to the following reaction diagram. Reduction of 3,4-dimethoxy-2-methylbenzoic acid (1) to aldehyde (2) can be carried out by the Rosenmund reaction (SOCl2 then H2, Pd/BaSO4) (see reference 27). The aldehyde (2) is then reacted with dimethyl succinate (Stobbe reaction) (see reference 28). The coupling product (3) is not isolated but is treated directly with sodium acetate in the presence of acetic anhydride and acetic acid (AcOH/Ac2O 1:1) to give 4. After saponification, 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (5) is obtained with a yield of 70% (3 steps). After esterification under the conditions described above (90%), compound 6 is hydrolysed to give 4,6,7-trimethoxy-8-methyl-2-naphthoic acid (7) (92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.C1CNC(=O)C1.[Br:26][Br-]Br>CO.C(Cl)Cl>[Br:26][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C1CCCN1
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethanone (2.92 g) was dissolved in methanol:DCM (2:1, 75 mL) and pyrolidinone hydrotribromide (7.5 g) was added and stirred at room temperature for 2.5 h. After completion of the reaction, the mixture was concentrated in vacuo and poured into saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were combined and concentrated in vacuo. Then this residue was dissolved in DCM (10 ml) and methanol (10 mL) was slowly added to this solution to precipitate the product. The colored solution was filtered through to give clear white powder product 2-bromo-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone with quantitative yield (3.75 g).
Reaction SMILES: [F:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](F)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CNC[C@@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of (±)-1,1-dimethylethyl cis-3-fluoro-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.45 g, 1.28 mmole) in DCM (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3 hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (5.12 mmole, 1.9 g) was added with vigorous stirring at RT. After 4 h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (0.32 g, 99%) as a light orange oil: LC-MS (ES) m/e 253 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].Cl.[N+:19]([CH3:22])([O-:21])=[O:20]>O>[N+:19]([CH:22]=[CH:12][C:10]1[O:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)([O-:21])=[O:20]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccc(-c2ccccc2)o1

Procedure:
Combine 5-phenylfuran-2-carbaldehyde (808 mg, 4.69 mmol), methanol (2.0 mL), and nitromethane (1.13 mL) and cool. Add a combination of 0.20 mL of 1M sodium hydroxide and 0.70 mL of water to the reaction. Stir the reaction for 15 minutes, dilute with water (5 mL), add 1.0 mL of concentrated hydrochloric acid, and stir for 20 additional hours. Extract the reaction with ethyl acetate, dry organics, filter and evaporate to yield 1.14 g of 2-(2-nitrovinyl)-5-phenylfuran as a brown oil which can be used without further purification. MH+ 216.0