Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C2C(=CC=CN=2)C=[CH:15][CH:14]=1.S(Cl)(Cl)=O>C(O)C>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([Cl:11])=[N:10][C:2]=1[Cl:1])[CH3:15]
Reactant: c1cnc2ncccc2c1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(Cl)nc1Cl

Procedure:
2,6 Dichloro-5-fluoro-nicotinic acid was selected as a starting material to make the compounds of structure (Ia) with fluoro substitution at 6-position of naphthyridine moiety. 2,6 Dichloro-5-fluoro-nicotinic acid was esterified by treating with thionyl chloride followed by refluxing with dry ethanol to yield 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester, depicted by formula 21 in Scheme 10. This ester gave 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, depicted by formula 22 in Scheme 10, when reacted with ethanethiol and sodium hydride. 6-Ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 23 in Scheme 10, was prepared by amination of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, which was converted into 5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 24 in Scheme 10, by refluxing with ethanol and raney nickel. 5-Fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester was then reacted with trichloromethylchloroformate to yield 6-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione, depicted by formula 25 in Scheme 10. The sequence of reactions is shown in Scheme 10.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:5][CH2:4]1)=O.[ClH:21]>CO>[ClH:21].[ClH:21].[ClH:21].[N:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[NH:16][C:12]=1[S:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
1-Formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (1.45 g, 5.0 mmol) was dissolved in methanol (20 mL) . 12N Hydrochloric acid (2 mL) was added to the solution, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the thus-formed solid material was crystallized from chloroform-methanol, to thereby yield 1.67 g of 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine trihydrochloride (yield: 90%) as a colorless crystalline powder.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[C:38]([SH:41])([CH3:40])[CH3:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[C:15]([SH:18])([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(CC)CC)C>C(#N)C.O>[CH3:16][C:15]1([CH3:17])[S:18][S:41][C:38]([CH3:39])([CH3:40])[C@H:37]([C:42]([OH:44])=[O:43])[NH:36][C:34](=[O:35])[C@@H:26]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:25][C:23](=[O:24])[CH2:22][NH:21][C:19](=[O:20])[C@@H:14]1[NH:13][C:11]([C@@H:2]([NH2:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:12]
Reactant: CC(C)(S)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)(C)S)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC1(C)SSC(C)(C)[C@@H](NC(=O)[C@@H](N)Cc2ccc(O)cc2)C(=O)NCC(=O)N[C@H](Cc2ccccc2)C(=O)N[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
3.0 mg of DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen) was dissolved in 5 ml of anhydrous acetonitrile. A 20% molar excess of PEG reagent (either mPEG-SPA 5K [27.9 mg] or mPEG-SPA 2K [11.1 mg]) and triethylamine (0.8μl) was added to the DPDPE. The reaction was allowed to proceed at room temperature under an argon atmosphere for 2 days. The sample was diluted to 15 ml with deionized water and lyophilized. The PEG-DPDPE powder was reconstituted in 5 ml of deionized water and purified on a Superdex 30 size exclusion column. The pertinent fractions were pooled together, dialyzed against water and frozen until in situ perfusion experiments.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[C:6](O)=[C:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8])[CH3:2].S(Br)(Br)=O.[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])/[CH:6]=[C:7](\[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH2:8][P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:32])[CH3:2]
Reactant: CCOC(=O)C(NC=O)C(O)=C(C)Cc1ccccc1
Reactant: CCOP(OCC)OCC
Agent: O=S(Br)Br
Solvent: CCOC(C)=O
Product: CCOC(=O)C(/C=C(\Cc1ccccc1)CP(=O)(OCC)OCC)NC=O

Procedure:
By reaction of 2-formylamino-3-hydroxy-4-benzyl-3-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite at 100° in a manner analogous to that described in Example 1, and after chromatography (silica gel; ethyl acetate), E-2-formylamino-4-benzyl-5-diethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a colourless oil, 1H-NMR (CDCl3): 2.45 (d, 2H, C(5)--H); 3.80 (s, 1H, CH2); 5.51 (m, 1H, C(3)--H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([Cl:17])=[CH:11][C:12]([O:15]C)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.CN(C=O)C.CC([S-])(C)C.[Na+]>O.Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([Cl:17])=[CH:11][C:12]([OH:15])=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2c(F)c(OC)cc(Cl)c12
Agent: CC(C)(C)[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1csc2c(F)c(O)cc(Cl)c12
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 84.6 %

Procedure:
To a mixture of methyl(4-chloro-7-fluoro-6-methoxy-1-benzothiophen-3-yl)acetate (284.8 mg) and DMF (dry) (8.0 mL) was added sodium 2-methyl-2-propanethiolate (443 mg). The mixture was stirred at 160° C. for 45 min. After cooling, the mixture was diluted with water and 1N HCl and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in MeOH (6.0 mL). To the solution was added conc. H2SO4 (0.100 mL). The mixture was stirred at 70° C. for 1 h. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residual solid was washed with toluene and hexane to give the title compound (229.3 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.CCCCCC.[C:25]1([CH:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33](=O)[O:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:33]1[O:32][C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[CH:39]2
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C1OC(c2ccccc2)c2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccccc2-c2oc(-c3ccccc3)c3ccccc23)cc1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
In Ar, 3.9 g (1.68E-2 mol) of o-bromobiphenyl was dissolved in 30 cm3 of tetrahydrofuran (THF) at −50° C. To the solution was added 10 cM3 of a nBuLi hexane solution (1.5 mol/l). After 2 hours, 3 g (1.4E-2 mol) of 3-phenylphthalide was added to the solution while it was kept cooled at −50° C. After 2 hours, the reaction solution was allowed to resume room temperature, and 10 cm3 of a 35% aqueous hydrochloric acid was added thereto. After 1 hour, toluene extraction was carried out using a separatory funnel, followed by thorough washing with distilled water. After the toluene solution was concentrated, the end product was isolated by silica gel chromatography (developer, toluene:hexane=1:4). There was obtained 4 g (80%) of a yellow viscous substance emitting bluish green fluorescence.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([C:26]=2[O:27]CC2C=CC=CC=2)=[N:24][C:23]([O:35][CH3:36])=[CH:22][CH:21]=3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:37])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([C:26]=2[OH:27])=[N:24][C:23]([O:35][CH3:36])=[CH:22][CH:21]=3)[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)c(OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)c(O)c2n1
Reaction time: 7 h
Yield: 92.8 %

Procedure:
10% Palladium on activated carbon (3.45 g, 3.29 mmol, 0.18 eq) is added at room temperature to a stirred solution of {1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (9.3 g, 18.28 mmol, 1.0 eq) in methanol (100 mL). The mixture is hydrogenated for 7 hours, then filtered through decalite. Solvent is removed to afford {1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an off-white solid (7.1 g, 91% yield).
Reaction SMILES: C[N:2]1[CH2:12][CH:11](C2C=CC=C(N=C=S)C=2)[C:10]2[CH:9]=[C:8]([OH:22])[C:7](Cl)=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:24]([OH:30])(C(F)(F)F)=[O:25]>O.C(#N)C>[CH2:4]([O:22][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:2]([C@H:3]([CH3:4])[C:24]([OH:30])=[O:25])[CH:12]=[CH:11]2)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc(N=C=S)c2)C1
Solvent: CC#N
Solvent: O
Product: C[C@H](C(=O)O)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.12 h

Procedure:
Reverse Phase HPLC conditions: Column: YMC-Pack ProC18 (AS-300), 50×4.6 mm (I.D.), S-5 μm, 12 nm (No. 040506614); Mobile Phase: A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile; Gradient: 90-5% A (10-95% B) in 7 min.; Flow rate: 4.0 mL/min; Detector (UV): 220 nm. Retention time of title compound: 3.53 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16].[Cl:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:21]2[N:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=3)[C:32]([OH:34])=[O:33])[N:23]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]=2[CH:45]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[C:19]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[CH:20][C:21]2[N:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=3)[C:32]([OH:34])=[O:33])[N:23]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]=2[CH:45]=1
Reactant: COc1ccc(Br)c(F)c1
Reactant: Cc1ccc(Oc2nc3cc(B4OC(C)(C)C(C)(C)O4)c(Cl)cc3n2COCC[Si](C)(C)C)cc1C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3nc(Oc4ccc(C)c(C(=O)O)c4)n(COCC[Si](C)(C)C)c3cc2Cl)c(F)c1
Temperature: 150 °C

Procedure:
K2CO3 (0.293 mL, 0.585 mmol) followed by Pd(PPh3)4 (6.76 mg, 5.85 μmol) were added to a solution of 4-Bromo 3-fluoro anisole (0.027 mL, 0.195 mmol) and 5-[(6-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoic acid (122 mg, 0.219 mmol) in DMF (2 mL). The reaction was heated at 150° C. under microwave irradiation for 10 min. Volatiles were removed to afford the desired product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH:10]1([Mg]Br)[CH2:12][CH2:11]1>>[OH:9][CH:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH:10]1[CH2:12][CH2:11]1
Reactant: Br[Mg]C1CC1
Reactant: Cc1ccnc(C=O)c1
Product: Cc1ccnc(C(O)C2CC2)c1
Yield: 87 %

Procedure:
The Grignard reaction of 4-methyl-2-pyridinecarboxaldehyde (1.21 g, 10.0 mmol) and cyclopropylmagnesium bromide (24 ml, 15.0 mmol, 1.5 equiv., 1.6 ml/mmol) provided 1.42 g (87%) of 2-(1-hydroxy-1-cyclopropylmethyl)-4-methyl-pyridine. TLC (silica gel GF): Rf =0.21 acetone-methylene chloride (1:6). 1H NMR (CDCl3,TMS): δ 8.47 (d, 1H, J=5.08 Hz), 7.30 (s, 1H), 7.12 (d, 1H, J=5.14 Hz), 4.70 (brs, 1H), 4.16 (d, 1H, J=7.92 Hz), 2.47 (s, 3H), 1.26-1.12 (m, 1H), 0.74-0.57 (m, 4H). Mass Spectrum: M/Z (relative intensity %): 163 (34), 162 (51), 146 (51), 135 (70), 122 (100), 107 (57), 92 (98).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>O>[CH2:5]1[C:6]2[NH:15][C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:1]=2[CH2:2][CH2:3][CH2:4]1
Reactant: NNc1ccccc1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: c1ccc2c3c([nH]c2c1)CCCC3
Temperature: 115 °C
Reaction time: 8 h

Procedure:
Cyclohexanone (2.0 ml., 0.020 mole), phenylhydrazine hydrochloride (2.88 g., (0.020 mole) and 6.0 ml. of freshly distilled pyridine are combined, heated at reflux (115° C) for 3 hours, then allowed to cool to room temperature and allowed to stir overnight. About 25 ml. of water is added and the precipitated solids are collected by decantation. After washing again with water, the solids are dissolved in a mixture of 20 ml. of ethanol and 5 ml. of water and set aside. The resulting crystals are collected by filtration, washed with aqueous ethanol and dried to afford 2.65 g. (77.5% of theory) of the title compound, M.P. 119°-120° C. A mixture of the product and an authentic sample of 1,2,3,4-tetrahydrocarbazole also melted at 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:14][C:13](=O)[C:12]3[N:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1>P(Cl)(Cl)(Cl)=O>[C:13]([C:12]1[C:11]([C:10]#[C:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14]
Reactant: COc1ccc(-c2cc3cccnc3c(=O)[nH]2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C#Cc2cccnc2C#N)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 151 %

Procedure:
Phosphorus oxychloride (20 ml) was added to 6-(4-methoxyphenyl)-7,8-dihydropyrido[2,3-c]pyridin-8-one (0.70 g, 2.77 mmol), and the mixture was heated under reflux for 1.5 hr. After cooling as it was, excess phosphorus oxychloride was evaporated. To the resulting residue was added N-ethylpiperazine (35 ml), and the mixture was stirred in nitrogen atmosphere at 100° C. for 2 hr. After cooling as it was, the reaction solution was evaporated. The resulting residue was dissolved in ethyl acetate, washed sequentially with a 10% aqueous solution of sodium carbonate, water and brine, and dried over magnesium sulfate. Then, the solvent was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (n-hexene/ethyl acetate system), to give the title compound as pale brown crystals (0.98 g, yield; quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Li])CCC.C[O:29][B:30](OC)[O:31]C>O1CCCC1>[F:1][C:2]1[C:3]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:4]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([F:8])=[CH:6][C:7]=1[B:30]([OH:31])[OH:29]
Reactant: COB(OC)OC
Reactant: CCCCCCOc1c(F)ccc(F)c1OCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCOc1c(F)cc(B(O)O)c(F)c1OCCCCCC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1,4-Difluoro-2,3-dihexyloxybenzene (11.2 g, 0.036 mol) was stirred, under nitrogen, in anhydrous tetrahydrofuran (150 ml). The reaction mixture was cooled to −78° C. and then butyl lithium (1.6M in hexanes, 24.38 ml, 0.039 mol) was added via cannular over one hour. Stirring was continued at −78° C. for 2 hours. This temperature was maintained whilst a solution of trimethylborate (4.05 g, 0.039 mol) in dry tetrahydrofuran (100 ml) was added drop-wise. The cooling bath was then removed and the reaction was stirred overnight at room temperature. Addition of HCl (1M, 36 ml) dissolved the white suspension and a yellow solution was formed. Extraction was performed with toluene (2×100 ml), the combined organics extracts were then washed with water (2×50 ml), dried with magnesium sulphate. Removal of the drying agent by filtration and the solvent in vacuo yielded a brown oil containing the crude product (11.95 g, 93%). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=2)[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:33][C:34]([Cl:38])([Cl:37])[C:35]#[N:36]>ClCCl>[Cl:33][C:34]([Cl:38])([Cl:37])[C:35](=[NH:36])[O:13][CH:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:7]=2)[CH:3]=[C:2]([F:1])[CH:10]=1)[CH3:12]
Reactant: CC(O)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(5-Fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (1.58 g, 5.09 mmol) was dissolved in dichloromethane (10 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (153 μL, 1.018 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (5.1 mL, 50.9 mmol) dropwise over 10 min. The reaction was stirred at room temperature for 2 h and concentrated. The resulting residue was dissolved in diethyl ether. The resulting solution was decanted to separate it from the resulting dark tar which formed. The ethereal was concentrated to give 2.247 g (97%). 1H-NMR (CDCl3, 300 MHz) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.16 (m, 1H), 6.63 (q, J=6.0 Hz, 1H), 5.68 (s, 2H), 3.62 (m, 2H), 1.78 (d, J=6.0 Hz, 3H), 0.89-0.94 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
The reaction was done as described in General Method 12 using 1-bromo-4-tert-butyl-benzene (15 g), acetic acid (10 mL), nitric acid (6.5 g), and sulfuric acid (13 g). MS(APCI): 291.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC=C2C=1C(C#N)=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Yield: 85 %

Procedure:
3-(3-Cyano-1H-Indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXIII (1.82 g, 85% yield) was prepared from 5-bromo-1H-indole-3-carbonitrile using the procedure described for 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][O:24]CC2C=CC=CC=2)[O:11][C@H:10]1[N:32]1[C:44]2[C:43]3[NH:45][C:46]4[CH:47]=[C:48]([F:53])[C:49]([F:52])=[CH:50][C:51]=4[C:42]=3[C:41]3[C:54](=[O:58])[NH:55][C:56](=[O:57])[C:40]=3[C:39]=2[C:38]2[C:33]1=[CH:34][C:35]([F:60])=[C:36]([F:59])[CH:37]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][OH:24])[O:11][C@H:10]1[N:32]1[C:44]2[C:43]3[NH:45][C:46]4[CH:47]=[C:48]([F:53])[C:49]([F:52])=[CH:50][C:51]=4[C:42]=3[C:41]3[C:54](=[O:58])[NH:55][C:56](=[O:57])[C:40]=3[C:39]=2[C:38]2[C:33]1=[CH:34][C:35]([F:60])=[C:36]([F:59])[CH:37]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](COCc2ccccc2)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: II
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
To a solution of 12-[4-deoxy-2,3,6-tri-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (6.49 g, 7.97 mmol) in 90 mL of acetic anhydride was added solid I2 (0.406 g, 1.6 mmol) and the mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with ethyl acetate, washed (30% aq. Na2S2O3, saturated aq. NaHCO3, H2O, brine) dried (MgSO4) and evaporated. The residue was taken up in methanol (150 mL), 15 mL of concentrated NH4OH was added and the mixture was stirred at room temperature for 18 h. The mixture was then evaporated to dryness and the residue was chromatographed (SiO2/hexane-ethyl acetate, 95:5 to 1:1) to give 12-[4-deoxy-2,3,-di-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (2.35 g, 41%) and then 12-[4 deoxy-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (2.40 g, 48%), both as yellow solids.
Reaction SMILES: [C:1](=O)([O-:3])[OH:2].[Na+].[CH3:6][N:7]1[S:16](=[O:18])(=[O:17])[C:11]2[CH:12]=[C:13]([Cl:15])[S:14][C:10]=2[C:9]([OH:19])=[C:8]1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:28]=1)=[O:21]>O.C(O)C>[C:1](=[O:3])=[O:2].[CH3:6][N:7]1[S:16](=[O:18])(=[O:17])[C:11]2[CH:12]=[C:13]([Cl:15])[S:14][C:10]=2[C:9]([OH:19])=[C:8]1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:28]=1)=[O:21]
Reactant: O=C([O-])O
Agent: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc(Cl)cc2S1(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C=O

Procedure:
8 g of sodium hydrogencarbonate was dissolved in 120 g of water and mixed with a suspension of 32 g lornoxicam in 600 g of ethanol. While forming gaseous carbon dioxide, lornoxicam dissolved. 100 g of Pharmacoat 606W was added and dissolved. 212 g of sodium hydrogen carbonate was admixed and dissolved. The solution obtained was mixed with Avicel in a lab size mixer. The wet mixture was dried and then magnesium stearate and polyplasdone XL were admixed in the lab scale mixer.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[CH:23][N:22]=[N:21]5)[CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.Cl>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:15][CH2:16][CH:17]([N:20]5[CH:24]=[CH:23][N:22]=[N:21]5)[CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3CCC(n4ccnn4)CC3)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(n4ccnn4)CC3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 47.1 %

Procedure:
A mixture of ethyl 1-cyclopropyl-6-fluoro-7-[4-(1,2,3-triazol-1-yl)piperidin-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (135 mg, 0.32 mmol) and 6N-HCl (6 ml) was heated at 110° C. for 18 hrs. The reaction mixture was concentrated and the residue was diluted with water. The pH of the suspension was adjusted to 7 by addition of NH4OH and this separated solid was filtered, washed with water, CH3CN and dried to give 60 mg of title product. m.p. 246°-248° C.; 1H NMR (TFA) δ: 9.25 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.25 (d, 1H), 5.35 (m, 3H), 4.12 (m, 1H), 3.75 (m, 2H), 2.40-2.85 (m, 4H), 1.25-1.70 (m, 4H).