Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](F)[CH:3]=1.C(S)[CH2:11][S:12]([O-])(=O)=O.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([S:12][CH3:11])[CH:3]=1
Reactant: Cc1ccc(Br)cc1F
Reactant: O=S(=O)([O-])CCS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Br)ccc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-1-methyl-benzene (3 mL, 26.3 mmol) in DMF (15 mL) was added MeSNa (1.84 g, 26.3 mmol). After the addition, the reaction mixture was stirred at 90° C. overnight. TLC (petroleum) showed the reaction was complete. Then the mixture was poured into aq. NaHCO3 (10 mL), extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (50 mL×3), dried over sodium sulfate and concentrated in vacuum. The residue was purified by a silica gel column chromatography (petroleum) to give 4-Bromo-1-methyl-2-methylsulfanyl-benzene (4 g, 68%) as a yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:9]=1[C:10](=[O:13])[CH2:11]Br.[CH3:19][C:20]1[C:21]([CH3:29])=[N:22][C:23]([SH:28])=[C:24]([CH:27]=1)[C:25]#[N:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:27]=[C:24]2[C:25]([NH2:26])=[C:11]([C:10](=[O:13])[C:9]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:8]=3[F:7])[S:28][C:23]2=[N:22][C:21]=1[CH3:29]
Reactant: O=C(CBr)c1cc(F)ccc1F
Reactant: Cc1cc(C#N)c(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(N)c(C(=O)c3cc(F)ccc3F)sc2nc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.399 g, 2.89 mmol), 2,5-difluorophenacyl bromide (0.408 g, 1.73 mmol) and 5,6-dimethyl-2-mercaptonicotine nitrile (0.19 g, 1.16 mmol) in dry DMF (4 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound with a m.p. of 188° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14]>O1CCCC1.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]1[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14]
Reactant: O=C1NC(=O)C(=Cc2ccccn2)S1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Cc2ccccn2)S1
Reaction time: 16 h

Procedure:
To a solution of 5-pyridin-2-ylmethylene-thiazolidine-2,4-dione (5.0 g, 0.024 mol, prepared in a similar way as described in J. Med. Chem. 41 (10), 1619–1630 (1998)) in tetrahydrofuran (300 ml) was added 10% palladium on carbon (1 g) and the resulting mixture was hydrogenated. After 50 ml of hydrogen was consumed and additional portion of 10% palladium on carbon (5 g) was added and the hydrogenation was continued at 50 psi for 16 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was subjected to flash column chromatography (1 l silicagel) using a mixture of ethyl acetate/hexane, (1:1) as eluant. Semi pure fractions were collected and the solvent evaporated in vacuo affording 0.8 g (16,%) of 5-pyridin-2-ylmethyl-thiazolidine-2,4-dione as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]([C:28]2([C:31]3[CH:41]=[CH:40][C:34]4[O:35][C:36]([F:39])([F:38])[O:37][C:33]=4[CH:32]=3)[CH2:30][CH2:29]2)=[O:27])[CH:22]=[CH:21][C:20]=1[CH3:42]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[F:39][C:36]1([F:38])[O:35][C:34]2[CH:40]=[CH:41][C:31]([C:28]3([C:26]([NH:25][C:23]4[CH:22]=[CH:21][C:20]([CH3:42])=[C:19]([C:6]5[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=5)[N:24]=4)=[O:27])[CH2:30][CH2:29]3)=[CH:32][C:33]=2[O:37]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(C)c1
Temperature: 120 °C
Yield: 63.5 %

Procedure:
To a mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (68 mg, 0.30 mmol), N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) in DME (1.5 mL) and 2 M Na2CO3 (0.24 mL) was added Pd(PPh3)4 (14 mg, 0.0030 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O before the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over MgSO4. After the removal solvent, the residue was purified by column chromatography (10-20% EtOAc-Hexane) to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (67 mg, 72%). 1H-NMR (400 MHz, CDCl3) δ 8.06 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.24 (td, J=10.0, 1.7 Hz, 2H), 7.12 (d, J=8.2 Hz, 1H), 6.61 (d, J=9.2 Hz, 1H), 3.60 (s, 3H), 2.33 (s, 3H), 1.77 (q, J=3.6 Hz, 2H), 1.19 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 440.2.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:47]=[N:46][C:8]2[O:9][C:10]([CH3:45])([CH3:44])[C:11](=[O:43])[N:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][C@H:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37])=[CH:23][C:22]=4[N+:40]([O-])=O)=[O:20])[CH2:15][CH2:14]3)[C:7]=2[CH:6]=1.[Cl-].[NH4+]>[Fe].O>[NH2:40][C:22]1[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C@H:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37])[CH:25]=[CH:26][C:21]=1[C:19]([N:16]1[CH2:17][CH2:18][CH:13]([N:12]2[C:11](=[O:43])[C:10]([CH3:45])([CH3:44])[O:9][C:8]3[N:46]=[CH:47][C:5]([Cl:4])=[CH:6][C:7]2=3)[CH2:14][CH2:15]1)=[O:20]
Reactant: C[C@H](CC(=O)O)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Cl)cc43)CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@H](CC(=O)O)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Cl)cc43)CC2)c(N)c1
Yield: 32.2 %

Procedure:
To an 80% aqueous ethanol solution (7.50 ml) of (3R)-3-[(4′-{[4-(7-chloro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidin-1-yl]carbonyl}3′-nitrobiphenyl-2-yl)oxy]butanoic acid (132 mg) were added at room temperature ammonium chloride (11.3 mg) and iron powder (59.0 mg), followed by stirring under heating at reflux for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford (3R)-3-[(3′-amino-4′-{[4-(7-chloro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidin-1-yl]carbonyl}biphenyl-2-yl)oxy]butanoic acid (40.5 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.[ClH:34].O1CCOCC1>C(Cl)Cl>[ClH:34].[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C@@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)=[CH:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc2c([C@@H]3CNC[C@H]3c3cn4c5c(cccc35)CCC4)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.205 g, 0.46 mmol) in DCM (10 mL) was added HCl 4M in dioxane (1.15 mL, 4.6 mmol) under N2. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue washed with DCM. Re-crystallization from EtOH gave 1-[(3R,4R)-4-(1H-Indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline HCl salt as a white solid. M.p.=dec.>70° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (s, 1H), 9.24 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.32-7.26 (m, 3H), 7.05 (t, J=7.6 Hz, 1H), 6.94 (t, J=7.6 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 4.03 (m, 4H), 3.85 (br s, 1H), 3.52-3.35 (m, 3H), 2.85 (t, J=6.0 Hz, 2H), 2.05 (m, 2H). LCMS: m/e 342.17 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[NH:11]1.[I-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[N:11]1[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CCCCl
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COC(=O)CCCN1[C@H](C)CCC[C@@H]1C

Procedure:
A mixture of 273 g. of methyl 4-chlorobutyrate, 460 g. of cis-2,6-dimethylpiperidine, 10 g. of sodium iodide and 300 ml. of xylene is stirred and heated at reflux for 44 hours, then cooled and filtered. The filter cake is washed with xylene and the combined filtrate and washings are evaporated at reduced pressure to give cis-2,6-dimethyl-1-piperidinebutyric acid, methyl ester which is purified by distillation; b.p. 79°-81° C./0.5 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[Br-].[CH2:26]([Zn+])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.CCOC(C)=O>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: [Zn+]Cc1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (800 mg, 2.06 mmol), benzylzinc bromide (10.3 mL, 5.14 mmol, 0.5 M in THF), and Pd(PPh3)4 (238 mg, 0.206 mmol) in THF (20 mL) was refluxed under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., 1 M HCl and EtOAc were added. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 470 mg of the title compound as a yellow solid. MS: (+) m/z 401.12 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(O[K])(C)(C)C.CC(O)(C)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCCOCCBr
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C1c2cc(Br)ccc2CC12CCOCC2

Procedure:
To a solution of 6-bromo-1-indanone (1.033 g, 4.89 mmol) in anhydrous THF (100 mL) under N2 atmosphere at room temperature was added a solution of tBuOK in tBuOH (1 M, 10.3 mL, 10.3 mmol) within 30 min (the color turned to deep black upon a drop of tBuOK solution was added), followed by 1-bromo-2-(2-bromoethoxy)ethane (1.134 g, 0.62 mL, 4.89 mmol). The reaction was quenched with saturated aqueous NH4Cl, and extracted with ether two times. The combined organic phases were washed with H2O, brine, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black tar. It was purified by flash chromatography on silica gel yield 300 mg of the desired product. MS ESI+ve m/z 281 (M+H)30.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:8]([C:10]3[S:14][C:13]4=[C:15]([S:18][CH3:19])[N:16]=[CH:17][N:12]4[CH:11]=3)[CH2:9][C@H:5]12)[CH3:3].[OH:35]OS([O-])=O.[K+]>>[OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[C:8]([C:10]3[S:14][C:13]4=[C:15]([S:18]([CH3:19])=[O:35])[N:16]=[CH:17][N:12]4[CH:11]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4C3)sc12
Reactant: O=S([O-])OO
Agent: [K+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(C)=O)c4s3)C[C@H]12
Yield: 40.5 %

Procedure:
A reaction was carried out in the same manner as in Example 44-b), except that 639 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate and 1.57 g of oxone were used as the starting compounds. The reaction product was purified by column chromatography on silica gel (dichloromethane:methanol=20:1 to 10:1) to give 267 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL) CHCl3 (40 mL) in a dry flask, under nitrogen. TEA (8.14 mL<58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5% HCl (2×40 mL), dried over anhydrous MgSO4 and concentrated to a brown paste (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10% EtOAc/hexane (1 L) followed by 15% EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91%) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H1: 249.0947, found 249.0947.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:44]([N:46]1[CH2:52][CH2:51][CH2:50][N:49]([C:53](=O)[CH2:54]Cl)[CH2:48][CH2:47]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:54][CH2:53][N:49]2[CH2:50][CH2:51][CH2:52][N:46]([CH3:44])[CH2:47][CH2:48]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCN(C)CC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 43.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-chloroacetyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.4 mg) was obtained.
Reaction SMILES: [CH:1]([C@@H:4]1[NH:19][C:18](=[O:20])[C@H:17]([NH:21]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH2:16][C:15]2=[CH:39][CH:40]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH:9]=[CH:8][CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[NH2:21][C@@H:17]1[CH2:16][C:15]2=[CH:14][CH:13]=[C:12]([CH:40]=[CH:39]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C@H:4]([CH:1]([CH3:2])[CH3:3])[NH:19][C:18]1=[O:20]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
A mixture of 6.82 g (12.62 mmol) of 9H-fluoren-9-ylmethyl ((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)-carbamate and 4.4 g of 10% Pd/C in 880 ml of methanol was stirred under a hydrogen atmosphere at RT. After 6 h, it was filtered and freed of solvent. The residue was separated by preparative HPLC. The required fractions were combined, acetonitrile was evaporated off, and the resulting aqueous solution was made slightly alkaline with sodium bicarbonate. The aqueous phase was extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel with ethyl acetate/methanol mixtures afforded the title compound (2.90 g).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1C=O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erlenmeyer flask with powdered potassium carbonate (569 g), dimethylformamide (1,000 ml), and methyl chloroacetate (478 g) and mechanically stirred at 65° C. for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25° C. The mixture was poured into cold water (0° C.) while stirring vigorously. An oil separated that suddenly solidified. Stirring was continued for 30 minutes and the solid isolated by filtration. The product was washed with water (2×1,000 ml) and pressed dry. The product can also be dried in vacuo at 25° C. A small sample (approx. 2 g) was purified by distillation. The boiling range of the pure product is 124°-128° C. at 2 mm Hg and has a melting temperature range of about 50.2°-50.6° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34]C)[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: CCOc1cccc(OCCCBr)c1
Product: COc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.808 g of 1-(3-bromopropoxy)-3-ethoxybenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtoAc-heptane); Rt=5.18.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:9]=2[S:8](=[O:22])(=[O:21])[CH:7]=1)C.[OH-].[Li+]>CO>[CH3:20][S:17]([NH:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:7][S:8](=[O:21])(=[O:22])[C:9]=2[CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (prepared as described in US patent application US 2008/0031852, 600 mg, 1.666 mmol) in methanol (30 mL) was cooled to 0° C. in an ice-water bath and treated with 2.0 M aqueous lithium hydroxide solution (4.17 mL, 8.332 mmol). The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. The methanol was removed in vacuo and the reaction mixture was poured into 0.5 M aqueous hydrochloric acid solution (20 mL) on ice, extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford an orange solid. The crude solid was triturated with diethyl ether to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (409 mg, 1.232 mmol, 73.9%), as a yellow solid. LC-MS calcd for C11H12N2O6S2 332.4, found 333.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[NH:9][CH:8]=[C:7]([C:20]#[N:21])[C:6]2=O.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:6]1[C:5]2[C:10](=[CH:11][C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: COc1cc2c(=O)c(C#N)c[nH]c2cc1N1CCN(C)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)c(C#N)cnc2cc1N1CCN(C)CC1
Temperature: 105 °C

Procedure:
A reaction mixture of 0.3 g (1.01 mmol) of 6-methoxy-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbonitrile in 5 mL of phosphorus oxychloride is heated at 105° C. for 45 minutes. After cooling, the mixture is concentrated to dryness in vacuo to give a brown solid. To this is added 5 mL toluene, and the solution is concentrated to dryness again. Dropwise, an ice-cooled saturated aqueous sodium carbonate solution is added to the residue. This mixture is extracted with 5×25 mL of a 95:5 mixture of methylene chloride/methanol. The organic layer is dried over magnesium sulfate. The magnesium sulfate is removed by filtration, and solvent is removed in vacuo to provide 0.255 g of 4-chloro-6-methoxy-7-(4-methylpiperazin-1-yl)-quinoline-3-carbonitrile as a yellow solid, mp 177-179° C.