Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]2[N:17]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[O:19][C:13]=2[CH:12]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[F:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]2[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([O:27][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:24]([CH3:26])[CH:25]=3)[O:19][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
110 mg of potassium carbonate were added to a solution of 70 mg of 4-[6-(2-fluorophenoxy)oxazolo[4,5-c]pyridin-2-yl]-2,6-dimethylphenol in 1 ml of dimethylformamide, and 51 mg of tert-butyl bromoacetate were then added. The mixture was stirred at room temperature for 16 h. The reaction mixture was then added to water and extracted twice with ethyl acetate. The collected organic phases were dried and concentrated. This gave 93 mg (100%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ncc(Br)cc2N)cn1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 5-bromo-6′-methoxy-3-nitro-2,3′-bipyridine (0.34 g, 1.10 mmol) in EtOAc (10 mL) was added tin(II) chloride dihydrate (1.26 g, 5.57 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the residue was identified as mostly 5-bromo-6′-methoxy-2,3′-bipyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.50 (1H, d, J=2.4 Hz), 8.18 (1H, d, J=2.0 Hz), 7.90 (1H, dd, J=8.6, 2.4 Hz), 7.26 (1H, m), 6.88 (1H, d, J=8.6 Hz), 4.07 (5H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[CH2:32][CH2:31][CH2:30][CH:29]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([C:28]1[CH2:32][CH2:31][CH2:30][CH:29]=1)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CN(c2cc3cc(C4=CCCC4)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reaction time: 0.25 h
Yield: 13 %

Procedure:
In a microwave vial is added 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.100 g, 0.224 mmol), cyclopentene (0.04 mL, 0.453 mmol), palladium acetate (0.010 g, 0.0445 mmol), triethylamine (0.063 mL, 0.448 mmol) and acetonitrile (2 mL). The vial is capped and placed in the microwave for 15 min at 110° C. The reaction mixture is filtered over Celite and washed with acetonitrile. The filtrate is concentrated and the residue is purified via Biotage Sp1, eluting with 15-60% EtOH/H2O to afford 5-(3-benzyloxy-7-cyclopent-1-enyl-naphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.0127 g): (M−H)−=433.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20](Cl)=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20]([CH3:25])=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCCC1(C(=O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1
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: C1COCCO1
Product: CCCC1(C(=O)c2cc(Cl)c(C)s2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 3-(4,5-dichloro-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.512 mmoles), trimethylboroxine (0.24 g, 1.91 mmoles), potassium carbonate (0.22 g, 1.59 mmoles), and tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.051 mmoles) in dioxane (10 ml) was refluxed for three hours, then cooled to room temperature. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% ethyl acetate in hexane) to yield 3-(4-chloro-5-methyl-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a solid (0.166 g, 87%). M+Na: 394
Reaction SMILES: [CH2:1]([N:5]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:23]=[CH:22][C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:16]=2[C:17](O)=[O:18])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[N:58]([CH2:61][C@@H:62]1[CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][NH:63]1)=[N+:59]=[N-:60]>>[N:58]([CH2:61][C@@H:62]1[CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][N:63]1[C:17]([C:16]1[CH:20]=[C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:15]=1[N:10]1[C:11]([CH3:14])=[C:12]([Cl:13])[C:8]([C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=2)=[O:7])=[N:9]1)=[O:18])=[N+:59]=[N-:60]
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C)c1Cl
Yield: 77.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(3-(butyl(3,4-dichlorobenzyl)carbamoyl)-4-chloro-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy)naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 186B, 17 mg, 0.020 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate 92A, 15 mg, 0.079 mmol) were converted to the title compound (16 mg, 79%). MS(ESI+) m/z 1028.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:14]=[C:13](O)[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:3].O=P(Cl)(Cl)[Cl:20]>C(Cl)(Cl)Cl>[Cl:20][C:13]1[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)Cc1nc(O)c2c(n1)CCC(C)(C)C2
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1nc(Cl)c2c(n1)CCC(C)(C)C2
Temperature: 90 °C
Yield: 48 %

Procedure:
To a solution of the final residue from step 2 in CHCl3 (10 mL) was added POCl3 (10 mL). The reaction mixture was heated (90° C.) for two hours and concentrated. This residue was partitioned between dichloromethane and aqueous sodium bicarbonate and the resulting organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (5-10% concentrated aqueous ammonia in methanol) in chloroform provided 1-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)-N,N-dimethylmethanamine (1.3 g, 48% yield). 1H NMR (400 MHz, CD3OD) δ 4.52 (s, 2H), 3.02 (s, 6H), 2.98 (t, 2H), 2.61 (s, 2H), 1.71 (t, 2H), 1.06 (s, 6H); MS (ES) for C13H20ClN3: 254 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])[C:11]=1[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([NH:8][CH2:12][C:11]2[C:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[CH:17][C:10]=2[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1N
Reactant: COC(=O)Nc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Nc1cccc(C)c1CNc1cccnc1N
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of 2,3-diaminopyridine (1.09 g) in methanol (22 ml) was added 2-methyl-6-methoxycarbonylaminobenzyl chloride (2.14 g) and potassium carbonate (1.38 g) at room temperature and the mixture was stirred for 1.5 hours. The insoluble material was removed by filtration and methanol in the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (30 g) and eluted with a mixture of chloroform and methanol (100:1) to give a crystalline product. The crystals were triturated with diisopropyl ether to give 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)pyridine (1.44 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH3:30][CH:31]([OH:33])[CH3:32].CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:33][CH:31]([CH3:32])[CH3:30])[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1
Reactant: CC(C)O
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC(C)C)c34)cc2o1
Temperature: 70 °C
Yield: 101 %

Procedure:
6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), propan-2-ol (1.1 equiv), sodium tert-butoxide (1.1 equiv), and 1,4-dioxane (0.1 M) were combined and the resulting mixture was allowed to stir at 70° C. for several hours. The reaction was cooled and concentrated to an oil under reduced pressure that was purified by silica gel chromatography (0-30% ethyl acetate/hexane) to afford the title compound (101% yield) that was used without further purification. MS (ESI) m/z 473.3 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[CH3:6][S:7]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:9])=[O:8]
Reactant: OCCCCl
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C(O)CCCl
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.5 %

Procedure:
To 3-chloro-1-propanol (5.02 mL, 60 mmole) in CH3CN (200 mL) was added methanesulfonyl chloride (10.4 g, 90 mmole) and triethyl amine (13 mL, 90 mmole). The reaction mixture was stirred at room temperature for 12 hours under an argon atmosphere. 200 mL of saturated NaHCO3 (aq) was added and the stirring was continued for 15 minutes. The mixture was extracted several times with ether. The combined ether layers were dried over Na2SO4, the Na2SO4 was filtered and the filtrate was evaporated to give 10 g (96.6%) of the title compound: TLC (Rf: 0.3; 20% EtOAc/Hexane), 1H NMR (CDCl3) δ 2.2 (m, 2 H, CH2), 3.0 (s, 3 H, CH3), 3.6 (t, 2 H, CH2), 4.4 (t, 2 H, CH2). 13C NMR (CDCl3): δ 31.5 (CH2), 37.0 (CH3), 40.2 (CH2), 66.3 (CH2).
Reaction SMILES: [C:1]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>C(OC(=O)C)(=O)C>[C:1]([CH2:11][CH2:12][C:13]([O:15][C:13](=[O:14])[CH2:12][CH2:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C(CCC(=O)OC(=O)CCC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
To 179 grams of beta-carbobenzyloxypropionic acid (IV) there are added 500 ml of acetic anhydride and the solution is heated on a boiling water bath for 45 minutes. The excess reactant is distilled off and the residue is crystallized from one liter of carbon tetrachloride, the result being 140 grams (81% of theory) of (VI), which has a melting point of 70°C-71°C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
59 mg (0.33 mol) 4-fluoro-1H-indol-7-carboxylic acid, 101 mg (0.30 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 120 mg (81%) product as a colorless viscous oil. MS (ISP) 497.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:7]1[CH2:6][CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCCC(Br)C1=O
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-oxocyclohexanecarboxylate (50 g, 0.29 mol) in CHCl3 (150 mL) there was slowly added bromine (47 g, 0.29 mol) at 0° C. under a blanket of nitrogen as inert gas dropwise over a period of 45 minutes and the resultant mixture was stirred for a period of 6 hours at 0° C. and then for 16 hours at room temperature. Air was then passed into the reaction solution over a period of 2 hours. The organic phase was washed with aqueous saturated NaHCO3 solution (2×15 mL) and aqueous saturated NaCl solution (3×20 mL). Following drying of the organic phase over Na2SO4 and filtration, the solvent was removed. The product ethyl 3-bromo-2-oxocyclohexanecarboxylate was obtained in a yield of 72.6 g (corresponding to 99% of theory).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1[F:18])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:18])[CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(O)c(F)c1
Reaction time: 8 h
Yield: 93.6 %

Procedure:
10% Palladium-on-carbon (26 mg, 0.11 mmol) was added to a solution of 1-benzyloxy-4-ethoxy-2-fluoro-benzene (260 mg, 1.06 mmol) in ethyl acetate (20 mL). The reaction mixture was shaken under hydrogen (30 psi) overnight. The reaction mixture was filtered through celite and a pad of silica gel, which was washed with 40% ethyl acetate/hexane. The solvent was removed to give 4-ethoxy-2-fluoro-phenol (155 mg, 94%) as a white solid which was used directly in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, 3H, J=6.9 Hz), 3.89 (q, 2H, J=6.9 Hz), 6.52-6.56 (m, 1H), 6.71-6.85 (m, 2H), 9.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH3:26]
Reactant: COc1cc2nccc(Oc3ccc(I)cc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-iodobenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodophenyl}-1-propanol.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1.[Cl-].[Li+].CS([Cl:26])(=O)=O>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:26][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2cc(CO)no2)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(-c2cc(CCl)no2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
3-Hydroxymethyl-5-(3,4,5-trimethoxyphenyl)isoxazole (1.62 g) was dissolved in pyridine (10 mL), and lithium chloride (336 mg) was added to the solution. Methanesulfonyl chloride (908 mg) was added dropwise to the resultant mixture under ice cooling, and the mixture was stirred at room temperature for2 hours. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([NH2:12])=[C:10]([C:13]([O:15]C)=[O:14])[S:9][N:8]=2)[CH:2]=1.C(O)C.[OH-].[Na+].Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([NH2:12])=[C:10]([C:13]([OH:15])=[O:14])[S:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)c1snc(-c2cccnc2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(-c2cccnc2)nsc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 1.8 g. of methyl 3-(3-pyridyl)-4-amino-5-isothiazolecarboxylate in 20 ml. of ethanol and 20 ml. of water containing three pellets of sodium hydroxide was heated at reflux for ninety minutes. The reaction mixture was then added to 50 ml. of ice water, and the aqueous mixture was acidified by the addition of 1 N aqueous hydrochloric acid. The solid precipitate was collected by filtration and recrystallized from acetic acid and water to provide 3-(3-pyridyl)-4-amino-5-isothiazolecarboxylic acid. M.P. 235°-236° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]([CH3:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[CH3:38][N:27]([CH3:26])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: CN(C)c1ccc(CC(=O)Nc2cccc(-c3n[nH]c4ccc(C(N)=O)cc34)c2)cc1
Yield: 14.3 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(dimethylamino)phenyl acetic acid (0.13 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 33 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.15 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.35 (br s, 1H), 7.18 (m, 2H), 6.68 (d, 2H), 3.5 (s, 2H), 2.9 (s, 6H); ES-MS (m/z) 414 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].C[Si](Cl)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N>N1C=CC=CC=1>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH:18][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of nucleoside 61A (0.32 g, 1.15 mmol) in anhydrous pyridine (1 cm3) was added trimethylsilyl chloride (0.73 cm3, 5.73 mmol) and the mixture was stirred at room temperature for 20 min. Benzoyl chloride (0.67 cm3, 5.73 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and ice-cold water (15.0 cm3) was added. After stirring for 5 min, a 32% (w/w) aqueous solution of ammonia (1.5 cm3) was added and the mixture was stirred for 30 min. The mixture was evaporated to dryness and the residue was dissolved in water (25 cm3). After evaporation of the mixture under reduced pressure, the residue was purified by silica gel chromatography using dichloromethane/methanol (97:3, v/v) as eluent to give nucleoside 61B as a white solid material (0.55 g).
Reaction SMILES: [CH3:1][Si:2]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([CH3:8])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].C(C(CCCC)C[O:18][C:19](=O)[C:20]([C:33]#[N:34])=[C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH3:32])C>>[CH3:8][Si:2]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:19](=[O:18])[C:20]([C:33]#[N:34])=[C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH3:32])([CH3:1])[O:3][Si:4]([CH3:5])([CH3:7])[CH3:6]
Reactant: CCCCC(CC)COC(=O)C(C#N)=C1c2ccc(OC)cc2CC1C
Reactant: C[Si](C)(C)O[Si](C)(C)CCCCO
Product: COc1ccc2c(c1)CC(C)C2=C(C#N)C(=O)OCCCC[Si](C)(C)O[Si](C)(C)C
Yield: 30 %

Procedure:
The reaction of Example 2b was repeated using 4-(1,1,3,3,3-pentamethy-disiloxanyl)-butanol (see above) instead of 3-(1,1,3,3,3-pentamethy-disiloxanyl)-propanol as well as the above cyano-(2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-ylidene)acetic acid 2-ethyl-hexyl ester instead of the product of example 1. After 9 hours of reaction time, the product was concentrated and then treated for another 5 hours as set forth above with new 3-(1,1,3,3,3-pentamethy-disiloxanyl)-propanol. The mixture was then concentrated and chromatographed as before to yield 30% of a liquid material. UV 347 nm (ε=32′500). This product had the same solubility and photostability qualities as described in Example 2b.