Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][OH:27])[CH2:24][S:25][C@H:20]12)(=[O:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>ClCCl>[C:8]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][O:27][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:24][S:25][C@H:20]12)(=[O:17])[CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: O=C(O)C1=C(CO)CS[C@@H]2[C@H](NC(=O)C(O)c3ccccc3)C(=O)N12
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(O)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
In dichloromethane (40 ml) was dissolved 7β-mandelamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.65 g), followed by addition of succinic anhydride (1.50 g). The mixture was stirred at room temperature for 1 hour and a half. After the reaction had been completed, the mixture was treated as in Example 8 to obtain 7β-mandelamido-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (4.45 g).
Reaction SMILES: [CH:1]1[N:9]=[C:8](Br)[C:7]2[C:3](=[N:4][S:5][N:6]=2)[C:2]=1[Br:11].[CH2:12]([C:28]1([CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[C:51]2[CH:50]=[C:49]([Sn](CCCC)(CCCC)CCCC)[S:48][C:47]=2[C:30]2[S:31][C:32]([Sn:34]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:33][C:29]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>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.C1(C)C=CC=CC=1>[Br:11][C:2]1[C:3]2[C:7](=[N:6][S:5][N:4]=2)[C:8]([C:49]2[S:48][C:47]3[C:30]4[S:31][C:32]([Sn:34]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][C:29]=4[C:28]([CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:51]=3[CH:50]=2)=[N:9][CH:1]=1
Reactant: CCCCCCCCCCCCCCCCC1(CCCCCCCCCCCCCCCC)c2cc([Sn](CCCC)(CCCC)CCCC)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Reactant: Brc1cnc(Br)c2nsnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC1(CCCCCCCCCCCCCCCC)c2cc(-c3ncc(Br)c4nsnc34)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Temperature: 75 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
To a solution of 4,7-dibromo-pyridal[2,1,3]thiadiazole (0.28 g, 0.95 mmol) and 1b (1.14 g, 0.95 mmol) in freshly distilled toluene (10 ml) was added Pd(PPh3)4 (109.8 mg, 0.095 mmol) under nitrogen, and then capped with a rubber septum. The reaction mixture was stirred at 75° C. for 10 hours. The solvent was removed and purified by column chromatography (silica was pretreated by 10 v/v % triethylamine/hexane solution) with hexane as eluent. The column separation was run for 3 times to give 268 mg of viscous purple oil, with yield of 25%. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.92 (s, 1H), 8.49 (s, 1H), 7.39 (s, 1H), 2.21 (m, 4H), 1.77 (m, 6H), 1.54-1.25 (m, 68H), 1.12-1.01 (m, 15H). 13C NMR (125 MHz, CD2Cl2) δ (ppm): 163.10, 160.00, 156.32, 148.09, 147.92, 145.93, 144.00, 142.24, 141.83, 140.28, 129.79, 127.62, 106.17, 53.53, 37.86, 31.92, 29.97, 29.66, 29.63, 29.59, 29.54, 29.42, 29.39, 29.35, 29.32, 29.29, 29.02, 28.99, 27.21, 24.58, 22.69, 22.65, 13.88, 13.45, 10.96.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[C:17]([CH:20]=1)[CH:18]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:17]3[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[O:21][C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1Oc1ncccn1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1Oc1ncccn1
Temperature: 70 °C
Yield: 52.9 %

Procedure:
To a mixture of 6-chlorooxindole (1.1 g, 6.4 mmol) and 5-chloro-2-(pyrimidin-2-yloxy)-benzaldehyde (1.5 g, 6.4 mmol) in methanol (10 mL) was added pyrrolidine (0.5 mL, 6.4 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (1.3 g).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[C:9]([C:11](=[O:16])N(C)OC)[CH:8]=[CH:7][N:6]=1.S([O-])(O)(=O)=O.[K+]>C1COCC1.O>[Cl:4][C:5]1[CH:10]=[C:9]([C:11](=[O:16])[CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methylmagnesium bromide (30 mL of 3.0 M in THF) was added a solution of 2-chloro-4-(N-methyl-N-methoxycarbamoyl)pyridine (6.0 g, 0.03 mol) in 20 mL of THF at 0 C. The reaction mixture was stirred overnight while allowing to warm up to room temperature. A solution of potassium hydrogensulfate (12 g) in 300 mL of water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated 4.0 g (86%) of product as a yellow oil. This was used in next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])=[CH:4][CH:3]=1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]>>[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)=[O:8])[CH2:10][CH:11]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CN(C(=O)Nc2ccc(F)cc2)CCN1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)Nc3ccc(F)cc3)CC2C(=O)OCC)cc1
Yield: 70 %

Procedure:
In the same manner as described in Step 2 of Example 215, ethyl 4-[(4-fluoroanilino)carbonyl]-2-piperazinecarboxylate (0.41 g, 1.4 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride provided 0.49 g (70%) of ethyl 1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-fluoroanilino)carbonyl]-2-piperazinecarboxylate as a white powder. Electrospray Mass Spec 504.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Cl[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:14][CH2:13][CH2:12][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]#[N:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#CCc1ccccc1O
Reactant: ClCCCN1CCCC1
Product: N#CCc1ccccc1OCCCN1CCCC1
Yield: 58 %

Procedure:
The title compound was prepared from 2-hydroxy-benzeneacetonitrile (J. Org. Chem.; 66, 3435; 2001) and 1-(3-chloropropyl)pyrrolidine, using a method similar to that of preparation 104, as a pale brown gum in 58% yield. 1H NMR (400 MHz, CD3OD) δ: 7.33-7.25 (2H, m), 7.02-6.90 (2H, m), 4.12-4.09 (2H, m), 3.75 (2H, s), 2.76-2.72 (2H, m), 2.62-2.57 (4H, m), 2.09-2.02 (2H, m), 1.87-1.78 (4H, m); LRMS APCI m/z 245 [M+H]+
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li+].[OH-].O.Cl>O1CCCC1>[N:1]1([CH2:7][C:8]2[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoate (may be prepared as described in Description 49; 248 mg, 0.61 mmol) was dissolved in tetrahydrofuran (4 ml). LiOH (43.8 mg, 1.83 mmol) and water (1 ml) were added and the mixture heated at 40° C. for 2 hours. The mixture was cooled and 2M hydrochloric acid (0.96 ml, 1.91 mmol) was added and the solvent removed in vacuo to give the title compound. 240 mg.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[N:23]=[N:24][C:25]([N:28]([CH3:30])[NH2:29])=[CH:26][CH:27]=1>>[Cl:21][C:22]1[N:23]=[N:24][C:25]([N:28]([CH3:30])[NH:29][C:18]([C:8]2[CH:9]=[N:10][C:11]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:20])=[CH:26][CH:27]=1
Reactant: CN(N)c1ccc(Cl)nn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and 3-chloro-6-(1-methylhydrazinyl)-pyridazine (CAN 76953-33-8) as starting materials; MS (EI) 430.4 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[Na].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH:11]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[CH:11]1([CH2:16][N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: c1c[nH]cn1
Reactant: BrCC1CCCC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: c1cn(CC2CCCC2)cn1

Procedure:
A solution of sodium ethoxide was made by dissolving sodium (2.3 g, 0.1 mole) in absolute ethanol (100 ml). Imidazole (6.8 g, 0.1 mole) was then added. The mixture was heated under reflux and cyclopentylmethylbromide (16.3 g, 0.1 mole) was added dropwise. The reaction mixture was allowed to reflux for a further 16 hours after addition. The mixture was then left to cool.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[CH2:23][CH2:22]1)=[O:20]>C(#N)C>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[S:27]([N:24]1[CH2:23][CH2:22][N:21]([C:19](=[O:20])[CH2:18][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)(=[O:29])=[O:28]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A stirred solution of aniline (15.3 g, 0.16 mol) and di-isopropyl ethylamine (DIEA, 56 mL, 0.33 mol) in acetonitrile (120 mL) is heated to 60° C. and 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) is added dropwise. The reaction mixture is kept stirring at this temperature for another 3 h and is then evaporated to dryness. Water is added to the residue, and extracted with ethyl acetate (2×30 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resultant crude product was purified by column chromatography on silica gel (hexane:ethyl acetate:3:7) to obtain the title compound (300 mg, 76.53%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:21])[CH2:16][CH2:17][C:18]=3[O:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].I[CH2:31][CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:21])[CH:16]([CH2:31][CH:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH2:17][C:18]=3[O:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: ICC1CCOC1
Reactant: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)C(CC2CCOC2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-cyclopent-2-enone (285 mg, 0.89 mmol) in anhydrous tetrahydrofuran (6 ml) at −78° C. under an atmosphere of nitrogen is added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 0.55 ml, 1.0 mmol) dropwise over a period of 5 minutes and the reaction allowed to stir at −78° C. for 30 minutes. A solution of 3-iodomethyl tetrahydrofuran (212 mg, 1 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 5 minutes before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic later separated, dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-5-(tetrahydro-furan-3-ylmethyl)-cyclopent-2-enone (150 mg)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[C:5]([O:15][CH3:16])[CH:4]=1)[CH3:2].Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CCO.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1)[CH3:2]
Reactant: BrCc1ccccn1
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(OC)c1
Agent: Br
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(OC)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
To a solution of 5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 18a) (100 mg, 0.43 mmol) in EtOH (2 mL) was added 2-(bromomethyl)pyridine hydrobromide (129 mg, 0.51 mmol). The suspension was heated at 60° C. for 22 h. The reaction mixture was diluted with EtOAc and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 5% MeOH in DCM) to give 2-((5-(4-ethyl-2-methoxyphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine (95 mg) as a white powder (68%). 1H NMR (300 MHz, dMSO): δ 1.19-1.22 (t, 3H), 2.63-2.69 (dd, 2H), 3.93 (s, 3H), 4.48 (s, 2H), 6.93-7.03 (m, 2H), 7.25-7.29 (m, 1H), 7.49-7.5 (m, 1H), 7.71-7.75 (m, 1H), 7.93-7.95 (d, 1H), 8.50-8,51 (d, 1H), 13.65 (bs, 1H), MS (M+H, 327).
Reaction SMILES: [CH3:1][C:2]1([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][CH:6]([C:8]#[N:9])[C:5](=[O:10])[CH2:4][CH2:3]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[CH3:1][C:2]1([C:11]#[C:12][Si:13]([CH3:15])([CH3:14])[CH3:16])[CH2:3][CH2:4][C:5](=[O:10])[C:6]([C:8]#[N:9])=[CH:7]1
Reactant: CC1(C#C[Si](C)(C)C)CCC(=O)C(C#N)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CC1(C#C[Si](C)(C)C)C=C(C#N)C(=O)CC1
Yield: 152.1 %

Procedure:
A solution of 5-methyl-2-oxo-5-((trimethylsilyl)ethynyl)cyclohexane-carbonitrile (270 mg) and DDQ (350 mg) in benzene (20 mL) was heated under reflux for 10 min. After removal of insoluble matter, the filtrate was concentrated in vacuo to give a residue (407 mg). The residue was purified by flash chromatography [hexanes-ethyl acetate (4:1)] to give 10 as a crystalline solid (142 mg, 78%): 1H NMR (acetone-d6) δ 7.71 (1H, d, J=1.5 Hz), 2.72 (1H, m), 2.62 (1H, m), 2.21 (2H, m), 1.55 (3H, s), 0.15 (9H, s); 13C NMR (acetone-d6) δ 192.0, 164.8, 116.4, 114.8, 106.5, 88.7, 35.9, 35.0, 0.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccc(Cl)cc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccc(Cl)cc4Cl)c3O2)cc1
Yield: 99.6 %

Procedure:
Treatment of ((2R)-8-(2,4-dichlorophenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.35 g, 0.73 mmol) with platinum (IV) oxide (84% Pt, 0.14 g) in ethanol (20 mL) and ethyl acetate (5 mL) according to the procedure described for Example 69, Step 8 provided 0.35 g (100%) of ((2R)-8-(2.4-dichlorophenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate as a light brown oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[N+:17]([O-:19])=[O:18])(=O)=O.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][NH2:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[C:22]([O:26][C:27](=[O:28])[NH:29][CH2:30][CH2:31][NH:32][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[N+:17]([O-:19])=[O:18])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2c1[N+](=O)[O-]
Yield: 90.5 %

Procedure:
1-Nitro-2-naphthyl trifluoromethanesulfonate (1.61 g, 5 mmol), N-(tert-butoxycarbonyl)ethylenediamine (0.80 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol), and toluene (20 mL) were mixed, and the mixture was refluxed by heating for 16 hours. This reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give yellow crystals, and the crystals were washed twice with hexane (20 mL) to obtain the title compound (1.50 g, yield 91%) as yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:18]([OH:20])=[O:19])=[CH:6][CH:7]=2.[OH:21]O>S(=O)(=O)(O)O>[O:21]=[C:2]1[O:1][C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([C:18]([OH:20])=[O:19])=[CH:4][C:3]1=2
Reactant: OO
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1cc(C(=O)O)ccc1-2
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)oc(=O)c1cc(C(=O)O)ccc12
Temperature: 0 °C

Procedure:
A suspension of 12.0 g (0.045 mole) of 9-oxo-fluorene-2,7-dicarboxylic acid in 100 ml of concentrated sulfuric acid is slowly reacted with 12.0 ml of a 30% hydrogen peroxide solution. The reaction is strongly exothermic and is controlled by cooling the stirred reaction mixture in a water bath. The cooled reaction mixture is poured onto 500 ml of an ice water mixture, filtered and washed with water. The residue is resuspended in water, stirred, filtered and washed with a total of about 350 ml of deionized water, to yield 11.2 g of 6-oxo-6H-dibenzo[b,d]pyran-3,8-dicarboxylic acid having a m.p. greater than 300°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH2:27])(=[O:26])=[O:25])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CO>[NH2:27][S:24]([NH:23][CH2:22][CH2:21][NH:20][C:16]1[C:15]([C:10](=[N:11][OH:12])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[N:19][O:18][N:17]=1)(=[O:25])=[O:26]
Reactant: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A solution of N-[2-({4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide (3.7 g, 8.8 mmol) in methanol (70 mL) was treated with 2 M NaOH (18 mL, 35 mmol) and stirred at 25° C. for 2 h. The reaction mixture was quenched with 6 N HCl to pH-7 and the methanol was removed under reduced pressure. The solid that precipitated was filtered and washed with water to give the desired product (3.2 g, 92%) as a white solid. LCMS for C11H14ClFN7O4S (M+H)+: m/z=394.0. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (dd, J=6.8, 2.1 Hz, 0.05H), 7.32-7.29 (m, 0.1H), 7.18 (dd, J=9.1, 9.1 Hz, 0.95H), 6.93 (dd, J=6.4, 2.7 Hz, 0.95H), 6.71-6.66 (m, 0.95H), 6.33 (br s, 1H), 3.35-3.27 (m, 2H), 3.10-3.06 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[N:41]=[C:40]1[CH3:48]>CN(C1C=CN=CC=1)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][N:26]([S:44]([C:42]3[N:41]=[C:40]([CH3:48])[N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH2:25][CH2:24]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCNCC4)c3c2)c1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)c5cn(C)c(C)n5)CC4)c3c2)c1
Yield: 26.7 %

Procedure:
Following the general procedure of Example 11, 5-[3-(acetylamino)phenyl]-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Example 69) (0.07 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (10 mg, 27% for 3 steps).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.[N+:16]([O-])([O-:18])=[O:17].[K+].Cl>CCO>[N+:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7][CH2:6]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sulfuric acid (9.90 mL, 0.186 mol) was cooled to 0° C. To the cooled solution was added 1,2,3,4-Tetrahydroisoquinoline (2.5 mL, 020.0 mmol) dropwise via syringe. Potassium nitrate (2.16 g, 0.0214 mol) was then added in small portions over 4 min. The cooling bath was removed and the mixture was allowed to stir at rt for 12 h. Ice was added to the slurry and the mixture basified with NH4OH (precipitate formed). The solution was extracted with chloroform, dried over Na2SO4, filtered, and concentrated to give a brown oil. The oil was dissolved in ethanol (14.8 mL, 0.254 mol) and to this solution was added HCl (2.47 mL, 0.0808 mol). Additional EtOH was added to transfer the precipitated solid for filtration. The white solid was dried under vacuum to yield the desired product without further purification (2.19 g, 51%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[O:11][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[O:11][CH:12]=1
Reactant: COC(=O)CCCCc1coc(-c2ccccc2OC)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCCc1coc(-c2ccccc2O)n1
Yield: 48.4 %

Procedure:
Using a method similar to that described in Example 165, 5-[2-(2-methoxy-phenyl)-oxazol-4-yl]-pentanoic acid methyl ester (1.65 g, 5.7 mmol) with boron tribromide (1.0 M in CH2Cl2, 17.2 mL) in CH2Cl2 gives 5-[2-(2-hydroxy-phenyl)-oxazol-4-yl]-pentanoic acid methyl ester (0.76 g, 48%). MS (ES): (M+1)+ 276.1, 277.2 m/z.