Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:11]([C:12](=[N:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([OH:15])=O)=[CH:10][S:9][CH2:8][CH2:7]1.[NH2:24][CH:25]1[C:42](=[O:43])[N:27]2[C:28]([C:39]([OH:41])=[O:40])=[C:29]([CH2:32][S:33][C:34]3[S:35][CH:36]=[N:37][N:38]=3)[CH2:30][S:31][C@H:26]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[O:6]1[C:11]([C:12](=[N:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([NH:24][CH:25]2[C:42](=[O:43])[N:27]3[C:28]([C:39]([OH:41])=[O:40])=[C:29]([CH2:32][S:33][C:34]4[S:35][CH:36]=[N:37][N:38]=4)[CH2:30][S:31][C@H:26]23)=[O:15])=[CH:10][S:9][CH2:8][CH2:7]1
Reactant: CCCCCCON=C(C(=O)O)C1=CSCCO1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSCCO1
Yield: 77.6 %

Procedure:
Phosphoryl chloride (1.214 g.), N,N-dimethylformamide (0.579 g.) and ethyl acetate (3 ml.) were treated in a conventional manner to give a Vilmeier reagent. To the solution were added ethyl acetate (7 ml.) and 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 2.18 g.) and treated in a similar manner to that of Example 24 to give an activated acid solution. The solution was added to a solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.18 g.) and trimethylsilylacetamide (6.93 g.) in ethyl acetate (50 ml.), and the mixture was treated in a similar manner to that of Example 24 to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.00 g.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][CH:14]1[C:16]([CH3:18])([CH3:17])[C:15]1([CH3:20])[CH3:19].C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][CH:14]2[C:15]([CH3:19])([CH3:20])[C:16]2([CH3:18])[CH3:17])[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1C(C)(C)C1(C)C
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCC2C(C)(C)C2(C)C)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A mixture of 0.34 g of 2,5-dimethyl-4-nitro-1-[(2,2,3,3-tetramethylcyclopropyl)methoxy]benzene, 0.34 g of iron powder, 5 mL of acetic acid and 5 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.24 g of 2,5-dimethyl-4-[(2,2,3,3-tetramethylcyclopropyl)methoxy]phenylamine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(Br)cc1

Procedure:
Into a 250-mL round-bottom flask were placed a solution of 4-bromoaniline (17.1 g, 99.42 mmol) and triethylamine (30 g, 297 mmol) in dichloromethane (100 mL). Then, 2-phenylacetyl chloride (18.6 g, 120 mmol) was added dropwise with stirring, and the resulting solution was stirred at room temperature for 6 hours. The solids were filtered out, and the filtrate was concentrated under vacuum. The crude product was purified by re-crystallization from ethyl acetate to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20]CC=C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CCCC)C([O-])=O)C.[Na+].C1(N)CCCCC1>ClCCl.C(OCC)(=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>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: NC1CCCCC1
Product: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of 100 mg (0.316 mmol) of (2S,5R)-allyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate in dichloromethane (2 mL) were added a solution of 0.5M sodium 2-ethylhexanoate in ethyl acetate (1 mL) and 12 mg of tetrakis(triphenylphosphine)palladium(0), followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, followed by liquid separation with saturated aqueous sodium dihydrogen phosphate solution, the aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The residue resulting from concentration of the solvent under reduced pressure was dissolved in ethyl acetate, followed by addition of cyclohexylamine (33 mg), and the deposited solid was filtered off, and washed with ether. The resulting solid was dissolved in saturated aqueous sodium dihydrogen phosphate solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Subsequently, the solvent was concentrated under reduced pressure to afford 68 mg of the title compound as a colorless foamy solid (yield 75%). Instrumental data were consistent with those of the compound of Example 9.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH2:22][CH2:21][CH2:20][C:19]=3[CH2:23][C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31]CC)=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2N=C(C3C(CC4C=C(C=CC=4)OCC(OCC)=O)CCC=3)OC=2C2C=CC=CC=2)C=CC=CC=1.C1(C2N=C(C3CCCC3CC3C=C(C=CC=3)OCC(OCC)=O)OC=2C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+:110]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O-:31])=[O:30])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:110]
Reactant: CCOC(=O)COc1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Agent: [Pd]
Agent: CCOC(=O)COc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCOC(=O)COc1cccc(CC2CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C([O-])COc1cccc(CC2CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 6 h

Procedure:
To a solution of a mixture (400 mg) of ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-1-cyclopenten-1-yl}methyl]-phenoxy]acetate and ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl}methyl]phenoxy]acetate in a mixture of ethanol (10 ml) and ethyl acetate (10 ml) was added 10% palladium on carbon (50 mg). After being stirred for 6 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated in vacuo to give a residue containing a mixture of ethyl [3-[{(1RS,2RS)-2-(4,5-diphenyloxazol-2-yl)cyclopentan-1-yl}methyl]phenoxy]acetate and ethyl [3-[{(1RS,2SR)-2-(4,5-diphenyloxazol-2-yl)cyclopentan-1-yl}methyl]phenoxy]acetate. The residue was dissolved in ethanol (20 ml), and 1N-sodium hydroxide solution (0.80 ml) was added. After being stirred for 8 hours, the solvent was evaporated in vacuo. The residue was triturated in ether to give a mixture (350 mg) of sodium [3-[{(1RS,2RS)-2-(4,5-diphenyloxazol-2-yl)cyclopentan-1-yl}methyl]phenoxy]acetate and sodium [3-[{(1RS,2SR)-2-(4,5-diphenyloxazol-2-yl)cyclopentan-1-yl}methyl]phenoxy]acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C(O)C.O>[F:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([C:8]3([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:28]=[N:27][CH:26]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2ccccc21
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cncc(F)c3)c2)c2ccccc21
Yield: 53.9 %

Procedure:
A mixture of 1-(3-bromophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #9, C) (0.073 g, 0.20 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.067 g, 0.30 mmol), potassium carbonate (0.055 g, 0.40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (0.020 g, 0.025 mmol), dimethoxyethane (2 mL), water (1 mL) and ethanol (0.3 mL) under an argon atmosphere was irradiated in a microwave at 100° C. for 15 min. The reaction mixture was filtered and partitioned between water and ethyl acetate, the organic phase was concentrated and the residue was purified by preparative HPLC, which gave the title compound (0.041 g, 54%). 1H NMR (DMSO-d6) δ 8.67-8.63 (m, 1 H), 8.57 (d, J=2.78 Hz, 1 H), 8.49-8.42 (m, 2 H), 7.99-7.90 (m, 2 H), 7.85-7.79 (m, 1 H), 7.67-7.62 (m, 2 H), 7.55-7.41 (m, 4 H), 7.37-7.28 (m, 2 H), 6.95 (br s, 2 H), 1.91 (s, 2.2 H); MS (ESI) m/z 381 [M+1]+.
Reaction SMILES: S1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.O[O:9][S:10]([O-:12])=O.[K+].C([O-])(O)=O.[Na+]>CC#N.O>[O:9]=[S:10]1(=[O:12])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: O=C1CCSCC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tetrahydrothiopyran-4-one in CH3CN (50 mL) and H2O (35 mL) at 0° C. was added in portions over 1 hour a mixture of oxone (70.5 g, 115 mmol) and NaHCO3 (29.9 g, 356 mmol). The reaction mixture was then stirred at room temperature for 1 h, diluted in CH3CN (250 mL) and filtered. The filtrate was concentrated, suspended in acetone and filtered. 1,1-Dioxo-tetrahydrothiopyran-4-one (6.3 g, quantitative yield) was obtained as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:9][S:10]SC.CS>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH3:9][S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: Oc1ccccc1
Reactant: CSSC
Agent: [Zr+4]
Agent: CS
Agent: Cl
Product: CSc1ccccc1O
Temperature: 150 °C
Yield: 38.7 %

Procedure:
Zirconium tetrachloride (23.4 g, 0.1 mole) was added to phenol (141.2 g, 1.5 moles). The mixture was slowly heated to 150° C. under nitrogen and maintained at this temperature for 12 hours during which HCl was allowed to escape. The mixture was cooled to ca. 100° C. and methyl disulfide (94.2 g, 1 mole) was added. The mixture was heated under nitrogen for 15 hours during which temperature was increased slowly to 159° C. Methyl mercaptan was allowed to escape continuously. Distillation of the mixture at 1.4 mm mercury to a maximum head temperature of 113° C. yielded 125.6 g of distillate. GC analysis indicated the distillate contained 59.1 g of phenol (42% recovered) and 54.2 g of ortho-(methylthio)phenol (39% yield). The unreacted phenol was removed from the distillate by fractional distillation through a 12 cm glass helices packed column. The remaining material was fractionally distilled through a 5 inch Vigreux column yielding a main fraction of 99.6% pure ortho-(methylthio)phenol distillating at 112°-114° C. at 30 mm mercury.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[N:9]=1>C(Cl)Cl>[F:22][C:7]([F:6])([F:21])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[C:14]([CH3:20])=[CH:15][C:16]([CH3:19])=[C:17]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:18]=2)[N:9]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 5 g of chlorosulphonic acid are introduced and are admixed at room temperature, in portions, with 3.6 g of 3-(trifluoromethyl)-1-(2,4-dimethylphenyl)-1H-1,2,4-triazole. The exothermic reaction raises the temperature of the mixture to around 45° C. The mixture is subsequently stirred at 70° C. for 3 hours and then cooled, and diluted with 20 ml of methylene chloride. The mixture is added with stirring to ice and then the phases are separated and washed with twice 20 ml of methylene chloride. The combined organic phases are concentrated on a rotary evaporator and then chromatographed (CH2Cl2). This gives 3.8 g of solid (76% of theory). This solid is reacted further directly.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[C:12](=O)[CH:13]([CH3:15])[CH2:14][C:3]=12.[BH4-].[Na+].O.Cl>C1COCC1.CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[CH:12]=[C:13]([CH3:15])[CH2:14][C:3]=12
Reactant: CC1Cc2c(cc3c(c2Br)CCCC3)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC1=Cc2cc3c(c(Br)c2C1)CCCC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 18.2 g (65.3 mmol) of 4-bromo-2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-1-one in 100 ml of THF-methanol (2:1, vol.), 3.47 g (91.3 mmol) of NaBH4 was added, while vigorously stirring, over 1 h at 0° C. This mixture was stirred overnight at room temperature and then added to 300 ml of cold water and acidified with 1 M HCl to pH 1. The organic layer was separated, and the aqueous layer was extracted with 2×100 ml of methyl-tert-butyl ether. The combined extract was dried over K2CO3 and evaporated to dryness, and 300 ml of toluene was added to the yellowish oil obtained. This toluene solution was treated with a catalytic amount of pTolSO3H (ca. 0.5 g) for 15 h at reflux, cooled to room temperature, and evaporated to dryness. The crude product was purified using flash chromatography on Silica Gel 60 (40-63 μm, d 70 mm, l 150 mm; eluent: hexanes). Yield 14.1 g (82%) of white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(C)[CH2:9][C:10]2C=CC=C[CH:11]=2)=[CH:4][CH:3]=1.O[C:25]1[CH:30]=CC(C(C2C=CC(O)=CC=2)(CC)C)=C[CH:26]=1>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)([CH2:26][CH2:25][CH3:30])[CH2:9][CH2:10][CH3:11])=[CH:22][CH:21]=1
Reactant: CC(Cc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CCCC(CCC)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
2,2-bis(4-hydroxyphenyl)-1-phenylpropane; 2,2-bis(4-hydroxyphenyl)butane;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>>[F:12][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:18]([C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)=[O:19])[S:3][C:4]=2[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1nc2c(F)cc(F)cc2s1
Product: O=C(Nc1nc2c(F)cc(F)cc2s1)c1ccco1

Procedure:
Using 2-amino-4,6-difluoro-benzothiazole and furan-2-carboxylicacid chloride the title compound was prepared as a grey solid (81% yield), MS: m/e=280 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.N1CCCCC1.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].Cl>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:21]([OH:23])=[O:22]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(OC)c(/C=C/C(=O)O)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
2,5-Dimethoxybenzaldehyde (1.7 g) was dissolved in pyridine (10 ml). Piperidine (0.2 ml) and malonic acid (2.0 g) were added to the solution. The solution was stirred for 1 hour at 85° C. and then for 3 hr. at 110° C. The solution was cooled. Water (80 ml) was added to the solution. Conc. hydrochloric acid was added to the solution until pH of the solution was down to about 2. The crystals were deposited. The crystals were separated from the solution by filtration, washed with water and dried to give the title compound (1.97 g) having the following physical data.
Reaction SMILES: C(OC[O:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:36])[N:10]([CH3:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([C:31]4([CH3:34])[CH2:33][CH2:32]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1)C.Cl.C(=O)([O-])O.[Na+]>C1COCC1.CO.O>[OH:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:36])[N:10]([CH3:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([C:31]4([CH3:34])[CH2:33][CH2:32]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4(C)CC4)CC3C=CCCCCN(C)C(=O)C2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)C2CC(O)CC2C1=O
Reaction time: 6.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of the cyclopropylmethyl derivative (119) (0.38 g, 0.72 mmol) in 1:1:1 THF-methanol-H2O (6 ml) was added conc. hydrochloric acid (0.89 ml), then stirred at r for 6.5 h. The reaction mixture was then neutralized using sodium hydrogen carbonate (approx. 0.9 g solid) and concentrated into approx. half the volume. The residue was partitioned between aq. 10% citric acid (40 ml) and dichloromethane (10 ml). The water layer was washed with dichloromethane (3×10 ml), and the combined organic layers were dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using stepwise gradient elution (methanol in ethyl acetate 5-10%) gave after concentration of the appropriate fractions the title compound as a colorless foam (0.315 g, 93%). LR-MS: Calcd for C22H34N3O6S: 468. Found: 468 [M+H].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].O>[N:11]1([C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccc(-n2ccnc2)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 1 -iodo-3-nitrobenzene (90g, 0.36mol), imidazole (54g, 0.79mol), potassium carbonate (54g, 0.39mol) and finely divided copper powder (1 g) is heated to 200° C. The melt is stirred for 2 hours under nitrogen. During the reaction water vapor is trapped by molecular sieves, placed between the reaction vessel and the condenser. Following the reaction the mixture is cooled to 100° C. and water is added. The mixture is allowed to cool to room temperature and the crude product is filtered off and dried. Recrystallization from toluene (200-250ml) affords pure 3-(1-imidazolyl)nitrobenzene (54.2g, 79%). Mp 101-102° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:24][C:23]([CH2:25][N:26]3[CH2:35][C:30]4([CH2:34][CH2:33][CH2:32][CH2:31]4)[O:29][CH2:28][CH2:27]3)=[N:22][N:21]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[CH:47][NH:48]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH:48]1[C:49]2[C:45](=[C:44]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([C:20]4[O:24][C:23]([CH2:25][N:26]5[CH2:35][C:30]6([CH2:31][CH2:32][CH2:33][CH2:34]6)[O:29][CH2:28][CH2:27]5)=[N:22][N:21]=4)[CH:3]=3)[CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:47]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCOC5(CCCC5)C4)o3)cc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: c1cc(-c2cc(-c3nnc(CN4CCOC5(CCCC5)C4)o3)c3cn[nH]c3c2)c2cc[nH]c2c1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
To a solution of 9-({5-[6-bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)-6-oxa-9-azaspiro[4.5]decane (100 mg, 0.179 mmol) in 1,4 dioxane (2.5 ml) and water (0.25 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (56.6 mg, 0.233 mmol, available from Frontier Scientific Europe), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (26.2 mg, 0.036 mmol) and potassium phosphate tribasic (114 mg, 0.537 mmol). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fractions were blown down under a stream of nitrogen to give a yellow solid. The solid was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 3 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the residue was freeze dried from 1,4-dioxane/water (1:1, 2 ml) overnight to give the title compound as a cream solid (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[CH3:11].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>C(Cl)Cl>[CH3:11][C:5]1[CH:6]=[C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1C
Temperature: 110 °C
Yield: 37.8 %

Procedure:
In a cylindrical quartz tube were placed 4-fluoro-2-methyl-benzoic acid methyl ester (1.2 g, 7.14 mmol), N-methylpiperazine (0.95 ml, 8.5 mmol), K2CO3 (990 mg, 7.14 mmol) and DMSO (4 ml). The reaction was heated for 20 hours at 110° C. until HPLC revealed the disappearance of the starting-material. DCM (15 ml) was added and the solution was washed twice with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (DCM/MeOH 95:5) affording the desired compound (670 mg, 38%).