Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][C:60]([F:64])([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 38.7 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (120.0 mg, 0.310 mmol) in tetrahydrofuran (3.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (156.4 mg, 0.620 mmol) and tributylphosphine (154.5 μL, 0.620 mmol). After 10 min, to the mixture was added 2,2,2-trifluoroethanol (225.9 μL, 3.100 mmol). The reaction mixture was stirred at 60° C. for 5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (56.5 mg, 0.120 mmol, 39%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:18]=[CH:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:7]=1.C(O)(=O)C.CCOCC.[BrH:28]>OS(O)(=O)=O.C(Cl)Cl.CCCCCC>[Br:28][C:18]1[CH:6]=[CH:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[CH:17]=1
Reactant: Br
Reactant: Nc1ccc2oc3ccccc3c2c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
NaNO2 (2.21 g, 32.05 mmol) was dissolved in 20 mL conc. H2SO4 in conical flask kept at 0° C. Solution of 2-aminodibenzofuran (5.3 g, 28.9 mmol) in minimum volume of glacial acetic acid was then slowly added to the flask so that temperature never raised above 5-8° C. and the mixture was stirred at 0° C. for another 1.5 h. 100 mL ether was added to the stirred mixture and precipitate of corresponding diazo salt immediately settled down. Brown color diazo salt was immediately filtered out and transferred to a flask containing CuBr (6.25 g, 43.5 mmol) in 150 mL 48% HBr. The flask was then placed in a water bath maintained at 64° C. and stirred for 2 h. After cooling down to room temperature, the dark color reaction content was filtered out and the precipitate was washed with water twice. Isolated solid was then flashed over Silica gel column with 5-10% DCM/Hexane to give 4.79 g final compound.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O-]S([O-])(=O)=O.[Mg+2].[Si:31]([O:38][CH2:39][CH:40]=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C(Cl)Cl>[C:34]([Si:31]([CH3:33])([CH3:32])[O:38][CH2:39][CH:40]=[N:7][S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)(C)[S@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-(+)-2-methyl-2-propanesulfinamide (8.70 g, 71.8 mmol), pyridinium p-toluenesulfonate (0.902 g, 3.59 mmol) and MgSO4 (43.2 g, 359 mmol) was suspended in methylene chloride (25 mL). A solution of (tert-butyldimethylsilyloxy)acetaldehyde (25.0 g, 144 mmol) dissolved in methylene chloride (10 mL) was added drop wise at room temperature. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness. Flash chromatography (silica, EtOAc/heptanes 1:4) gave the title compound as an oil that slowly solidified upon standing (18.3 g, 92%) sufficiently pure for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O.[Fe]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C(=O)OC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 2000 mL 3-necked round-bottom flask, was placed a solution of 6-nitroisobenzofuran-1(3H)-one (prepared as described in the previous step, 136 g, 759.78 mmol, 1.00 equiv) in water (50 mL), Fe (126.4 g), ethyl acetate (500 mL), acetic acid (180 mL). The reaction mixture was stirred for 2 h at 60° C. in an oil bath. The resulting mixture was added sodium bicarbonate 500 mL. The resulting solution was extracted with 5×500 mL of ethyl acetate. The combined organic layer was washed with 500 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.Cl.[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Product: Cc1ccn(-c2cccc(Br)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-bromophenyl hydrazine.HCl substituted for phenyl hydrazine. There was obtained 1-(3-bromophenyl)-3-methyl-1H-pyrazole-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide; HRMS(M+H)+ calc. 511.043949; found: 511.043295.
Reaction SMILES: C([Li])CCC.C[CH2:7][O:8]CC.[C:11]([Si:15]([O:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([Si:15]([CH3:17])([CH3:16])[O:18][CH:19]1[C:28]2[C:23](=[C:24]([CH:7]=[O:8])[CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)OC1CCOc2ccccc21
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCOc2c(C=O)cccc21
Temperature: 3 °C
Reaction time: 15 h

Procedure:
Butyllithium was added to an Et2O (80 mL) solution of tert-butyl-(chroman-4-yloxy)-dimethyl-silane (6.21 g, 23.5 mmol) at −80° C. After stirring the mixture at 3° C. for 15 h, DMF (10 mL) was added at 0° C. Following a 30 min stirring at RT, the reaction was quenched with saturated NH4Cl solution. The reaction was diluted with Et2O (200 mL) and washed with brine. The organic phase was dried over MgSO41 filtered, and concentrated in vacuo to provide the crude compound (40% conversion by 1H NMR) which was purified by column chromatography (silica, 0 to 10% ether in hexane) to provide the title compound.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([O:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), N-(4-hydroxyphenyl)acetamide (85 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, and washed with H2O. The precipitate was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 81 (48 mg, 74% yield) as a tan solid. LC-MS (M+H=346, obsd.=346). 1H NMR (400 MHz, d6-DMSO): δ 11.92 (s, 1H), 10.04 (s, 1H), 8.69 (dd, 1H), 8.50 (dd, 1H), 8.30 (d, 1H), 8.05 (d, 1H), 7.68 (m, 2H), 7.29 (dd, 1H), 7.16 (m, 3H), 2.08 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[C:20]1([CH2:19][CH2:18][CH2:17][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
There was dissolved 3.574 g of p-cyanophenol in 30 ml of N,N-dimethylformamide, followed by addition of 4.364 g of a 90% potassium t-butoxide and stirring at room temperature for 30 minutes. Then 6.570 g of 1-bromo-3-phenylpropane was dropwise added to the solution and the mixture was stirred for 20 hours. The reaction solution was added to ice water, the resulting precipitates were filtered off, washed with water and recrystallized from a mixture of ethanol and n-hexane to give 5.176 g (yield 72.7%) of 4-(3-phenylpropoxy)benzonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[CH:13]=[C:14]([C:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[CH:13]=[C:14]([C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([CH3:28])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Yield: 86.4 %

Procedure:
4-[1-(6-Benzyloxy-benzofuran-2-yl)-1-ethyl-propyl]-2-methyl-phenol (5.50 g, 13.7 mmol) and 1-bromopinacolone (4.92 g, 27.5 mmol) and K2CO3 (3.80 g, 27.5 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (5.90 g, 86%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])(=O)C.[NH4+:17]>C(O)C>[NH2:17][CH:4]([CH2:3][CH:2]([CH3:12])[CH3:1])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)CC(C)C
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)CC(N)CC(C)C
Temperature: 80 °C
Reaction time: 15 h
Yield: 34.8 %

Procedure:
Ru(OCOCH3)2((R)-dm-binap)(5.5 mg, 0.058 mmol), ethyl 5-methyl-3-oxo-hexanoate (500 mg, 2.903 mmol), ammonium acetate (224 mg, 2.903 mmol) and ethanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo and the residue was purified by column chromatography on silica gel (eluent:hexane ethyl acetate/triethylamine=50/50/5) to give ethyl (−)-3-amino-5-methylhexanoate (175 mg) as a colorless oil in 35.0% yield. The resulting ethyl (−)-3-amino-5-methylhexanoate was converted into ethyl 3-(4-nitrobenzoylamino)-5-methylhexanoate, and the enantiomeric excess of the product was found to be 97.3% ee by HPLC analysis using a CHIRALCEL OD-H column.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][S-:15].[Na+].Cl>CO>[CH3:14][S:15][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[S-]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])cc1C(=O)O
Reaction time: 24 h

Procedure:
Combine 2-fluoro-5-nitrobenzoic acid (prepared by the method of Tetrahedron, 23, 4041-4045 (1967)) (3.7 g, 20 mmol) and sodium thiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux. After 24 hours, cool the reaction mixture, adjust the pH to about 2 using aqueous 1 M hydrochloric acid solution. Extract the reaction mixture with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic acid: Rf=0.5 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [Cl-:1].[NH4+:2].CO[C:5]1[CH2:6][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:8][N:9]=1>C(O)C>[Cl-:1].[CH2:10]([CH:7]1[CH2:8][NH:9][C:5](=[NH2+:2])[CH2:6]1)[CH2:11][CH3:12]
Reactant: [NH4+]
Reactant: CCCC1CN=C(OC)C1
Agent: [Cl-]
Solvent: CCO
Product: CCCC1CNC(=[NH2+])C1
Yield: 76.7 %

Procedure:
Ammonium chloride (110 mg, 2.06 mmol) was added to a solution of 5-methoxy-3-propyl-3,4-dihydro-2H-pyrrole (306 mg, 2.17 mmol) in ethanol (12 ml) and the mixture was heated to reflux for 4 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure to yield a crude product of the title compound (257 mg) as a white solid. 1H-NMR (DMSO-d6) δ(ppm) 0.86 (3H, t, J=7.2 Hz), 1.12-1.52 (4H, m), 2.34-2.60 (1H and DMSO, m), 2.78-2.93 (1H, m), 3.05-3.22 (2H, m), 3.54-3.70 (1H, m)
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]1[C:33]2([CH2:36][NH:35][CH2:34]2)[CH2:32][N:31]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:35]5[CH2:34][C:33]6([CH2:30][N:31]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:32]6)[CH2:36]5)=[O:22])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5(CN(C(=O)OC(C)(C)C)C5)C4)cn3)nc2n1C1CCCC1
Yield: 74 %

Procedure:
Following amide formation method 1, 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (199 mg, 0.5 mmol, 1.0 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.5 mmol, 1.0 eq) were combined and gave tert-butyl 6-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (214 mg, 0.37 mmol) in 74% yield. 1H NMR (400 MHz, chloroform-d) δ ppm 8.79 (s, 1H) 8.53-8.66 (m, 2H) 8.08 (dd, J=8.84, 2.27 Hz, 1H) 6.53 (s, 1H) 4.74-4.92 (m, 1H) 4.20-4.61 (m, 4H) 4.07-4.16 (m, 4H) 3.18 (br s, 6H) 2.47-2.65 (m, 2H) 2.03-2.20 (m, 4H) 1.68-1.85 (m, 3H) 1.46 (s, 9H). MS (m/z, MH+): 575.6
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]=[C:13](SC)[NH2:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:17](N)[CH2:18][NH2:19]>CO>[IH:1].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]=[C:13]2[NH:14][CH2:17][CH2:18][NH:19]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: CSC(N)=NC(=O)Nc1cccc(Cl)c1
Agent: I
Solvent: CO
Product: O=C(N=C1NCCN1)Nc1cccc(Cl)c1

Procedure:
To 37.1 grams (0.1 mole) of methyl N'-{[(3-chlorophenyl)amino]carbonyl}-carbamimidothioate hydroiodide thus prepared is added 6.0 grams (0.1 mole) of ethylenediamine in 100 milliliters of methanol and the resulting mixture allowed to heat under reflux for five hours. The resulting reaction mixture is evaporated to dryness in vacuo and diluted with tertiary-butyl alcohol to obtain crystals of N-(3-chlorophenyl)-N'-(2-imidazolidinylidene) urea hydroiodide product as a crystalline solid. The crystals are recrystallized from tertiary butyl alcohol several times to obtain a purified product, m.p. 192°-194° C. (dec.).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:31][C:9]1[C:8]2[N:18]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)c1ccccc1

Procedure:
To a vigorously stirred mixture of the 4-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one from the previous step in dichloromethane (49 mL) and ammonium hydroxide (16 mL) was added p-toluenesulfonyl chloride (2.34 g, 12.3 mmol) portionwise over several minutes. After 15 minutes the reaction mixture was diluted with chloroform (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The layers were separated and the organic phase was washed again with a saturated aqueous sodium bicarbonate solution (100 mL). The aqueous portions were then back extracted with chloroform (50 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated to a dark yellow solid. The dark yellow solid was slurried in diethyl ether and filtered to form a fine off-white solid. This solid was recrystallized from N,N-dimethylformamide (DMF) and water to afford 4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one as an off-white fluffy solid, mp 178-180° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11](O)[CH2:12][OH:13]>[Ni]>[OH:13][CH2:12][CH2:11][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: OCCO
Agent: [Ni]
Product: O=C1Nc2ccccc2C1CCO
Yield: 70 %

Procedure:
A stirring mixture of oxindole (5.7 g, 43 mmol) and Raney nickel (10 g) in ethane-1,2-diol (100 mL) was heated in an autoclave. After the reaction was complete, the mixture was filtered and the excess of diol was removed under vacuum. The residual oil was triturated with hexane to give 3-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one as a colorless crystalline solid (4.6 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][C:16](=O)[CH3:17])[CH3:12].C(O)(=O)C.[O-]S([O-])(=O)=O.[Ca+2]>C(O)C>[CH2:11]([O:13][C:14](=[O:19])[CH:15]=[C:16]([NH:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][CH3:10])[CH3:17])[CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(F)cc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1cc(F)ccc1OC
Temperature: 25 °C

Procedure:
A suspension of 5-fluoro-2-methoxy-phenylamine (3.3 g, 23 mmol), 3-oxo-butyric acid ethyl ester (3.0 g, 23 mmol), acetic acid (120 μL), and Drierite® (12.0 g) in ethanol (20 mL) was heated to reflux for 5 d. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (elution with EA/hexane 1:3) to give crude 3-(5-fluoro-2-methoxy-phenylamino)-but-2-enoic acid ethyl ester.
Reaction SMILES: [O:1]=O.[C:3]([NH:6][CH:7]([C:20]1[CH:24]=[CH:23][O:22][C:21]=1[Si](CC)(CC)CC)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:5])[CH3:4].[BH4-].[Na+]>>[C:3]([NH:6][CH:7]([C:20]1[C:21](=[O:1])[O:22][CH2:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:5])[CH3:4]
Reactant: CCCCCCCCCCCCC(NC(C)=O)c1ccoc1[Si](CC)(CC)CC
Reactant: O=O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCCCCCCC(NC(C)=O)C1=CCOC1=O

Procedure:
Reacting 3-(1-hydroxytridecyl)-2-triethylsilylfuran with diphenylphosphoryl azide and diethyl azidocarboxylate gives 3-(1-azidotridecyl)-2-triethylsilylfuran. Reducing this intermediate with lithium aluminum hydride, followed by acetylation with acetic anhydide gives 3-(1-acetamido tridecyl)-2-triethylsilylfuran. Singlet oxygen oxidation of this amide, followed by reduction with sodium borohydride gives 3-(1-acetamidotridecyl)-2(5H)-furanone.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)=[N:7][C:6]=23)[CH:25]=1
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Temperature: 25 °C
Yield: 372.1 %

Procedure:
Isopropyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (2.86 g, 7.8 mmol), 5-fluoro-2-methoxyphenyl boronic acid (2.64 g, 15.5 mmol), potassium carbonate (3.22 g, 23.3 mmol), Pd(OAc)2 (35 mg, 0.155 mmol), and x-Phos (146 mg, 0.31 mmol) were taken up in 15 mL dioxane and 7 mL water under nitrogen and stirred at 80° C. for 2 hours. Reaction then cooled to room temperature, filtered through celited plug with ethyl acetate. Reduced in vacuo and run through an isco silica column with hexane:ethyl acetate 75-100%. Product plus desbromo co-elute, reduced in Vacuo. Product recrystallized 2 times from ethyl acetate:Hexane, washed with heptanes dried to get 12 g product. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J=7.78 Hz, 1H), 8.50 (s, 1H), 8.29 (dd, J=3.14, 11.17 Hz, 1H), 7.04 (dd, J=5.02, 9.03 Hz, 1H), 6.95 (dd, J=3.26, 7.78 Hz, 1H), 6.79 (d, J=8.03 Hz, 1H), 4.77-4.85 (m, 1H), 3.87 (s, 3H), 3.70-3.78 (m, 4H), 3.48-3.56 (m, 4H), 1.21 (d, J=6.27 Hz, 6H). LRMS (ESI) m/z 414 [(M+H)]+, calc'd for C21H24N5O3: 413.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.CS(C)=O.[NH+]1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]=[O:11]
Reactant: OCCCc1ccccc1Cl
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCc1ccccc1Cl
Yield: 43 %

Procedure:
Using the procedure of Stage B of Preparation 9, 1 g of the product of Stage B and 2.5 ml of triethylamine, 1.75 ml of dimethyl sulfoxide and 2.8 g of pyridinium sulfotrioxide complex were reacted to obtain after chromatography on silica, eluant: ethyl acetate-hexane (1-9), 425 mg (43%) of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[C:5]([N+:11]([O-])=O)[CH:4]=1)[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[C:5]([NH2:11])[CH:4]=1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(N)cc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCc1cc(N)c(N)cc1C
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A stirred solution of 4-ethyl-5-methyl-2-nitro-aniline [484 mg, Reference Example 31(b)] in methanol (20 ml) was treated with tin chloride (5.09 g), then heated at reflux for 16 hours and then cooled to ambient temperature. The pH of the reaction mixture was adjusted to pH 8 by addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give 4-ethyl-5-methyl-phenylene diamine (374 mg) as an off-white solid. LC-MS (METHOD B): RT=1.80 minutes; 151.25 (M+H)+. (b) 4-Isopropyl-5-methyl-phenylene diamine