Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(Br)C=C.CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:3]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13])[CH:2]=[CH2:1]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCC1CCCCC1=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
Ex-6a) A suspension of potassium t-butoxide (200 g, 1.78 mol) in toluene which was cooled to 0° C. in an ice bath under N2 was treated with cyclohexanone (157 g, 1.60 mol). To the reaction mixture was slowly added allyl bromide (194 g, 1.60 mol) over a 2 hour period. The reaction was warmed to room temperature over 5 hours. The reaction was then poured into EtOAc (400 mL) and washed once with 10% potassium hydrogen sulfate (250 mL). The organic solution was then washed with brine (3×200 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The resulting oil was then chromatographed to yield 158.4 g (71.6%) of 2-allyl cyclohexanone as an oil.
Reaction SMILES: C([C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(OC)=O.[C:16](Cl)(=[O:20])[C:17](Cl)=O.CN(C=[O:26])C>C1COCC1>[C:16]([CH2:17]/[C:10](=[CH:9]\[C:8]1[CH:7]=[CH:6][CH:5]=[CH:15][CH:14]=1)/[C:11]([OH:13])=[O:12])([OH:20])=[O:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(/C=C/C(=O)O)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)C/C(=C\c1ccccc1)C(=O)O
Temperature: 50 °C

Procedure:
A solution of (E)-4-carbomethoxycinnamic acid (5.09 g, 24.7 mmol) was dissolved in dry THF (25 mL) and treated under an argon atmosphere with oxalyl chloride (3.00 mL, 34.4 mmol) and a drop of dry DMF. After heating at 50° C. for 2 hours, the reaction mixture was concentrated in vacuo to yield the acid chloride of (E)-carboxymethyl cinnamic acid as a tan solid.
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=CC([C:29]5[NH:30][N:31]=[CH:32][CH:33]=5)=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:41]([O:45][C:46](=[O:78])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62](Br)[C:63]([O:69][CH3:70])=[CH:64][CH:65]=4)[O:60][C:59]=3[C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42].CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[C:41]([O:45][C:46](=[O:78])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62]([C:33]5[CH:29]=[N:30][NH:31][CH:32]=5)[C:63]([O:69][CH3:70])=[CH:64][CH:65]=4)[O:60][C:59]=3[C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1-c1cn[nH]c1
Yield: 52 %

Procedure:
Following the procedure used to prepare (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.173 mmol) was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give the title compound (51 mg, 52%). LCMS (Method H): RT=3.77 min, [M+H]+=564.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:30]([CH2:32][CH3:33])[CH3:31]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:30]([CH2:32][CH3:33])[CH3:31])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Oc1cccc(-c2nc(-c3ccc(F)cc3)ncc2OC)c1
Yield: 70.1 %

Procedure:
1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine, 5.5 g of potassium carbonate, and 5.5 g of 2-bromobutane were added to 200 ml of acetone, and the resulting mixture was heated under reflux for 2 days. The solvent was distilled away under reduced pressure. The residue was washed with water, and then purified by column chromatography on silica gel, thereby obtaining 1.0 g of 2-(4-fluorophenyl)-4-[3-sec-butoxyphenyl)-5-methoxypyrimidine (Compound 50).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)C(=O)C2=CC=CC=C12.O.NN.C(OCC)(=O)C>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: NCCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a suspension of 12.50 g (40 mmol) of 4-(4-phthalimidobutylthio)pyridine in 200 ml of ethanol, 5.82 ml (120 mmol) of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 4 hours. Then, 200 ml of ethyl acetate was-added, and the insoluble material was filtered off. The volatile components were distilled off and chloroform was added to the residue. The mixture was washed with saturated saline and dried over potassium carbonate. The solvent was distilled off and 7.30 g of the desired compound were obtained (quantitative yield, yellow oil).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[H-].[Na+].[C:21](=O)([O:29]C1C=CC=CC=1)[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O>[C:23]1([O:22][C:21](=[O:29])[NH:1][C:2]2[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:11])[C:4](=[O:18])[N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F)Oc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
To a suspension of 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (0.20 g, 0.74 mmol) in anhydrous THF (3 mL) was added NaH (0.044 g of 60 wt % suspension in mineral oil, 1.11 mmol) at 0° C. After gas evolution had subsided, the mixture was transferred via cannula to an ice-cold mixture of diphenyl carbonate (1.5 g, 7.4 mmol) in anhydrous THF (5 mL) and stirred for 6 h. The reaction was diluted with EtOAc (25 mL) and the resulting solution was washed with satd aq NH4Cl (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, filtered, and the solvent evaporated. The residue was purified by precipitation from MeOH and Et2O to give (1-benzenesulfonyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamic acid phenyl ester as a light brown solid (0.070 g, 24%): mp 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (m, 2H), 7.87 (d, J=7.0 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.61 (t, J=7.7 Hz, 2H), 7.33 (t, J=7.9 Hz, 2H), 7.15 (d, J=7.3 Hz, 1H), 7.06 (d, J=7.6 Hz, 2H); ESIMS m/z 390 ([M+H]+), 388 ([M−H]−).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3].[C:17](OC(=O)C)(=[O:19])[CH3:18]>[OH-].[Na+]>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C=CC(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1cc(C=CC(=O)O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
115.5 g (0.525 mol) of 3-allyloxy-4-hydroxy-cinnamic acid are dissolved in 530 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 107 g (1.05 mols) of acetic anhydride are introduced dropwise over the course of quarter of an hour at 0°-5° C, whilst stirring. The crystals which have precipitated are then filtered off, suction-dried and recrystallised from chloroform. 3-Allyloxy-4-acetoxy-cinnamic acid of melting point 154°-155° C is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][O:22][CH3:23].C(OCC)(=O)C.CCCCCC>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][O:22][CH3:23]
Reactant: COCCCBr
Reactant: COc1ccc(CO)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COCCCOc1cc(CO)ccc1OC

Procedure:
7.7 g of 3-hydroxy-4-methoxy-benzyl alcohol, 10.35 g of potassium carbonate and 12.1 g of 1-bromo-3-methoxy-propane are stirred under reflux in 150 ml of acetone for 3 days. After evaporation of the solvent, water is added to the residue and extraction is carried out with ethyl acetate. After evaporation of the solvent the title compound is obtained from the organic extracts by means of FC (240 g of silica gel, dichloromethane/methanol=96:4): Rf (ethyl acetate/hexane=2:1)=0.31.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccccc3-c3ccccc3)cc21
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 35.2 g (100 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 21.8 g (110 mmol) of biphenyl-2-ylboronic acid, 2.31 g (2 mmol) of Tetrakis(triphenylphosphine)palladium, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 12 h. After finishing the reaction. The mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product (26.8 g, 63.0 mmol, 63%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J=7.8 Hz, 1H), 7.55˜7.53 (m, 2H), 7.49˜7.42 (m, 5H), 7.29 (d, J=8.0 Hz, 1H), 7.20˜7.14 (m, 5H), 6.98 (s, 1H), 1.21 (s, 6H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])=O.[NH4+]>[Pd].C(O)C.O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2n1C
Temperature: 20 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
Alternative A. To a mixture of ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate (420 g), from step (a) or commercial sources, and 10% palladium on carbon catalyst (50% wet) (42 g) in ethanol (4200 mL) was added a solution of ammonium formate (541.59) in demineralized water (840 mL) at between 25-35° C. over 3 hours. The mixture was stirred for 18 hours at 20° C., and then filtered, washing the solids with ethanol (2100 mL). The combined filtrate and washings were concentrated to 840 mL under vacuum at about 20° C. The resulting slurry was granulated at 5° C., filtered, washed with chilled ethanol (420 mL), and dried to give product ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (316.5 g, 86%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH:19]1([C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH:19]1([C:22]2[N:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=3[C:10]#[C:11][C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=3)=[CH:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Reactant: OB(O)c1ccc(C2CC2)nc1
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: O
Solvent: COCCOC
Product: CCc1nccc(-c2ccc(C3CC3)nc2)c1C#Cc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 150 mg (0.58 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 142 mg (0.87 mmoL) 2-cyclopropyl-pyrid-5-yl boronic acid, 4.5 mg (0.03 mmol) Pd(PPh3)4 and 154 mg (1.11 mmol) K2CO3 in a mixture of 6.0 mL DME and 1.5 mL water. The reaction mixture is stirred twice under microwave irradiation at 150° C. for 120 min. The reaction mixture is concentrated in vaccuo and the crude product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 68 mg (34%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5]C=C[CH:2]=1.[C:7]([Cl:15])(=[O:14])[O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13].[O:16]1CCCC1>>[ClH:15].[C:7](=[O:14])([O:16][CH2:5][CH2:6][NH:1][CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: c1ccncc1
Reactant: C1CCOC1
Reactant: COCCCOC(=O)Cl
Product: CNCCOC(=O)OCCCOC
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution (50 mL) of bis(trichloromethyl)carbonate (4.45 g) in tetrahydrofuran was dropwise added N-ethyldiisopropylamine (5.75 mL) under ice-cooling. After stirring for a while, a solution (15 mL) of 3-methoxypropanol (2.70 g) obtained above in tetrahydrofuran was dropwise added. The mixture was stirred for 30 min. under ice-cooling and at room temperature for 1 day. After concentration of the reaction mixture under reduced pressure, diluted hydrochloric acid (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-methoxypropyl chlorocarbonate (4.39 g). To a solution (20 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 in tetrahydrofuran was added pyridine (0.97 mL) and a solution (5 mL) of a 3-methoxypropyl chlorocarbonate (1.83 g) obtained above in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 2 hrs. A solution (5 mL) of pyridine (0.65 mL) and 3-methoxypropyl chlorocarbonate (1.22 g) in tetrahydrofuran was added and the mixture was further stirred for 1 hr. The reaction mixture was concentrated under reduced pressure and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (80 mL), and the ethyl acetate layer was washed with a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:9, then 3:7). The purified product (3.40 g) was dissolved in diethyl ether (5 mL) and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. The mixture was stirred overnight at room temperature and the reaction mixture was concentrated under reduced pressure. Diethyl ether was added for crystallization to give the title compound (2.06 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[N:3]=1
Reactant: OCC(O)CBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Br)nn(CC(O)CO)c1Br
Temperature: 80 °C
Yield: 63.7 %

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (40.0 g; 147 mmol) in DMF (200 ml) was added over 15 minutes to a suspension of NaH (6.5 g, 162 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (320 ml) with stirring and under an inert atmosphere. After stirring for 30 minutes, a solution of 3-bromo-1,2-propanediol (19.4 ml; 221 mmol) in DMF (80 ml) was added dropwise. The reaction mixture was heated at 80° C. for 3 hours and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (480 ml, 2/1) was added. A yellow solid precipitated out. After washing with ether (50 ml), the 3-(3,5-dibromo-4-nitropyrazol-1-yl)-propane-1,2-diol (32.3 g, 63%) was obtained as a white solid (23.3 g; 48%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].C(N(CC)CC)C.Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].[C:44]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[CH:45]=1>O1CCCC1.O>[C:44]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:32]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:5]3[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]5[NH:14][CH:15]=[CH:16][C:9]=45)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[CH:18][CH:19]=2)=[O:33])[CH:45]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3cccc(-c4ccccc4)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.23 mmol) in tetrahydrofuran (1 mL) was treated with triethylamine (0.23 mmol) and 4-nitrophenyl chloroformate (0.23 mmol). The reaction stirred for 1 h at room temperature and was then treated with 3-biphenylamine (5 eq). After stirring 18 h at room temperature the reaction was poured into water (1 mL), and extracted with (3×1 mL) ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide (3×1 mL), brine (1×1 mL), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC provided the title product as a white powder (45%). ESMS [M+H]+: 499.2
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22](=[O:26])(=[O:25])([OH:24])O.[OH:27][S:28](O)(=[O:30])=[O:29].O=S(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[S:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:28]([OH:30])(=[O:29])=[O:27])[CH:7]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:24])(=[O:26])=[O:25]
Reactant: c1ccc(CN(Cc2ccccc2)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)=O
Agent: [Na+]
Product: O=S(=O)(O)c1cccc(CN(Cc2cccc(S(=O)(=O)O)c2)c2ccccc2)c1

Procedure:
With stirring, 150.0 g of N,N-dibenzylaniline was added slowly over approximately two hours to 425.0 g of 100 percent sulfuric acid while maintaining a temperature in the range of 25° to 30° C. The resulting solution was set aside at ambient temperature for approximately fourteen hours. Then, 165 g of 65 percent oleum was added to the solution with stirring while maintaining a temperature in the range of 25° to 30° C. using an ice water bath. The resulting solution was stirred approximately 19 hours at ambient temperature and then was poured slowly onto ice with stirring. Sufficient sodium carbonate was added gradually to the drowned mixture to adjust the pH to approximately 7.0 and thus obtaining a solution of N,N-bis(3-sulfobenzyl)aniline.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:5].C(NCC)C.Cl[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>>[CH2:16]([CH2:5][C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])=[O:3])[CH:17]=[C:18]([CH3:20])[CH3:19]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Product: CC(C)=CCCC(=O)C=C(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To a well stirred mixture of 60 g of 96% sodium hydroxide and 600 g of mesityl oxide was added 3 g of diethylamine, followed by 105 g of 94% 1-chloro-3-methyl-2-butene. The mixture was then heated to 70° C. over a 10 minute period, and the external heat source immediately removed. The mass continued to rise in temperature to 80° C. over a 10 minute period, and was then maintained at between 79° and 82° C. over a 2.3 hour period, with either heating or cooling, as needed. After cooling to 30° C., the mixture was quenched with 250 ml of water and stirred vigorously. The organic phase was then separated and the aqueous layer extracted four times with 20 ml portions of benzene. The organic phases were combined and dried overnight over sodium sulfate. The dried oil phase was then treated with 2 ml of acetic acid prior to distillation. The yield was 123.7 g of the mixture of prenyl mesityl oxide isomers.
Reaction SMILES: [CH:1]1([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]3[CH2:25][O:24]3)[CH:16]=2)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][NH:27]1>CCO>[CH:1]1([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][N:27]3[CH2:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:26]3)[CH:16]=2)[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(OCC2CO2)c1)C1CCCC1
Reactant: c1ccc2c(c1)CNC2
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(OCC(O)CN2Cc3ccccc3C2)c1)C1CCCC1
Temperature: 110 °C
Yield: 55 %

Procedure:
To a solution of tert-butyl cyclopentyl(3-(oxiran-2-ylmethoxy)benzyl)carbamate (300 mg, 0.86 mmol) in EtOH (5 mL) was added isoindoline (113 mg, 0.95 mmol). The reaction mixture was heated under microwave conditions at 110° C. for 0.8 h. The mixture was concentrated and the crude product was used in the next step without further purification. (220 mg, yield 55%) MS (ESI+) e/z: 467.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([N:9]([CH3:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.C[NH:21][CH2:22][C:23]1[CH:28]=[CH:27]N=[CH:25][CH:24]=1.[CH2:29](N(CC)CC)C.COC1C=CC(C(Cl)=O)=CC=1>C(Cl)Cl>[CH3:17][N:9]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:22]([C:23]2[CH:28]=[CH:27][CH:29]=[CH:25][CH:24]=2)[N:21]=[C:7]1[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)N(C)Cc2ccncc2)cc1
Reactant: CCN(CC)CC
Reactant: CNCc1ccncc1
Agent: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
4-Methoxy-N-methyl-N-(4-picolyl)benzamide--To a solution of N-methyl-N-(4-picolyl)amine (0.40 g, 3.3 mmol) and triethylamine (1.5 mL, 10.8 mmol) in CH2Cl2 (15 mL) was added 4-methoxybenzoyl chloride (1.2 g, 7.3 mmol). The resulting mixture was stirred at rt for 15 min, and then partitioned between 2.5N NaOH and Et2O. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacito, and the residue was purified by flash chromatography, eluting with a solvent gradient of 2-4% MeOH/CHCl3. The material that was isolated was triturated with Et2O to provide the title compound as a light yellow solid (0.18 g, 21%): 1H NMR (CDCl3): d 8.60 (d, 2H); 7.43 (brd, 2H); 7.20 (br s, 2H); 6.90 (br d, 2H); 4.66 (br s, 2H); 3.80 (s, 3H); 3.00 (s, 3H).