Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]([C:12]3[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=3[C:3]=2[CH:2]=1)=O.[OH-].[Na+].O.NN.Cl>C(O)COCCO.O>[CH:17]1[C:12]2[CH2:10][C:4]3[C:3](=[CH:2][CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=3)[C:13]=2[CH:14]=[CH:15][C:16]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1cc(C(=O)O)ccc1-2
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)c1ccc2c(c1)Cc1cc(C(=O)O)ccc1-2

Procedure:
In an argon-purged flask, 9-fluorenone-2,7-dicarboxylic acid (10.0 g, 0.037 mol) was suspended in diethylene glycol (75 mL). The flask was placed in a room temperature oil bath then NaOH (6.2 g, 0.155 mol) and an 80% solution of hydrazine hydrate (7.4 mL, 0.12 mol) were added successively. The reaction mixture was slowly heated to 110 C and refluxed for approximately four hours. The reaction mixture was cooled, carefully poured into water and acidified to pH 2 with concentrated HCl. The product was filtered and washed with water. Product was dissolved in warm NaOH solution (0.5M, warm) and precipitated by acidification to pH 2 with HCl. The product was filtered and washed with water. Product was an yellow solid (9.0 g, 96%). 1H-NMR (d6-DMSO): δ (ppm) 8.2 (s, 2H, Ar); 8.1 (m, 2H, Ar); 8.0 (m, 2H, Ar); 4.1 (s, 2H, CH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13]CC)=O)[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:5]2=[CH:6][N:7]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[CH:34]=1>>[CH3:33][C:31]1[S:32][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:11]([C:9]3[N:8]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:5]4=[CH:6][N:7]=[C:2]([F:1])[CH:3]=[C:4]4[CH:10]=3)=[O:13])=[CH:34][C:29]=2[N:30]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: CCOC(=O)c1cc2cc(F)ncc2n1Cc1cccc(F)c1
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ncc4n3Cc3cccc(F)c3)ccc2s1
Yield: 87.2 %

Procedure:
The process is performed according to the method described in step 2.4 of Example 2, starting with 0.3 g (0.95 mmol) of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Example 2.3) and 0.189 mg (1.14 mmol) of 5-amino-2-methylbenzothiazole. 0.36 g of expected compound is isolated.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([O-])=O>O.C1COCC1.[Zn]>[C:13]1([NH:12][C:9]2[CH:10]=[CH:11][C:6]([NH2:3])=[CH:7][CH:8]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ammonium chloride (48 mg, 9 mmol) in water (1 mL) was added to a stirred solution of (4-nitro-phenyl)-phenyl-amine (200 mg, 0.9 mmol) in THF (4 mL). Zinc powder (48 mg, 7.4 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 2 hours then filtered over celite. The filtrate was extracted with ethyl acetate and the ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated to 160 mg (96%) of N-phenyl-benzene-1,4-diamine. LCMS: 185.1 (M+1)+, 93.9%, 1H NMR: (DMSO-d6): 67.2 (t, 2H), 7.0 (d, 2H), 6.8 (m, 2H), 6.7 (d, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)C(=O)C)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1.Cl.[C:34]([O-])(O)=O.[Na+]>CCO>[CH3:1][O:2][CH2:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][CH2:26][C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:34][CH2:6]1
Reactant: O=C([O-])O
Reactant: COCC1(c2ccc(NC(=O)c3ccccc3N(Cc3ccncc3)C(C)=O)cc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCC1(c2ccc(NC(=O)c3ccccc3NCc3ccncc3)cc2)CCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of N-[2-(N-{4-[(methoxymethyl)-cyclopropyl]phenyl}carbamoyl)-phenyl]-N-(4-pyridylmethyl)acetamide (100 mg) and 20% HCl (5 ml) in EtOH (15 ml) was stirred at 80° C. overnight. The solution was basified with NaHCO3 and evaporated with silica gel and purified by column chromatography to give the title compound. Mass: (M+1), 402.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C@H:2]([CH2:3][OH:4])[C@@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC[C@@H](CC(F)(F)F)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
To a stirred solution of (2S,3S)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol (145 mg, 0.78 mmol), triethylamine (0.22 mL, 1.56 mmol) and methylene chloride (5 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (225 mg, 0.861 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction mixture was allowed to attain 25° C. overnight. Additional methylene chloride (15 mL) was added and the reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (0.250 g) that was purified via flash chromatography, eluent: 1:6 ethyl acetate-hexane. This produced the title compound 5-chloro-N-[(1S,2S)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as an oil (140 mg, 53.8%). The crude oil was further purified by recrystallization from 1:4 EtOAc-heptane. The mixed solvent system was added to 5-chloro-N-[(1S,2S)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, heated to obtain a solution, allowed to cool to 25° C. for 3 h and then stored at 0° C. for 19 h. A crystalline white solid precipitated which was filtered and washed with ice-cold heptane to afford 5-chloro-N-[(1R,2S)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (50 mg, 19.2%, chiral purity 91%, analytical purity 100%). Mass Spectrum (−ESI): 364 (M−H)−.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=3)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: OCCc1ccncc1
Product: CC(=O)N1CCc2cc(OCCc3ccncc3)c(Br)cc21
Yield: 84 %

Procedure:
This was prepared from 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron 1973, 29(8), 1115) and 2-(4-pyridyl)ethanol (D65), following the procedure of Description 8a. This gave the title compound (84%), as a yellow solid.
Reaction SMILES: C([NH:5][C:6](=[O:18])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:8])(C)(C)C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O>C1(C)C=CC=CC=1>[N+:15]([C:11]1[CH:10]=[C:9]([C:7](=[O:8])[C:6]([NH2:5])=[O:18])[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)NC(=O)C(=O)c1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: NC(=O)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 37.8 %

Procedure:
Under nitrogen atmosphere, (tert-butyl)-2-(3-nitrophenyl)-2-oxoacetamide (1.50 g, 5.99 mmol) was taken in toluene (10 ml) at room temperature, tert-butyldimethylsilyl trifluoromethane sulfonate (1.378 ml, 5.99 mmol) was added and the reaction mixture was heated at 100° C. for 8 hrs. The reaction mixture was concentrated under vacuum and satd. sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (3×20 ml). Combined organic layer was dried over sodium sulfate and the mixture was concentrated under vacuum to afford the crude product, which was purified by column chromatography to afford yellow solid product (440 mg).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][C:34]([F:43])([F:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:38][CH2:37][N:36]([CH2:35][C:34]([F:42])([F:43])[F:33])[CH2:41][CH2:40]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: FC(F)(F)CN1CCNCC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCN(CC(F)(F)F)CC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-(2,2,2-trifluoroethyl)piperazine to afford an off-white powder. HPLC (Condition 4) tR=6.3 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=531 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.59-2.70 (m, 4H) 3.08-3.26 (m, 6H) 6.59-6.73 (m, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.86 (d, J=9.38 Hz, 3H) 8.27-8.37 (m, 1H) 8.73 (s, 1H) 10.40 (br. s, 1H) 13.02-13.18 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[Na+].[CH3:25][NH:26][CH3:27]>O1CCOCC1>[CH3:25][N:26]([CH3:27])[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)c1ccccc1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CC#CCNC(=O)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (0.70 g), sodium iodide (0.1 g) and 50% aqueous dimethylamine (2.2 ml) in 1,4-dioxane (7 ml) was stirred at room temperature overnight and then evaporated in vacuo. After an addition of saturated sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (20:1) as an eluent to give N-(4-dimethylamino-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (0.35 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][N:6]=[CH:5]2.B([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19]([OH:21])=[O:20])(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.C1(NC2CCCCC2)CCCCC1.[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)CCC>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: Oc1nncc2cc(Cl)ccc12
Reactant: Cc1ccc(C(=O)O)cc1B(O)O
Agent: [Pd]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(O)nncc2c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A 10 mL round bottom flask was charged with 6-chlorophthalazin-1-ol (0.35 g, 1.94 mmol), 3-borono-4-methylbenzoic acid (0.42 g, 2.3 mmol), Pd2(dba)3 (9 mg, 9.8 μmol), and 2-(dicyclohexylphosphino)-2′-methylbiphenyl (9 mg, 25 μmol). The flask was evacuated and back-filled with nitrogen. Deoxygenated solvents, 1-butanol (2.0 mL), water (0.5 mL) and dicyclohexylamine (1.5 mL, 7.8 mmol), were added sequentially. The reaction mixture was then heated at 85° C. under nitrogen with efficient stirring overnight. 6 N NaOH aq. (2 mL, 12 mmol) was added and the reaction mixture was stirred until all solids dissolved. The reaction mixture was allowed to warm to RT and water (10 mL) was added. The reaction mixture was transferred into separatory funnel where the layers were separately collected. The aqueous layer was extracted with DCM (2×10 mL). All the organic solutions were discarded. The aqueous layer was adjusted to about pH 6 using 5N HCl. The resulting fine precipitate was collected by filtration, rinsed thoroughly with water, and air-dried. Oven drying of the solid afforded 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoic acid as a fine off-white powder.
Reaction SMILES: Cl[CH2:2][S:3][CH3:4].[C:5]1([C:11]2[NH:16][C:15](=[S:17])[NH:14][C:13](=[O:18])[C:12]=2[CH3:19])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:4][S:3][CH2:2][N:16]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15]1=[S:17]
Reactant: CSCCl
Reactant: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCn1c(-c2ccccc2)c(C)c(=O)[nH]c1=S
Yield: 8.1 %

Procedure:
To 4 ml of dimethylformamide, 0.17 ml (2.0 mmol) of chloromethylmethylsulfide, 0.47 g (2.0 mmol) of 6-phenylthiothymine, 0.56 ml (2.0 mmol) of triethylamine were added and allowed to react for 22 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was adsorbed on a silica gel column and eluted with chloroform. The eluate was concentrated and crystallized from ethyl acetate to obtain 45 mg of the target compound (Yield: 8%).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)C1CC=CCC1
Agent: [Pd]
Product: O=C(O)C1CCCCC1

Procedure:
3.2 g (2.5 wt. % of 3-cyclohexene-1-carboxylic acid) 3% Pd/C was added to the 3-cyclohexene-1-carboxylic acid solution and the reaction was activated at the temperature of 100° C. with a hydrogen pressure of 120 psi to yield cyclohexanecarboxylic acid with a conversion rate of more than 99%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=3)[CH2:15][CH:10]2[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>>[CH2:13]1[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH2:15][N:14]1[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1
Reactant: CCOC(=O)c1cnc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.7 %

Procedure:
To ethyl 2-[5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-5-carboxylate (0.345 g, 0.9 mmol) was added 4M HCl in dioxane (2 ml, 8 mmol). The mixture was stirred at r.t. for 1 h, then evaporated to dryness. The residue was dissolved in methanol, loaded onto a SCX-2 cartridge, washed with methanol (100 ml), then eluted with 2M ammonia in methanol to give the title compound (0.285 g, 100%). LCMS purity >95%, m/z 263 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:18](=[O:20])[CH3:19])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 88.7 %

Procedure:
To a solution of 5.0 g (0.0202 mole) of 1-(4-(methylsulfonyl)phenoxy)benzene and 2.20 g (0.0280 mole) of acetyl chloride dissolved in 35 ml of methylene chloride (CH2Cl2) was slowly added 6.70 g (0.0503 mole) of anhydrous aluminum chloride. The mixture was heated at reflux for 45 minutes, cooled and poured over ice and concentrated hydrochloric acid (conc. HCl). Additional CH2Cl2 was added and the organic layer separated, washed with water and dried (Na2SO4). Removal of solvent in vacuo yielded 5.2 g (88.9% yield) of purified 1-(4-(4-(methylsulfonyl)phenoxy)phenyl)ethanone, mp 131°-132.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:12])[N:7]([CH2:40][CH2:41]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.CCOC(C)=O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:19][CH:20]=2)=[O:12])[N:7]([CH2:40][CH2:41][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCOS(C)(=O)=O)n1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCN2CCOCC2)n1
Yield: 62 %

Procedure:
In a round bottomed flask, dissolve methanesulfonic acid 2-[3-tert-butyl-5-(3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-ureido)-pyrazol-1-yl]-ethyl ester (75 mg, 0.11 mmol) in DMF (2 mL). Add morpholine (0.1 mL, 10 eq) and heat the reaction to 70° C. overnight under N2. Dilute the reaction with EtOAc then wash with water, 1 N NaOH, and saturated aqueous saturated sodium chloride. Dry the organics over magnesium sulfate, filter, and concentrate. Purify the compound on a silica gel column (EtOAc to 5% MeOH: DCM to 10% 2 M NH3 in MeOH: DCM) to give a pale yellow solid (46 mg, 62%). MS (ES), m/z 656 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.[CH:16]1[C:21]([CH:22]=[O:23])=[CH:20][C:19]2[O:24][CH2:25][O:26][C:18]=2[CH:17]=1.O>O1CCCC1>[O:8]1[C:5]2[CH:6]=[CH:7][C:2]([CH:22]([C:21]3[CH:16]=[CH:17][C:18]4[O:26][CH2:25][O:24][C:19]=4[CH:20]=3)[OH:23])=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 933.6 %

Procedure:
A solution of 4-bromo-1,2-(methylenedioxy)benzene (5.02 g, 2.5 mmol) in 100 mL of dry tetrahydrofuran is cooled to -78° C. n-Butyllithium (15.6 mL, 2.5 mmol) is added dropwise to the reaction. The white suspension is stirred for another hour. Piperonal (4.12 g, 2.4 mmol) in 20 mL of tetrahydrofuran is added. The reaction is warmed to room temperature and stirred overnight. Water (50 mL) is added to quench the reaction. Layers are separated and the aqueous phase is extracted with 3×40 mL of ethyl acetate. The combined organics are dried (magnesium sulfate) and filtered. Solvent is removed in vacuo and the residue is purified by silica gel chromatography eluting with 20% ethyl acetate-hexane to give 6.1 g (90%) of product as a white solid;
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:28][C:26]1[CH:27]=[C:22]([O:21][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=2)[CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])[CH:23]=[C:24]([CH3:30])[C:25]=1[C:38]1[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(OC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 566.2 [M−H]−.
Reaction SMILES: C1(=O)OC(=[O:5])C=C1.OO.[Br:10][CH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]>C(O)(=O)C>[Br:10][CH2:11][C:12]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[O:5]1
Reactant: Fc1ccc(C(=Cc2ccccc2Cl)CBr)c(F)c1
Reactant: O=C1C=CC(=O)O1
Agent: OO
Solvent: CC(=O)O
Product: Fc1ccc(C2(CBr)OC2c2ccccc2Cl)c(F)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
Maleic anhydride (2.05 g, 20.9 mmol) and then hydrogen peroxide (35% by weight strength solution, 2.04 g, 20.9 mmol) were added to a stirred solution of 1-[3-bromo-1-(2-chlorophenyl)prop-1-en-2-yl]-2,4-difluorobenzene (720 mg, 2.09 mmol) in acetic acid (20 ml). The reaction mixture was stirred at 40° C. for 24 h, more hydrogen peroxide (35% by weight strength solution, 2.04 g, 20.9 mmol) was then added and the reaction mixture was stirred at 20° C. for 66 h. Excess oxidizing agent was quenched by addition of sat. aq. sodium thiosulphate. The mixture was extracted with dichloromethane, and the organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue on silica gel gave 2-(bromomethyl)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxirane as a 59/41 mixture of diastereoisomers [316 mg, colourless oil, yield 40%; GC/MS: m/z=279 ([M-Br]+); HPLC/MS: log P(HCOOH)=4.61 (major diastereoisomer), 5.00 (minor diastereoisomer)].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 4 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.7 mmol) in THF (30 mL) was cooled to 4° C. Phenyl isocyanate (0.3 g, 2.7 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The solid was collected and slurried with ethanol (10 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-phenyl-urea (0.7 g, 89%) as a white solid: mp 328-330° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.36-2.64 (m, 2H), 2.86-2.98 (m, 1H), 4.37-4.58 (m, 4H, 2CH2), 5.12-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 6.71 (t, J=5.7 Hz, 1H, NH), 6.89 (t, J=7.3 Hz, 1H, Ar), 7.21 (t, J=7.6 Hz, 2H, Ar), 7.38 (d, J=7.6 Hz, 2H, Ar), 7.48-7.65 (m, 3H, Ar), 8.61 (s, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.67, 46.20, 51.58, 117.80, 121.20, 121.54, 128.29, 128.62, 130.33, 131.64, 135.59, 139.90, 140.29, 155.22, 168.09, 171.01, 172.84; Anal. calcd. for C21H20N4O4: C, 64.28; H, 5.14; N, 14.28. Found: C, 64.36; H, 4.96; N, 14.17.