Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]CS([O-])(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OC(NC1C=CC(CCCS([O-])(=O)=O)=CC=1)=O)(C)(C)C>[CH2:22]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:13]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCS(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Yield: 99648.8 %

Procedure:
2-[4-(tert-Butoxycarbonylamino)phenyl]ethylmethanesulfonate (described in Example40a) (52.9 g; 0.168 mmole), (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 40h) (40 g; 0.168 mmole) and potassium carbonate (69.5 g; 0.503 mmole) were mixed in acetonitrile (1200 ml) and refluxed over night. Another portion of 2-[4-(tert-butoxycarbonylamino)phenyl]ethylmethanesulfonate (2.5 g; 7.9 mmole) was added. The reaction mixture was refluxed for 8 more hours then filtered. Evaporation of the filtrate gave 76.6 g 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: C1(S(O[CH2:11][C:12]([O:14]CCCC)=[O:13])(=O)=O)C=CC=CC=1.[OH-].[Na+].[C:21]1([CH3:29])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1>O.CO>[C:21]1([CH3:29])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: Cc1cc(C)cc(C)c1
Reactant: CCCCOC(=O)COS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(CC(=O)O)c(C)c1
Yield: 85 %

Procedure:
8.0 g (0.06 tool) and 5.4 g (0.0198 mol) of n-butyl phenylsulfonyloxyacetate are reacted in 60 ml of mesitylene by the method of Example 7, and the reaction mixture is hydrolyzed with 5 g of NaOH in 15 ml of water and 50 ml of methanol to give the acid. 3.0 g (85% of theory) of mesitylacetic acid are isolated.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].C([OH:15])C.C([O-])=O.[Na+]>O.C(O)=O>[OH:15][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: CCO
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: O=C(CO)c1ccc(O)c(O)c1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A 1 liter reactor equipped with a reflux condenser and magnetic stirring bar was charged under argon with 45 g of 4-chloroacetyl-catechol of a purity of ca. 90%, 260 ml of ethanol, 130 ml of water, 38 g of sodium formate and 17 ml (˜21 g) of formic acid. The stirred mixture was heated under reflux (˜100° C.) for 24 hours. Under vacuum a part of the solvents was distilled off. The remaining solution of about 100 ml was acidified by addition of 35.5 g of conc. hydrochloric acid (37%) resulting in a pH of about 0.5. 200 ml of water were added and the mixture was refluxed for 10 minutes. Upon stirring over night without heating crystals separated. The slurry was filtered by suction and the crystals were washed with 50 ml of cold water. After drying over night at 70° C. at ˜20 mbar the yield of 4-hydroxyacetyl-catechol was 34.2 g with a purity of 89.2% corresponding to a yield of 82.6%. In the mother liquors additional 14% of the product was detected by analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[I:17].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1C=CC=CC=1>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[I:17])=[O:21]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1I
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Product: O=C(CCl)Nc1ccc(-c2nc3ccccc3s2)cc1I
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of 2-(4'-amino-3'-iodophenyl) benzothiazole (DF129) (0.15 g, 0.426 mmol) in benzene (15 ml) was added dropwise chloroacetyl chloride (0.18 g) at room temperature. A yellow precipitate was formed and the resulting mixture was stirred at 50° C. for 30 minutes, and then cooled in an ice-bath. The solid was filtered off, washed with cold benzene and petroleum ether, and dried to give a yellow powder (0.13 g, 71.2%), m.p. 192.1-193.8° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:15][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide, synthesized as in J. Org. Chem 2005, 70, 1771, (1.02 g, 4.80 mmol) in chloroform (25 mL) was added 1-chloropyrrolidine-2,5-dione (0.62 g, 4.67 mmol) and the mixture was refluxed in an oil bath for 3 hrs. It was allowed to cool to room temperature overnight. The reaction mixture was evaporated in vacuo and re-dissolved in DMF (15 mL). Another 480 mg 1-chloropyrrolidine-2,5-dione was added and the resulting solution was heated overnight in an oil bath at 95-100°, then cooled again to room temperature. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was washed twice more with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. TLC (10% ethyl acetate/hexane) showed a robust spot at Rf 0.6 with smaller spots at Rf 0.4 and 0.2. The material was subjected to the Biotage in 5-10% ethyl acetate/hexane, collecting the Rf 0.6 fraction to give 790 mg (66%) white solid, N-(5,6-dichloropyridin-2-yl)pivalamide. 1H NMR (500 MHz, CDCl3) δ ppm 8.17 (s, 1 H), 7.96 (s, 1 H), 7.72 (s, 1 H), 1.31 (s, 10 H). MS (LC/MS) R.T.=1.85; [M+H]+=248.8.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[CH:1]1[C:6]2[CH:7]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2Nc3ccccc3Oc3ccccc32)cc1
Yield: 67 %

Procedure:
Title compound 4 was dissolved in ethanol (25 mL) and THF (5 mL). Platinum (IV) oxide (0.075 g, 10% wt) was added. The mixture was stirred at room temperature for 3 h under 1 atmosphere of hydrogen. The catalyst was filtered and the filtrate was concentrated under reduced pressure to one third volume. The precipitate was filtered to afford title compound 5 (510 mg, 67%) as a white solid. LRMS (ESI): (calc) 345.14 (found) 346.3 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.88 (d, J=8.4 Hz, 2H), 7.48 (dd, J=7.5, 1.7 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.33 (td, J=7.7, 1.8 Hz, 1H), 7.19 (td, J=7.4, 1.2 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.90-6.83 (m, 3H), 6.77 (dd, J=7.9, 1.4 Hz, 1H), 6.50 (td, J=7.3, 1.6 Hz, 1H), 5.55 (d, J=6.1 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:7]([O:28][CH3:29])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:25](=[O:27])[CH3:26])[CH:19]=1
Reactant: COc1ccc(Oc2ccnc3cc(OCCCCl)c(OC)cc23)c(C(C)=O)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OCCCN4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
1-(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone (compound 121) (100 mg), morpholine (63 mg), and potassium carbonate (166 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (55 mg, yield 49%).
Reaction SMILES: [F:1][C:2]([F:29])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1COCC1.[OH-].[Li+]>O>[F:29][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 39 h
Yield: 95.9 %

Procedure:
In a 250 mL round bottomed flask equipped with an overhead stirrer, T-type thermocouple, and nitrogen inlet were added methyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (11.1 g, 26.9 mmol) and THF (100 mL). To this yellow suspension were added water (10 mL) and lithium hydroxide.monohydrate (LiOH.H2O; 3.4 g, 81 mmol). The reaction was stirred at 23° Cfor 39 h during which time it became a yellow solution. The solution was warmed to 60° C. and stirred at 60° C. until complete by LC-MS. The reaction was cooled to 4° C. in an icebath and water (100 mL) was added to give a light yellow solution. Concentrated HCI (8.0 g) was added (note: exothermic) resulting in a thick white precipitate. The white suspension was stirred at 5° C. for 30 min and then the solid was collected by vacuum filtration. The filter cake was washed with water (2×25 mL), air dried for 3 h, and dried under vacuum (700 mm Hg) at 50° C. for 16 h to give the title compound as a white solid (10.3 g, 96%): mp 227-229° C.; 1H NMR (400 MHz, CDCI3) δ 8.65 (s, 1H), 8.32 (d, J=8.4 Hz, 2H), 8.23 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 2H).
Reaction SMILES: [O-]CC.[Na+].[C:5](OCC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CS[C:18]1[N:19]=[CH:20]C2C(=O)OC(=O)N(C(C)C)C=2[N:32]=1.Cl>O>[CH2:10]([O:9][C:7]([C:6]1[N:32]=[CH:18][N:19]=[CH:20][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CSc1ncc2c(=O)oc(=O)n(C(C)C)c2n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccncn1

Procedure:
To a solution of sodium ethoxide (0.9 g. .039 g. atom of sodium in 75 ml. of ethanol) was added 6.24 g. (0.03 mole) of diethyl malonate. The ethanol was removed in a rotary evaporator. To the residue was added 100 ml. of dimethyl formamide followed by 3.3 g. (0.013 mole) of 7-methylthio-1-isopropyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione. The reaction mixture was heated under reflux for 1 hour, cooled in ice and poured into 400 ml. of water. The solution was acidified with conc. hydrochloric acid and the resulting product was collected by suction filtration. Recrystallization from ethanol gave 2 g. of product--m.p. 138°-140° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH3:28])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=[O:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.Br.[CH3:48][C:49](O)=O>C1COCC1.C1([Mg]Br)C=CC=CC=1.CCOC(C)=O.Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH:45]([OH:46])[C:49]1[CH:48]=[CH:13][CH:14]=[CH:9][CH:10]=1)[CH:27]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: CC(=O)O
Agent: Br
Agent: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc2ccc(C(O)c3ccccc3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.020 g, 0.032 mmol) (from Example 15, step 5) in THF (0.50 mL), phenylmagnesium bromide in THF (3.0 M, 0.032 mL, 0.096 mmol) was added slowly at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (10 mL), and 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) and HBr in AcOH (8.0 M, 1.0 mL, 8.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. To the residue was added 1 M NaOH, and the aqueous layer was extracted with DCM. The combined organic extracts were dried, filtered and concentrated under reduced pressure. The resulting crude product was purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C27H29N6O2 (M+H)+: m/z=469.3. Found: 469.2.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:52]([N:2]([CH3:1])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: BrCc1ccccc1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) and 18 μL benzyl bromide were reacted in the same manner as in Example 746, to give 64 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid benzyl-methylamide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 11 mg of the title compound as orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:12][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
4-Bromo-3-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44: 4733 (1979)). To a solution of 3-fluoro-6-nitroaniline (500 mg, 3.2 mmol) in dry DMF (15 mL) under N2 was added dropwise a solution of N-bromosuccinimide (626 mg, 3.2 mmol) in dry DMF. The reaction was allowed to stir 48 h. The solution was then poured into 100 mL H2O. The cloudy yellow suspension which formed was then extracted with 4×25 mL of methylene chloride. The combined organic extracts were washed with 4×25 mL of H2O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1H NMR showed this solid to be a mixture of mono- and dibrominated products in a 3.8:1 ratio. The mixture was separated by flash chromatography (2:1 hexanes:ethyl acetate) to yield 324 mg of a yellow solid (43%). 1H NMR (CDCl3) δ 6.19(br s, 2H, NH2); 6.58(d, 1H, JHF =9.6, ArH); 8.39(d, 1H, JHF =6.9, ArH).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)[C:14]#[N:15]>C1COCC1>[C:14]([C:13]([NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:29])[CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)#[N:15]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C#N)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-cyanobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (10.5 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=432, RT=0.66 min.
Reaction SMILES: C(I)I.[Zn]([CH2:7][CH3:8])CC.[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:36])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32](=C)[CH2:33][CH3:34])[C:13]2=[CH:12][CH:11]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:36])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]3([CH2:7][CH3:8])[CH2:34][CH2:33]3)[C:13]2=[CH:12][CH:11]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]
Reactant: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: CC[Zn]CC
Agent: COC(C)[Si](C)(C)C
Solvent: ICI
Solvent: Cc1ccccc1
Product: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Reaction time: 0.17 h

Procedure:
CH2I2 (1.2 g, 4.6 mmol) was dissolved in dry toluene (5 mL) at 0° C. After stirred for 10 min under Argon, Et2Zn (1 M in THF, 3.3 mL, 3.67 mmol) was added. After stirred for 15 min, a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (270 mg, 0.46 mmol) prepared in example 161b in dry toluene (10 mL) was added. After stirred at room temperature for 3 h, the reaction was quenched with saturated NH4Cl (20 mL). The aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated, the residue, was used for next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-])=O)[CH:9]=[C:8]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C.C1(C)C=CC=CC=1.C[O-].[Na+]>O1CCCC1.[C].[Pd]>[O:3]=[C:4]1[CH2:6][N:7]2[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9][C:10]3[C:15]2=[C:14]([CH:13]=[CH:12][CH:11]=3)[NH:16]1
Reactant: CCOC(=O)Cn1c(C(=O)OCC)cc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cccc3c2n1CC(=O)N3
Yield: 85.7 %

Procedure:
Ethyl 1-ethoxycarbonylmethyl-7-nitro-1H-indole-2-carboxylate (2.11 g, 6.59 mmol) was subjected to catalytic reduction in the presence of 10% palladium-carbon (0.20 g) in tetrahydrofuran (70 ml) at ordinary temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Toluene (100 ml) and sodium methoxide (0.35 g, 6.48 mmol) were added to the residue, and the resulting mixture was heated under reflux for 2 hours. Then, the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/8) to obtain ethyl 2,3-dihydro-2-oxo-1H-pyrrolo [1,2,3-de]quinoxaline-5-carboxylate (1.38 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[O:8]=[C:9]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42].O>CN(C=O)C>[O:8]=[C:9]([N:27]1[CH2:28][CH2:29][N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:42])([F:43])[F:44])[CH2:31][CH2:32]1)[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(Cc2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
K2CO3 (130 mg, 0.95 mmol) was added to N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (141 mg, 0.38 mmol) in 5 mL of DMF. After 10 minutes atr room temperature, 1-Bromomethyl-2-trifluoromethyl-benzene (75 mg, 0.32 mmol) was added and the resulting mixture was stirred at 60° C. for 4 hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulphate and concentrated. Purification by column chromatography (60-120 mesh silica gel using 6:4 EtOAc and Hexane as the eluent) afforded N-{2-Oxo-2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-ethyl}-4-phenoxy-benzamide in 39% yield. LC-MS purity: 86%. 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.7 (q, 2H), 7.4 (m, 3H), 7.2 (t, 1H), 7.1 (m, 2H), 7 (m, 2H), 4.1 (d, 2H), 3.7 (s, 2H), 3.5 (m, 4H), 2.4 (m, 4H).