Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][NH:10][S:9]2(=[O:15])=[O:14])=[CH:5][CH:4]=1.[H-].[Na+].[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:39])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:39])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:10]3[CH2:11][C:12](=[O:13])[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[S:9]3(=[O:15])=[O:14])[CH:30]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(F)cc2)n(-c2cccc(CCl)c2)n1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CN(Cc3cccc(-n4nc(C(C)(C)C)cc4NC(=O)Nc4ccc(F)cc4)c3)S2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methoxy-benzyl)-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-3-one (64 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added NaH (11 mg, 0.27 mmol) at 0° C. After stirred for 0.5 h at 0° C., a solution of 1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-urea from the previous reaxtion (100 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added to the reaction mixture, then was stirred overnight at RT. The crude was purified through prepared-HPLC to yield 1-(5-t-butyl-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1λ6-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-fluoro-phenyl)-urea (45 mg). 1H NMR (DMSO-d6): 8.95 (s, 1H), 8.37 (s, 1H), 7.50-7.54 (m, 3H), 7.36-7.41 (m, 3H), 7.25 (d, J=8.8 Hz, 2H), 7.07 (t, J=8.8 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.35 (s, 1H), 4.64 (s, 2H), 4.47. (s, 2H), 4.19 (s, 2H), 3.75 (s, 3H), 1.26 (s, 9H). MS (ESI) m/z: 515 (M+H+).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)=[C:6]1[CH3:25])[CH2:2][CH2:3][CH3:4].[CH2:26]([N:28]([CH2:40][CH3:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:30]=1)[CH3:27]>>[CH2:36]([N:35]([CH2:38][CH3:39])[C:31]1[CH:30]=[C:29]([N:28]([CH2:26][CH3:27])[CH2:40][CH3:41])[CH:34]=[CH:33][C:32]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:20])[O:19]1)[CH3:37]
Reactant: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Product: CCCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c2ccccc21

Procedure:
In a manner similar to that described in part B above, 3.35 g (0.01 mole) of 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-benzoic acid and 2.42 g (0.011 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted to obtain 3-[2,4-bis(diethylamino)phenyl-3-(1-n-butyl-2-methyl-3-indolyl)phthalide (Formula III: Ro =R1 =R2 =R3 =Y1 =H; R=CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; R6 =(CH2)3CH3), as tan-colored crystals which melted at 78°-80° C. A toluene solution of the product spotted on silica gel developed an intense blue-black-colored image.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:30]=[CH:29][C:18]([CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>CO.O1CCOCC1.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Yield: 91.1 %

Procedure:
To a solution of dimethyl 4-[2-(6-quinolinoxy)ethoxy]benzylidenemalonate (2.23 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.04 g, 90%). HRMS calcd for C23H27NO6: 413.4670. Found: 413.4672. MA calcd for C23H27NO6: C, 66.81%; H, 6.58%; N, 3.39%. Found: C, 66.53%; H, 6.55%; N, 3.36%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:18]=1.C(Cl)(Cl)Cl.Cl.[N:24]([O-])=[O:25].[Na+]>O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=[CH:6][N:5]2[C:18]=1[N:24]=[O:25]
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2c(OCc3ccccc3)cccn2c1N=O
Temperature: 25 °C

Procedure:
To a stirred mixture of 10.0 g (42.2 mmol) of 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, 150 ml of water and 150 ml of chloroform is added cautiously (EXOTHERM) 179.5 ml (2.15 moles) of concentrated hydrochloric acid and the resultant mixture is heated to an internal temperature of approximately 55° C. To this stirred and heated mixture is added at a rate of approximately 7 ml/minute a solution of of 151 g (2.11 moles) sodium nitrite (97%) in 660 ml of water to produce a vigorous, but manageable, reflux. When the addition is complete,the reaction mixture is allowed to cool to room temperature. The lower (CHCl3) layer is drawn off and the aqueous layer extracted with three--150 ml portions of chloroform. The combined chloroform extracts arewashed with two--450 ml volumes of 2.4 M sodium carbonate solution, then with a single 500 ml portion of saturated aqueous sodium chloride. The extracts are concentrated in vacuo (rotary evaporator, 45°) to lessthan one-half the original volume, dried over anhydrous sodium sulfate and evaporated to a viscous oil. Chromatography of the oil on silica gel, eluting with chloroform/ethyl acetate (1/1) yields the title compound as acrystalline solid, mp 147.5°-149.5° C. (dec).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC([O-])=O.[Na+].[N:30]#[C:31]Br>CO.C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:31]#[N:30])[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine (346 mg, 1 mmol) in MeOH (20 mL) was treated with NaOAc (574 mg, 7 mmol) then was warmed and stirred for 30 min. The suspension was then treated with a solution of cyanogen bromide (318 mg, 3 mmol) in CH2Cl2 (1.5 mL) at 0° C. The mixture was stirred and allowed to warm to room temperature overnight. The mixture was filtered, washed with MeOH and CH2Cl2, and the material was purified by chromatography on a silica gel column using 0 to 100% CH2Cl2/EtOAc, then 2.5% MeOH/CH2Cl2 to afford (4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbonitrile (250 mg, 61%).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:71])[C@H:30]([CH3:70])[CH2:31][C@H:32]([O:62][Si](C(C)(C)C)(C)C)[C@@H:33]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:34][C@@H:35]([CH:51]([CH3:53])[CH3:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:38]=1)(=[O:24])[NH2:23]>CN(C)C=O>[C:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:71])[C@H:30]([CH3:70])[CH2:31][C@H:32]([OH:62])[C@@H:33]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:34][C@@H:35]([CH:51]([CH3:53])[CH3:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:38]=1)(=[O:24])[NH2:23]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)NCCCC(N)=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC(N)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
50 mg of tetrabutylammonium fluoride trihydrate are added to 115 mg of 5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(3-carbamoyl-propyl)]-amide in 4 ml of dimethylformamide at 0° C. The reaction mixture is stirred for a further 5 hours at room temperature and then concentrated by evaporation. 20 ml of saturated sodium hydrogen carbonate solution are added to the evaporation residue and the mixture is extracted repeatedly with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and concentrated by evaporation. The residue is purified by means of FC (18 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1): 0.24.
Reaction SMILES: [SH2:1].[CH2:2]([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:19]#[N:20])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3]>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:2]([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:19](=[S:1])[NH2:20])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3]
Reactant: S
Reactant: CCOC(=O)c1cn(CC)c2cc(C#N)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(CC)c2cc(C(N)=S)c(F)cc2c1=O
Reaction time: 8 h

Procedure:
Hydrogen sulfide was passed through a solution of 1.50 g (5.2 mmol) 7-cyano-1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 25 ml pyridine and 1 ml triethylamine for five hours. After stirring overnight in a closed flask, the precipitated solid was filtered, washed with pyridine and ether, and dried to afford 1.28 g of yellowish solid of the title compound, mp 198°-199° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([S:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:29])[CH:21]=1)(=[O:19])=[O:18])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])=[CH:21][C:22]=2[CH3:29])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(C)c1
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(C)c1

Procedure:
4 g of 4-bromo-2-methylbenzonitrile was used in Procedure Q with ethanethiol to afford 4-(ethylthio)-2-methylbenzonitrile. 2 g of 4-(ethylthio)-2-methylbenzonitrile was reacted via Procedure R to give 4-(ethylsulfonyl)-2-methylbenzonitrile. 2.5 g of 4-(ethylsulfonyl)-2-methylbenzonitrile was reacted via Procedure T to give 4-(ethylsulfonyl)-2-methylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(ethylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)-2-methylbenzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]([F:29])([F:28])[C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>CN(C)C=O.CCOCC>[F:7][C:8]([F:29])([F:28])[C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([Cl:4])=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (1.56 g, 1.1 ml, 12.32 mmol) is added to a stirring solution of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid (2.00 g, 6.16 mmol), dimethylformamide (DMF; 4 drops) and ether (50 ml). The mixture is stirred at RT for 3 hours. Insoluble material is filtered off and solvent is removed in vacuo to give 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid chloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=1[Cl:22].O>C1COCC1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:22])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: Fc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A thin slurry of 4-hydroxypiperidine (50 g, 494 mmol) in THF (200 ml) was added to a stirred suspension of potassium tert-butoxide (110.9 g, 990 mmol) in THF (650 ml) at room temperature and washed in with THF (50 ml). The resultant mixture was stirred under nitrogen for 20 minutes. 1,2-Dichloro-4-fluorobenzene (98 g, 594 mmol) was added and the resultant mixture heated at reflux for 90 minutes. The reaction mixture was cooled to room temperature and water (500 ml) added. The layers were separated and the solvent removed from the organic fraction. The material was then partitioned between MTBE and 10% aqueous citric acid solution. The layers separated and the aqueous layer washed with further MTBE (2×250 ml). The aqueous phase was basified to pH>10 by addition of 10N NaOH solution and the product extracted with iso-propyl acetate (2×30 ml). The organics were washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step (109.1 g, 90%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:6][C:5]1=S.[O:24]1CCOCC1.[K]>C(O)=O.O>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:24]
Reactant: C1COCCO1
Reactant: FC(F)(F)CN1C(=S)NC(c2ccccc2)c2cc(Cl)ccc21
Agent: [K]
Solvent: O
Solvent: O=CO
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinethione in 50 ml. of dioxane was added dropwise a solution of 3 g of potassium permangenate in 20 ml. of water. The mixture was stirred at room temperature for 2 hours and then a few drops of formic acid was added. The resultant brown precipitate was filtered off and washed with chloroform. The filtrate was concentrated under reduced pressure and the residue was dissolved in 30 ml. of chloroform. The chloroform solution was combined, washed successively with dilute sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was recrystallized from isopropyl alcohol to give 1 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone, m.p. 184.0°-185.0° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[CH3:18][CH:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24]1
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: CC1CNCCN1
Product: CC1CN(c2nccnc2OCCOc2ccccc2)CCN1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.54 mmol; from Example 1, Step 1) and 2-methylpiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 138 mg (73%) of the title product. Anal. (C17H22N4O2) C, H, N.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C(=O)c2ccccc2)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 13.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56.5 mg), 2-hydroxy-4-methoxybenzophenone (286 mg), and 4-dimethylaminopyridine (163 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensioon was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution 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 column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (14.5 mg, yield 14%).
Reaction SMILES: [C:1]([N:9]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[NH:11][C:10]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(Cl)(Cl)Cl>CN(C)C=O>[C:1]([N:9]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[N:11]([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:10]1=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: O=C1NC2CCCCC2N1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1C(=O)N(CCCCBr)C2CCCCC21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 3-benzoylperhydrobenzimidazol-2-one (2.7 9, 10.0 mmoles) in 50 ml of dimethylformamide was added 60% sodium hydride (400 mg, 10.0 mmoles), and the mixture was stirred at 60° C. for 30 minutes. To this mixture having been cooled to room temperature was further added 1,4-dibromobutane (10.8 g, 50.0 mmoles), and the resulting mixture was stirred at 60° C. for 4 hours. After chloroform was added to the reaction, insolubles were removed by filtration, the filtrate was washed with water, and the solvent was evaporated. The residue thus obtained was purified by chromatography on a silica gel column to give 1.5 g of the title compound as an oil.
Reaction SMILES: Cl[CH:2]([C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][CH:22]=[N:21][C:20]=2[CH:19]=1)[N:3]1[CH2:8][CH2:7][CH:6]([S:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])(=[O:11])=[O:10])[CH2:5][CH2:4]1.[NH2:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1>>[NH2:33][C:34]1[N:39]=[CH:38][C:37]([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:25]3[S:26][C:18]([CH2:2][N:3]4[CH2:8][CH2:7][CH:6]([S:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])(=[O:11])=[O:10])[CH2:5][CH2:4]4)=[CH:19][C:20]=3[N:21]=2)=[CH:36][N:35]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CN(C)C(=O)CS(=O)(=O)C1CCN(C(Cl)c2cc3ncnc(N4CCOCC4)c3s2)CC1
Product: CN(C)C(=O)CS(=O)(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[1-(Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidine-4-sulfonyl]-N,N-dimethyl-acetamide was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 309. NMR (CDCl3): 1.98-2.08 (2H, m), 2.18-2.28 (4H, m), 3.04 (3H, s), 3.13-3.17 (2H, m), 3.22 (3H, s), 3.45-3.53 (1H, m), 3.85 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 4.08 (2H, s), 5.20 (2H, br), 7.27 (1H, s), 9.30 (2H, s). MS (ESI+): MH+ 561.20 (100%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:12]=1
Reactant: Brc1ccccc1-c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of crude 4-(2-bromo-phenyl)-1H-imidazole (73.5 g, 0.33 mol) and triethylamine (45.8 ml, 0.33 mol) in dry dimethylformamide (750 ml) at 0° C. was added a solution of trityl chloride in dry dimethylformamide (850 ml) dropwise over 40 min. When the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 1.5 h. Then the reaction mixture was poured into a stirring mixture of ice water (ca. 2.0 L). A light orange solid precipitated. After stirring for 20 min the solid was filtered and dried to give a light amber solid. This solid was used in the next reaction without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:11]=[N:10][CH:9]=[C:8]2[CH3:25])=[O:4].[Li+].[OH-].Cl>C1COCC1.O.O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:13]([F:24])=[C:12]2[C:7]([C:8]([CH3:25])=[CH:9][N:10]=[N:11]2)=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2c(C)cnnc2c(F)c1Nc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnnc2c(F)c(Nc3ccc(Cl)cc3Cl)c(C(=O)O)cc12
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid methyl ester (54 mg, 0.14 mmol) in THF-water (3 mL/l mL) was added 1 N aqueous LiOH (0.30 mL, 0.30 mmol) at room temperature. After 30 minutes, the reaction mixture was adjusted to pH 6-7 with 1 N aqueous HCl, diluted with water, and extracted with EtOAc-THF. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 31 mg (60%) of the crude product (31 mg, 60%), which was used directly without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)cc1
Yield: 56.5 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (98 mg), 120 mg 6-(4-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 118 mg (57%) of the title compound as a brown solid.