Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].C(O)(=[O:23])C.OO>C(Cl)Cl>[C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:23])=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Reactant: CC(=O)O
Agent: OO
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 51.6 g (0.178 mol) of 2-propionyl-3-hydroxy-5-(4-methylthiophenyl)cyclohex-2-en-1-one (prepared as in U.S. Pat. No. 4,555,263) in 150 mL of methylene chloride and 150 mL of glacial acetic acid was added 20.15 g (0.178 mol) of 30 percent hydrogen peroxide dropwise over 20 minutes. The reaction temperature rose 20° to 28° C. at which point, the reaction mixture was cooled in a cold water bath. After 20 minutes, an additional 6.75 g (0.0595 mol) of 30 percent hydrogen peroxide was added dropwise and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with 150 mL of methylene chloride, washed thrice with 250 mL portions of water and then with 200 mL of aqueous sodium bicarbonate. The organic layer was separated and dried over Na2SO4 and the solvent removed in vacuo leaving 51.6 g (94.8 percent of theoretical) of the above named product melting at 111°-117° C. Recrystallization of the residue from 2-propanol gave the pure product in a yield of 46.1 g (84.7 percent of theoretical). The product melted at 116°-117° C.; Rf -0.07 (silica gel, 50:50 ethyl acetatehexane and 1.0 percent acetic acid), 1H NMR (CDCl3): δ1.1 (t, 3H, --CH2CH3), 2.70 (s, 3H, CH3SO--), 2.7-3.7 (m, 7H, ring protons and --CH2CH3), 7.25-7.70 (m, 4H, ArH), 18.1 (s, 1H, OH).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C(F)(F)F)cc2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(C(F)(F)F)cc2)n1
Yield: 58.3 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.36 g, 4.80 mmol) and phenyl chloroformate (1.82 mL, 14.4 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (113 mg, 2.80 mmol, 58%). 1H NMR (300 MHz, DMSO-d6) δ 10.20 (br s, 1H), 7.93 (d, 2H), 7.81 (d, 2H), 7.40-7.10 (m, 5H), 6.44 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:19][OH:20])[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH:19]=[O:20])[N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
While under nitrogen, a stirred solution of tert-butyl 7-chloro-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (Step 6, 270 mg, 0.907 mmol) in methylene chloride (11 mL) was cooled in an ice-water bath and treated dropwise with a solution of Dess-Martin periodinane (461 mg, 1.09 mmol) in methylene chloride (3 mL) over several minutes. The cooling bath was removed, and the resulting clear mixture was stirred at room temperature for 1.5 h. Once complete, the mixture was re-cooled in an ice-water bath, quenched portionwise with a 1:1 mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 (20 mL total) and stirred for 10 min at room temperature. The layers were separated, the aqueous phase was re-extracted with methylene chloride (20 mL), and the combined organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (40 g column, 10-30% ethyl acetate in hexanes) gave tert-butyl 7-chloro-3-formyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (162 mg, 60%) as a clear gum. 1H NMR (DMSO-d6, 400 MHz) δ 9.45 (bs, 1 H), 7.34 (m, 1 H), 7.26 (m, 2 H), 4.78 (m, ˜0.5 H), 4.64 (m, ˜0.5 H), 4.50 (m, 2 H), 3.21 (m, 1 H), 3.05 (m, 1 H), 1.46 (s, ˜4.5 H), 1.38 (s, ˜4.5 H) (mixture of rotamers).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[OH:12].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([S:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:22][CH:21]=2)[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1O
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A mixture of 2-Methyl-4-nitro-5-chloro phenol (1.5 g, 8.0 mmol), 4-Acetamido thiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF (10 mL) was heated 2.5 h at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum leaving the title compound as a solid (2.5 g, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[O:34][CH3:35])[C:18]([Cl:36])=[CH:17][N:16]=1.ClC1N=C(Cl)C(Cl)=CN=1.COC1C=C(N2CCOCC2)C=CC=1N>CO.C(Cl)Cl>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:24][C:23]=2[O:34][CH3:35])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCCc2cc(N)ccc21
Agent: COc1cc(N2CCOCC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCCCN3C)ncc1Cl

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (33 mgs, 0.19 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (1.2 eq) [prepared using a procedure analogous to Example 1d using 2,4,5-trichloropyrimidine and 2-Methoxy-4-morpholin-4-yl-phenylamine] were reacted except that the ISCO chromatography gradient was 0% to 5% MeOH/CH2Cl2 to give 5-Chloro-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-N*2*-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-pyrimidine-2,4-diamine (46.96 mgs) as an off-white/grey solid. MP=206-207° C. 1H-NMR (CDCl3) δ 8.27 (d, J=8.9 Hz, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.36 (s, 1H), 7.28-7.24 (m, 1H), 6.91 (d, J=9.1 Hz, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 6.50 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.91-3.89 (m, 4H), 3.17-3.15 (m, 4H), 2.91-2.85 (m, 4H), 2.82-2.77 (m, 4H), 1.89-1.78 (m, 2H), 1.71-1.58 (m, 2H); LC/MS (ESI+): 495.29 (M+H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(SCc3ccccc3)c2n1
Reactant: C1CNCCN1
Product: c1ccc(CSc2ncnc3c(N4CCSCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 162°-164° C.) and piperazine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26][CH2:25]1.[Na]>CN(C)C=O>[C:28]1(=[O:30])[N:29]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:29]2[C:24](=[O:31])[CH2:25][CH2:26][CH2:27][C:28]2=[O:30])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:24](=[O:31])[CH2:25][CH2:26][CH2:27]1
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Reactant: O=C1CCCC(=O)N1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1CCCC(=O)N1CCOC(OCCN1C(=O)CCCC1=O)(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
Benzil-di-(β-bromoethyl)ketal (13.26 g) and 8.91 g of sodium glutarimide were dissolved in 50 ml of N,N-dimethylformamide, and reacted at 50° C. for 7 hours. When the reaction mixture was poured into 200 ml of ice water, white crystals formed. These crystals were washed with water, and dried to give 13.6 g of benzil-di-(β-glutarimidoethyl)ketal.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3(O)[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][CH:17]34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
The 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (5 g, 11.73 mmol) was mixed with thionyl chloride (1.712 mL, 23.45 mmol) and anhydrous toluene (80 mL). Pyridine (0.190 mL, 2.345 mmol) was then added dropwise. The mixture was stirred under nitrogen at room temperature for 30 min and 90° C. for 15 min. The mixture was concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and dichloromethane (100 mL, 2×50 mL). The combined dichloromethane extracts were dried over sodium sulfate, filtered through a pad of silica gel and concentrated under reduced pressure. Flash chromatography purification (220 g silica gel column, 25→60% dichloromethane in hexanes) and trituration with methanol gave 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (1.96 g, 4.80 mmol, 40.9% yield) as a white solid. The compound had an HPLC retention time=4.28 min (condition C); LC/MS M+1=408.9.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[N:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[N:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)nnc1OCC(F)(F)F
Yield: 52 %

Procedure:
The title compound is prepared in 52% yield (37 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (58 mg, 0.15 mmol, Intermediate-65, single enantiomer) and phenyl formate (37 mg, 0.30 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24](C(=S)N)[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])O.[Na+].BrC[C:36](=O)[CH3:37]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24]([SH:18]3[CH:37]=[CH:36][N:21]([CH3:20])[CH2:17]3)[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(=O)CBr
Reactant: NC(=S)c1ccc2nc(C(O)(Cn3cncn3)c3ccc(F)cc3F)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1C=C[SH](c2ccc3nc(C(O)(Cn4cncn4)c4ccc(F)cc4F)sc3c2)C1

Procedure:
1-(2,4-Difluorophenyl)-1-(6-thiocarbamoylbenzothiazol-2-yl)-2-(1H-1,2,4-triazol-yl)ethanol is reacted with sodium hydrogencarbonate and bromoacetone to obtain 1-(2,4-difluorophenyl)-1-(6-(3-methylthiazol-1-yl)-benzothiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([C:33]2[N:37]3[CH:38]=[C:39]([O:42][C@H:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[C@@H:46]([NH2:53])[CH2:45][CH2:44]4)[CH:40]=[CH:41][C:36]3=[N:35][N:34]=2)[CH2:28]1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:46]2[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@H:29]5[CH2:30][CH2:31][CH2:32][N:27]([CH3:26])[CH2:28]5)=[N:34][N:35]=4)[CH:38]=3)[CH2:44][CH2:45]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCC[C@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@H]5CCCN(C)C5)n4c3)c3ccccc32)cc1
Yield: 74 %

Procedure:
An orange-brown solution (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 243 mg, 0.600 mmol), Intermediate 88e (151 mg, 0.400 mmol) and DIPEA (0.122 mL, 0.700 mmol) in dry dioxane (5 mL) was stirred at 65° C. for 15 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (30 mL); concentration in vacuo left a brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a pale yellow solid (188 mg, 74%). LCMS (Method 5): Rt 3.63 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.55 (1H, qd, J 11.9, 5.3), 1.68-1.79 (2H, m), 1.83-2.03 (4H, m), 2.06-2.14 (2H, m), 2.22 (1H, t, J 10.9), 2.22 (3H, s), 2.36 (3H, s), 2.83 (1H, br d, J 10.9), 3.01 (1H, ddd, J 11.1, 3.6, 1.6), 3.54 (1H, tt, J 11.1, 3.7), 4.83 (1H, td, J 8.4, 5.5), 5.57 (1H, t, J 4.5), 6.33 (1H, s), 7.09 (1H, d, J 8.5), 7.15 (1H, dd, J 9.8, 2.0), 7.27-7.42 (8H, m), 7.68 (1H, d, J 9.9), 8.03 (1H, s), 8.32 (1H, d, J 2.0).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[S:37][C:36]([NH2:38])=[N:35][CH:34]=2)=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:27]=[CH:28][C:29]([O:32][C:33]2[S:37][C:36]([NH:38][C:14](=[O:15])[CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:12][CH:11]=3)[O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[N:35][CH:34]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(Oc2cnc(N)s2)cc1
Reactant: O=C(O)C(O[C@@H]1CCOC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 72 %

Procedure:
The compound of example A77 was obtained by similar method described in example A75 using (4-Cyclopropanesulfonyl-phenyl)-[(R)-(tetrahydro-furan-3-yl)oxy]-acetic acid (preparation 15) (0.150 g, 0.46 mmol), 4-(2-Amino-thiazol-5-yloxy)-benzoicacid methyl ester (0.140 g, 0.55 mmol), HOBt (0.075 g,0.55 mmol), and EDCI (0.106 g, 0.55 mmol), N-methyl morpholine (0.055 g, 0.55 mmom) in DMF (10 mL) to provide the title compound (185 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:28][CH:29]=2)=[O:23])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:38]([O:44][CH2:45][I:46])(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[I-:46].[I-:46].[CH3:37][N+:34]1([CH2:45][O:44][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:33][CH2:32][N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:22](=[O:23])[NH:21][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([NH:8][C:9]4[N:14]=[C:13]([C:15]5[CH:20]=[N+:19]([CH2:45][O:44][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:18]=[CH:17][CH:16]=5)[CH:12]=[CH:11][N:10]=4)[CH:6]=3)=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CC(C)(C)C(=O)OCI
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(CN3CC[N+](C)(COC(=O)C(C)(C)C)CC3)cc2)cc1Nc1nccc(-c2ccc[n+](COC(=O)C(C)(C)C)c2)n1
Product: [I-]
Temperature: 25 °C
Yield: 25 %

Procedure:
Imatinib [148] (0.100 g, 0.2 mmol, 1 eq) was dissolved in DCM (10 ml) in a 25 ml two-necked round bottomed flask and iodomethyl pivalate [40] (0.185 g, 0.77 mmol, 3.8 eq) was added while stirring at RT. After 48 h stirring, the precipitate formed was filtered under vacuum and washed with DCM to give the product, 1-methyl-4-(4-((4-methyl-3-((4-(1-((pivaloyloxy)methyl)pyridin-1-ium-3-yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)-1-((pivaloyloxy)methyl)piperazin-1-ium diiodide [42], as a yellow solid. (0.050 g, 25% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:11])[CH3:2].C[Al](C)C.N#N.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])=[CH:6][C:5]=1[F:11])[CH3:13]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CCN(CC)c1ccc(N)cc1F
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: CCN(CC)c1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.2 %

Procedure:
To a solution of N1,N1-diethyl-2-fluorobenzene-1,4-diamine (1.50 g, 8.23 mmol) in anhydrous CH2Cl2 (60 mL) was added trimethylaluminium (33 mL, 33 mmol, 1 M in heptane) dropwise slowly under N2. Upon the end of addition the mixture was stirred at rt for 40 min. To this mixture was added a solution of methyl 3-acetaminocrotonate (2.58 g, 16.40 mmol) in anhydrous CH2Cl2 (20 mL). The resulting reaction mixture was stirred at rt for another 6 h, then quenched with water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was recrystallized from EtOAc to give the title compound as a pale yellow solid (1.60 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)C.BrBr.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[C:19]([O:18][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCCCCC(CCC1=C(OC(C)=O)CCC1)OC(C)=O
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCC(CCC1=CCCC1=O)OC(C)=O
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
To a stirred solution of 1-acetoxy-2-(3-acetoxyoctyl)cyclopent-1-ene (59.2 g.) [prepared as described in (e) above] in dry carbon tetrachloride (350 ml.) was added dropwise, during 30 minutes, a solution of bromine (32 g.) in dry carbon tetrachloride (100 ml.) at -10° to -5° C. The solution was stirred for a further 20 minutes without cooling. Triethylamine (22.2 g.) was then added and the resulting mixture stirred and refluxed for 90 minutes. The mixture was filtered, and the filtrate washed with aqueous 2N sodium carbonate and with water. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the residue was distilled, in the presence of a few crystals of potassium acetate, at 132°-168° C./0.25 mm.Hg, to give crude 2-(3-acetoxyoctyl)cyclopent-2-enone. This was redistilled, with potassium acetate, at 116°- 135° C./0.15 mm.Hg to give 2-(3-acetoxyoctyl)cyclopent-2-enone (28.7 g.), nD28 = 1.470.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1.C(Cl)Cl>CCOCC>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:10]2[CH2:11][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[N:9]2)=[S:31])=[CH:25][CH:24]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: FC(F)(F)c1ccc(C2=NN(C(=S)Nc3ccc(Cl)cc3)CC2c2ccccc2)cc1
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of 0.7 g of the compound from Step B and 0.41 g of 4-chlorophenyl isothiocyanate were combined in a solvent mixture of 2 mL methylene chloride and 5 mL ether. After stirring overnight the precipitated solids were filtered and dried to afford 0.69 g of the title compound as a white solid, mp 208°-210° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH2:21]([O:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:30]=2[N:31]=1)=[O:26])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[CH2:21]([O:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:4]=3)=[CH:32][C:30]=2[N:31]=1)=[O:26])[CH2:22][CH3:23]
Reactant: CCCOC(=O)c1nc2cc(O)ccc2o1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOC(=O)c1nc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1

Procedure:
A mixture of 3.47 g of 2-((3-chloromethylphenoxy)methyl)quinoline, 2.7 g of n-propyl-5-hydroxybenzoxazole-2carboxylate, 1.69 g of potassium carbonate and 1 ml of dimethylformamide is refluxed in 50 ml of acetone for 41 hours. The mixture is concentrated in vacuo and the residue is dissolved in water. This solution is neutralized with diluted hydrochloric acid and the resulting solid is filtered off and purified by flash silica gel chromatography in propanol-dimethylformamide to give n-propyl-5-(3-(quinolin-2-ylmethyloxy)benzyloxy)-benzoxazole-2-carboxylate