Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH2:17]([Mg]Br)[CH:18]=[CH2:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:19][CH:18]=[CH2:17])[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.9 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)benzaldehyde (10 g, 41 mmol) in THF (100 mL) was drop wise added allylmagnesium bromide (50 mL, 1 M in THF, 50 mmol) at −40° C. The reaction mixture was stirred at room temperature for 5 h and then poured into saturated aqueous NH4Cl solution and extracted with EtOAc (2×100 mL). The organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (800 mg, yield: 7%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][NH:23][CH2:24]2>CN(C=O)C>[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:24]2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: Nc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4cccc(N)c4C3)cc21
Yield: 54.9 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 282 mg of 4-amino-isoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 141 mg of the target compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N:30]1[N:31]=[CH:32][N:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][N:41]([C:38]3[CH:37]=[CH:36][C:35]([N:33]4[CH:34]=[N:30][N:31]=[CH:32]4)=[CH:40][CH:39]=3)[C:42](=[O:44])[CH3:43])[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: CC(=O)Nc1ccc(-n2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(-n2cnnc2)cc1
Temperature: 50 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (60 mg, 0.14 mmol) from Example 5 step 1 and N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide (30.6 mg, 0.15 mmol) were added in DMF (0.7 mL), then cesium carbonate (224 mg, 0.69 mmol) was added and the reaction was heated to 50° C. overnight. The reaction was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™silica gel cartridge eluting with 50% acetone/hexanes to give the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[CH:9]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([S:29]([CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])(=[O:31])=[O:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:43]([C:42]2[CH:41]=[CH:40][C:39]([C:35]3[O:36][C:37]([CH3:38])=[C:33]([CH2:32][S:29]([CH:26]4[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]4)(=[O:30])=[O:31])[N:34]=3)=[CH:47][CH:46]=2)=[O:44])[CH:9]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Triethylamine (440 mg, 4.36 mmol, 3.00 equiv) was added dropwise with stirring to a solution of pyridin-3-ylmethanamine (170 mg, 1.57 mmol, 1.10 equiv), 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid (670 mg, 1.44 mmol, 1.00 equiv), EDCI (330 mg, 1.73 mmol, 1.20 equiv) and HOBT (230 mg, 1.70 mmol, 1.20 equiv) in N,N-dimethylformamide (10 mL) contained in a 50-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water/ice. The precipitate was collected by filtration and dried in an oven under reduced pressure to give 0.74 g (93%) of tert-butyl 4-((2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 555 [M+H]+, 455.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)[CH:9]=1)([O-])=O.[H][H].Cl>C(O)(C)C.[Pd]>[NH2:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=[C:4]([NH2:1])[CH:5]=2)[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Oc2cccc(Oc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)c2)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: Nc1cc(Oc2cccc(Oc3cc(N)cc(C(F)(F)F)c3)c2)cc(C(F)(F)F)c1

Procedure:
Into a reducing device equipped with a thermometer, a reflux condenser and an agitator were charged 72 g of 1,3-bis(3-nitro-5-trifluoromethylphenoxy)benzene (0.147 mol), 500 mL of isopropyl alcohol and 7.2 g of 5%-Pd/C (50% of water content), and the mixture was reacted at 50° C. for 5 hours in an atmosphere of hydrogen. At the end of the reaction, the catalyst was filtered out, the filtrate was condensed under a reduced pressure and the residue was dissolved in 200 g of isopropanol and 400 g of 36% HCl was added to the solution to precipitate the desired hydrochloride. The hydrochloride was suspended in 150 g of water and 200 g of 1, 2-dichloroethane (EDC), the mixture was neutralized with 28% ammonium hydroxide aq. and separated, and the EDC layer was washed with water and evaporated to give 1,3-bis(3-amino-5-trifluoromethylphenoxy)benzene as a brown viscous liquid; Yield: 33.8 g (53.7%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([I:1])[CH:3]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a flask containing the product of Step 2 (2.79 g, 7.06 mmol) in AMY (71 mL) were added tert-butyldimethylsilyl chloride (1.60 g, 10.59 mmol), imidazole (0.96 g, 14.12 mmol) and DMAP (86 mg, 0.71 mmol). After two hours, The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel was used for purification to yield N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodophenyl]-4-(trifluoromethyl)pyrimidin-2-amine (3.46 g, 6.79 mmol, 96% yield). MS ESI: [M+H]+ m/z 510.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=1[F:46])=[O:37])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[O:18])[CH:13]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][C:40]1[CH:41]=[CH:42][C:43]([CH3:45])=[CH:44][C:39]=1[NH:38][C:36]([NH:35][C:34]1[CH:33]=[CH:32][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]3[NH:16][CH:15]=[C:14]([C:17]([N:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[O:18])[CH:13]=3)[CH:7]=2)=[CH:3][C:2]=1[F:1])=[O:37]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c[nH]4)c3)cc2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCNCC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazine-1-carboxylate (200 mg, 0.32 mmol) in 10 ml of methylene chloride was added 3 ml of TFA. The mixture was stirred at room temperature for 30 minutes, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5 ml of methanol and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 12% methanol in chloroform to give 1-(2-fluoro-5-methylphenyl)-3-[2-fluoro-4-({2-[4-(piperazin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]urea as white solid. Yield: 145 mg, 86%
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([O:17]CC)=O)[CH2:12][C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([NH:24][CH2:21][CH:22]=[CH2:23])=[O:17])[CH2:12][C:11]=3[CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCN
Reactant: CCOC(=O)C1Cc2cc(-c3ccccc3)ccc2O1
Solvent: CCO
Product: C=CCNC(=O)C1Cc2cc(-c3ccccc3)ccc2O1

Procedure:
An ethanol solution of 1E and an excess of 2-propenamine was refluxed for 2.5 days. The excess amine and the solvent were evaporated under reduced pressure. The resulting gum was recrystallized from methylene chloride/hexane to give 1, as a white solid, mp: 112° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:10]=1[C:11](Cl)=[O:12].[CH:20]1([NH:25][C:26]([CH3:33])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[CH:20]1([NH:25][C:26]([CH3:33])=[C:27]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:9]=2[F:8])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C=C(C)NC1CCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)c1cc(F)c(F)cc1F)=C(C)NC1CCCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under ice cooling, triethylamine and 2,4,5-trifluorobenzoyl chloride were added to a solution of ethyl 3-(cyclopentylamino)buta-2-enoate in dioxane, for stirring at ambient temperature for 30 minutes and at 65° C. for one hour, to obtain ethyl 3-(cyclopentylamino)-2-(2,4,5-trifluorobenzoyl)buta-2-enoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:19]([NH:20][C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH:18]=[C:17]([O:16][CH3:15])[C:23]=1[O:24][CH3:25]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)C2CSC(c3cccnc3)N2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 630 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 520 mg of 3,4,5-trimethoxyaniline, 650 mg of dicyclohexylcarbodiimide and 430 mg of 1-hydroxybenzotriazole in 8 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with aqueous sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent: ethyl acetate) gave 370 mg of N-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in 10 ml of ethyl acetate, and 2 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give mg of N-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. Melting point 130°-132° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:32])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(C)=O

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (2.15 g, 6.95 mmol) by reaction with m-CPBA (1.71 g, 7.64 mmol) to provide 5-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one followed by reaction with p-toluenesulfonyl chloride (1.46 g, 7.64 mmol) and ammonium hydroxide solution (10 mL) to provide 5-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one as an off-white solid, mp 173-176° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([O:11]CC)=[O:10])=[N:4][O:5][C:6]=1[CH:7]=[CH2:8].CO.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][O:5][C:6]=1[CH:7]=[CH2:8]
Reactant: C=Cc1onc(C(=O)OCC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1onc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 4-methyl-5-vinylisoxazole-3-carboxylate (250 mg, 0.993 mmol) was dissolved in THF (5.3 mL) and MeOH (3.2 mL) and to this was added 2M NaOH (aq) (497 μl, 0.993 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The resulting mixture was concentrated under reduced pressure and treated with 2M HCl (5 mL) and water (5 mL). DCM was added to the aqueous resulting in the formation of an emulsion. The solvent was removed under reduced pressure. The resulting residue was suspended in DCM (25 mL) and passed through a phase separating column. The organic solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23]SC1C(C2C=NC=CC=2)=NNC=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH2:18][N:19]([CH3:23])[CH2:20][CH2:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C(#Cc1c[nH]nc1-c1cccnc1)CCCC1CCCCC1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CN1CCC=C(c2n[nH]cc2C#CCCCC2CCCCC2)C1
Yield: 90 %

Procedure:
Compound 44E was converted to compound 45E, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 90% (amorphous). LCMS (method A); Rt 2.28 min, ([M+H]+=312). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.76-6.71 (bs, 1H), 3.41-3.37 (m, 2H), 2.59 (bt, J=7 Hz, 2H), 2.45-2.35 (m, 7H), 1.75-1.55 (m, 6H), 1.35-1.10 (m, 7H), 0.94-0.8 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:21][O:22]CC3C=CC=CC=3)=[O:20])[O:16][C:15]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:21][OH:22])=[O:20])[O:16][C:15]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(NOCc1ccccc1)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: O=C(NO)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
To a mixture of (5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-N-benzyloxy -2-oxo-5-oxazolidinecarboxamide (Step 1, 300 mg, 0.722 mmol) in methanol (28.8 mL) is added 5% palladium-on-carbon (77 mg) under nitrogen. The resulting mixture is degassed and stirred under a hydrogen atmosphere (balloon) for 1 h. The catalyst is then removed by filtration through Celite, rinsing with methanol (60 mL), and the filtrate is concentrated under reduced pressure. Trituration of this residue with (5% methanol methylene chloride)/diethyl ether gives the title compound, mp 141-143° C.; MS (ESI+) for C14H16FN3O5 m/z 326 (M+H)+; [α]25D=−70° (c 0.99, DMSO).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[C:19]([CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#[N:20]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1CC#N
Temperature: 0 °C

Procedure:
To 32 parts 4-bromomethyl-2,5-diisopropylbenzenesulfonamide in 100 parts dimethylsulfoxide is added 10 parts sodium cyanide. The reaction is heated at 65°-70° for 30 minutes and then poured into ice water to give 4-cyanomethyl-2,5-diisopropylbenzenesulfonamide. Purification is accomplished by recrystallization or chromatography on Florisil, silica gel, alumina, etc., but the relatively pure reaction product is useful in the compositions and methods of this invention without purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1)(=[O:21])[CH3:20].C(OCC)C.C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[N:11]=[C:10]([NH:12][C:13]3[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (200 mg, 0.77 mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed in tert-butanol (3 mL) over a 20 hour period. Diethylether (10 mL) is added to the mixture and a solid forms that is collected by filtration. This solid is suspended in EtOH/H2O 1 mL/3 mL), then K2CO3 (110 mg, 0.8 mmol) is added and the suspension is stirred for 2 h at room temperature. A solid forms and is collected and dried under vacuum to give the product [2-(4-acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])=[CH:10][CH:9]=1.[F:33][C:34]([F:41])([F:40])[C:35]([O:37]CC)=O>CO>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11]([NH:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[C:35](=[O:37])[C:34]([F:33])([F:40])[F:41])=[CH:10][CH:9]=1)[C:35](=[O:37])[C:34]([F:41])([F:40])[F:33]
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN(CCO)C(=O)C(F)(F)F)ccc(NCCN(CCO)C(=O)C(F)(F)F)c21

Procedure:
A suspension of 1.50 g. of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone in 75 ml. of ethyl trifluoroacetate and 75 ml. of methanol is stirred for 10 minutes. Evaporation of the resulting solution in vacuo at 30° C. leaves a residue which is washed and macerated with methylene chloride, giving 2.11 g. of blue-black solid, m.p. 162° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([O:23][CH3:24])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:12]=1>>[CH3:31][C:29]1[NH:28][N:27]=[C:26]([NH:25][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:20]3[C:15]([CH:14]=2)=[C:16]([O:23][CH3:24])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH:30]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(Oc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-hydroxy-benzonitrile and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-5,6-dimethoxy-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 402(MH+).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.I[CH:19]([CH3:21])[CH3:20].C[Si](C)(C)N[Si](C)(C)C.[Li]>C1COCC1>[CH:19]([C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (0.55 g, 2.26 mmol) and 2-iodopropane (0.32 mL, 3.2 mmol) in THF (2.5 mL) was stirred at −78° C. Lithium hexamethyldisilazane (3.2 mL, 3.2 mmol) was added, then the reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was partitioned between diethyl ether and brine. The ether extract was dried (MgSO4), filtered and concentrated in vacuo, to give the title compound (0.54 g, 84%) as a pale yellow syrup, which was used without further purification. δH (400 MHz, DMSO-d6) 3.86 (m, 2H), 3.68 (m, 3H), 2.69 (m, 2H), 1.99 (m, 2H), 1.68 (m, 1H), 1.53 (m, 1H), 1.36 (s, 9H), 1.28 (m, 1H), 0.80 (d, J 6.9 Hz, 6H).