Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[CH:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
Compound 26.2 (542 mg, 1.25 mmol, 1.00 equiv) was treated with Dess-Martin periodinane (637 mg, 1.50 mmol, 1.20 equiv) in 20 mL of DCM at 0° C. The resulting solution was stirred for 4 h at room temperature then quenched with water and extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2) to provide the desired tert-butyl N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino]cyclohexyl)carbamate 26.3 (494 mg, 92%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19]([OH:21])=[O:20].C([SiH](CC)CC)C>C(Cl)Cl>[F:25][C:24]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[NH:15][CH2:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a suspension of 2-(pyridin-2-ylamino)-thiazole-5-carbaldehyde (1.0 g, 4.90 mmol, compound 1A) in methylene chloride (20 mL) at RT 3-amino-4-fluorobenzoic acid (0.95 g, 4.90 mmol) TFA (5 mL) and triethylsilane (1.71 mg, 14.7 mmol) were added. The above reaction mixture was stirred at RT for 4 h, then concentrated in vacuo and the resulting slurry was triturated with methanol to afford 4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzoic acid as light yellow solid (1.54 g, 91%) (M+H)+=345.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[N:14])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1.[Cl-].[NH4+]>[NH2:14][C:13]1[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)CNc1ccccc1C#N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1N

Procedure:
To a solution of N-(2-Cyanophenyl)glycine ethyl ester (8.1 g) in THF (125 mL) was added potassium t-butoxide (4.5 g) in one portion with stirring. After 10 min at room temperature the mixture was diluted with saturated ammonium chloride solution and the product was extracted with ether. After drying over magnesium sulfate the solvent was removed in vacuo and the residue was recrystallized from 80% methanol to afford 3-Amino-2-carboethoxyindole as a tan solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26]([Cl:29])(=[O:28])=[O:27].Cl>O.C(Cl)Cl.CCOCC>[ClH:29].[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[NH:9][CH2:10][CH2:11][N:12]([S:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)(=[O:28])=[O:27])[CH2:13]2)[CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: C1CNC(CC2CCOCC2)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCNC(CC2CCOCC2)C1
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
A 100 mL round-bottomed flask was charged with 2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine (0.950 g, 5.16 mmol), 20 mL of CH2Cl2, triethylamine (0.790 mL, 5.67 mmol), and 2-thiophenesulfonyl chloride (0.942 mL, 5.16 mmol, Sigma-Aldrich, St. Louis, Mo.). After 15 min at room temperature, the mixture was diluted with water (50 mL) and CH2Cl2 (50 mL), the organics were separated, dried (MgSO4) and concentrated to give a dark oil. To this oil was added 50 mL of ether and 10 mL of 1N HCl in ether. The resulting white precipitate was collected by filtration to give 3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-thiophenylsulfonyl)piperazine hydrochloride (1.45 g) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH2:8][CH2:7]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.CC(C)=O.C(OCC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:28])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(-c3cccnc3)cc(Cl)c2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(-c3cccnc3)cc(Cl)c2N1

Procedure:
A mixture of 8-chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one (900 mg, 3.48 mmol) and Lawessons reagent (985 mg, 2.44 mmol) was refluxed in 50 ml toluene for 2 h. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (ethyl acetate, Rf=0.26) and crystallization from acetone/diethylether. 8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione was obtained as yellow needles (212 mg, 0.77 mmol, 22%), mp (acetone/diethylether) 175° C. 1H-NMR (500 MHz, DMSO-d6): δ=2.91 (m, 2H), 3.00 (m, 2H), 7.46 (ddd, 3J=7.9 Hz, 3J=4.9 Hz, 5J=0.9 Hz, 1H), 7.66 (d, 4J=2.1 Hz, 1H), 7.76 (d, 4J=2.0 Hz, 1H), 8.09 (ddd, 3J=7.9 Hz, 4J=2.4 Hz, 4J=1.5 Hz, 1H), 8.56 (dd, 3J=4.9 Hz, 4J=1.5 Hz, 1H), 8.91 (dd, 4J=2.4 Hz, 5J=0.9 Hz, 1H), 11.31 (bs, 1H). 13C-NMR (125 MHz, DMSO-d5): δ=25.6, 39.4, 120.5, 123.8, 125.2, 126.0, 129.7, 133.4, 133.6, 133.8, 133.9, 147.5, 148.8, 201.5. MS m/z=273.95 (M35Cl+), 275.95 (M37Cl+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
A slurry of dichlorobis(triphenylphosphine)palladium(II) (119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00 g, 2.79 mmol). The reaction slurry was stirred at 25° C. for 10 min and then treated with a solution of pyridine-3-boronic acid (515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8 mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was heated under reflux for 90 min. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the catalyst. The filtrate was partitioned between water and methylene chloride, and the layers were separated. The aqueous layer was further extracted with methylene chloride (75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester (800 mg, 92%) as a brown oil: EI-HRMS m/e calcd for C20H23NO2 (M+) 309.1729, found 309.1728.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:16]([Cl:25])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[Cl:25][C:16]1[CH:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][CH:22]([F:24])[F:23]
Reactant: CC(c1ccc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Reactant: O=COc1ccccc1
Product: CC(c1ccc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 70 %

Procedure:
The title compound is prepared in 70% yield (86 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-25, single enantiomer) and phenyl formate (63 mg, 0.52 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH:31]([NH2:34])([CH3:33])[CH3:32].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:34][CH:31]([CH3:33])[CH3:32])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(I)cc3F)c2C#N)CC1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)Nc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C#N)c(F)c1
Temperature: 80 °C
Yield: 22.8 %

Procedure:
4-[5-Cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (250 mg, 0.48 mmol), isopropylamine (408 μL, 4.8 mmol), proline (99 mg, 0.86 mmol), copper iodide (92 mg, 0.48 mmol) and potassium carbonate (152 mg, 1.1 mmol) were mixed together in DMSO (4 mL). The reaction vessel was heated in a microwave at 80° C. for 1.0 hour. Progress of the reaction was monitored by TLC and LCMS. Purification by HPLC afforded compound A63 as a white solid (50 mg, 23%). 1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 7.99 (t, 1H), 7.12 (s, 1H), 6.93 (t, 2H), 5.38 (h, 1H), 4.87 (h, 1H), 3.72 (m, 2H), 3.52 (m, 1H), 1.91 (m, 2H), 1.77 (m, 2H), 1.92 (m, 2H), 1.26 (d, 6H), 1.13 (d, 6H). Exact mass calculated for C23H29FN6O3 456.51, found 457.1 (MH+).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:13]([CH3:14])=[CH:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[CH:1]1([CH:7]([C:9]2[C:13]([CH3:14])=[CH:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[CH:10]=2)[O:8][C:26]2[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(O)C1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])N=NC(=O)[O-]
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 87.4 %

Procedure:
To a solution (15 mL) of cyclohexyl{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methanol (0.81 g) synthesized in Example 298 (6) in tetrahydrofuran were added methyl 4-hydroxybenzoate (0.4 g), tributylphosphine (1.2 mL) and dipiperidide azodicarboxylate (1.2 g) with stirring under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature overnight. Hexane was added to the reaction mixture, and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was purified by silica gel chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a methyl ester form of the title compound (0.96 g). This was dissolved in ethanol (5 mL), 1N sodium hydroxide (4 mL) was added at 60° C. and the mixture was stirred for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (4 mL) was added to the residue to give the title compound (0.88 g, 80%) as an amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[C:30]#[C:29][C:26]1[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: C#Cc1ccc(C)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#Cc2ccc(C)cc2)c(OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of ethyl 3-methoxy-4-trifluoromethane-sulfonyloxybenzoate (3.95 g), 4-methylphenylacetylene (1.54 g) and triethylamine (5.0 ml) in DMF (40 ml) was added bistriphenylphosphine palladium dichloride (0.25 g), and the mixture was stirred at 100° C. for 3 hours and then cooled to room temperature. To the mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:9) and recrystallized from ethyl acetateihexane to give pale yellow crystals of ethyl 3-methoxy-4-[2-(4-methylphenyl)ethynyl]-benzoate (2.02 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:4][CH:5]=3)=[O:27])[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: O=C(Cn1ccc(OCc2ccc(F)cc2)cc1=O)c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc(C(=O)Cn3ccc(OCc4ccc(F)cc4)cc3=O)cc2)CC1

Procedure:
4-(4-Fluoro-benzyloxy)-1-{2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2-oxo-ethyl}-1H-pyridin-2-one is prepared following example 1.1b from 100 mg (0.26 mmol) 1-[2-(4-chloromethylphenyl)-2-oxo-ethyl]-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (preparation 32.1) and 65 mg (0.65 mmol) N-methylpiperazine.
Reaction SMILES: [CH:1](=[N:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>CC1C=CC=CC=1C>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:18]([C:19]([OH:21])=[O:20])[CH2:17][C:16]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NCc1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Benzylidene-benzylamine [145.5 gm., 0.75 mole] and succinic anhydride [74.5 gm., 0.745 mole] were refluxed with o-xylene [750 ml.] for 12 hours. The solid, formed upon cooling to room temperature, was filtered, washed with ethanol and air dried. The solid was recrystallized from ethanol to give white needles of the title compound [76.0 gm., 34% yield]. After drying under vacuum and over boiling xylene the solid had a melting point of 169°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[C:7](C2C=CC(C)=CN=2)[CH:6]=1)=[O:4].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN[C@H]1CCCC[C@@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Ic1ccccc1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)c2cn[nH]c2c1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cnn(-c3ccccc3)c2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid methyl ester (0.183 g, 0.684 mmol) in DMF (5 mL) was added iodobenzene (0.15 g, 0.753 mmol), CuI (0.028 g, 0.137 mmol), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (0.04 g, 0.274 mmol), and Cs2CO3 (0.15 g, 1.36 mmol). The reaction mixture was stirred at 110° C. overnight, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gave 0.12 g (53%) of 445-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid methyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH:26]1([CH2:29]O)[CH2:28][CH2:27]1>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH2:29][CH:26]2[CH2:28][CH2:27]2)=[O:13])=[CH:6][CH:5]=1
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Reactant: OCC1CC1
Agent: Cl
Product: Nc1ccc(CC(C(=O)OCC2CC2)c2cn(C3CCCCC3)cn2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 ml of an HCl-saturated ether solution was added to a solution of 50.0 mg (0.16 mmol) of the compound from example 1i in 2 ml of cyclopropylcarbinol and stirred at room temperature for 12 h. The solution was then concentrated to dryness, and the resulting residue was dried under high vacuum. Purification by chromatography on silica gel with CH2Cl2/methanol as mobile phase afforded 29 mg of the title compound in the form of an amorphous solid.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.F[C:10]1[CH:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>CN(C=O)C>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:10]2[CH:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: FC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1cc(N2CCC(F)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-fluoropiperidine×HCl (691 mg, 4.9 mmol), TEA (2.2 ml, 16 mmol), 2-fluoro-4-amino-5-nitro-benzoic acid (900 mg, 4.5 mmol) and DMF (15 mL) is stirred for 4.5 h at 50° C. Then the mixture is concentrated, diluted with water and the precipitate is filtered and dried.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>CCOCC>[CH2:9]([N:11]([CH2:12][CH3:13])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)Cc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 11.9 ml of benzyl bromide in 100 ml of ether was added dropwise to a mixture of 30.9 ml of diethylamine in 100 ml of ether. This mixture was stirred overnight then filtered and washed with ether. The combined filtrate and wash was washed with water, dried and concentrated to an oil. This oil was distilled through a Kugelrohr and the fraction boiling at <70° C., 1.5 mm collected, giving 10.6 g of N,N-diethylbenzenemethanamine as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cccnc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Fc1cnc(Nc2cccnc2)nc1Nc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 24 h
Yield: 16.2 %

Procedure:
A mixture of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (280 mg, 1 mmol), 3-aminopyridine (113 mg, 1.2 mmol), sodium t-butoxide (134 mg, 1.4 mmol), binap (38 mg, 0.06 mmol), and palladium(II)acetate (14 mg, 0.06 mmol) in 9 mL of toluene was purged with N2 (3 cycles of alternating N2 and vacuum). The mixture was heated to 80° C. (oil-bath temperature). After 24 h, the mixture was cooled to room temperature and EtOAc (30 mL) and of water (10 mL) was added. After stirring 15 min, the precipitate was collected by filtration. A 1H NMR spectrum and ESI mass spectrum of the solid (150 mg) indicated the product (TLC analysis of the organic layer of the filtrate detected only starting materials). The crude product was slurried in 2 N HCl and the mixture was filtered. The filtrate was neutralized with 10% aqueous NaOH and concentrated. The material was slurried with MeOH and the solids removed by filtration. The concentrated material was slurried in CH3CN and TFA was added to afford a solution. N,N-diisopropylethylamine was added to the solution and the solid was collected by filtration, washing with CH3CN followed by Et2O to afford N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-pyridyl)-2,4-pyrimidinediamine (55 mg, 14%): Rf 0.42 (silica gel, 4:1:0.1:0.1 dichloromethane/ethyl acetate/methanol/concentrated ammonium hydroxide); mp 251-253° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.26 (s, 1H), 8.74 (s, 1H), 8.20-8.17 (m, 1H), 8.09-8.08 (m, 2H), 7.29-7.28 (m, 1H), 7.23-7.17 (m, 2H), 6.83-6.80 (m, 1H), 4.24 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 155.2, 149.8, 142.9, 141.6, 140.5, 140.0, 139.8, 139.7, 137.5, 132.1, 124.8, 123.0, 116.4, 115.1, 110.9, 64.1, 64.0; IR (ATR) 3264, 3195 cm−1; APCI MS m/z 340 [C17H14FN5O2+H]+. Anal. Calcd for C17H14FN5O2.0.5H2O: C, 58.70; H, 4.20; N, 20.13. Found: C, 58.71; H, 4.20; N, 19.51.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH3:22])[CH:16]=[C:15]3C(F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:27]C1C2C(=CC=C(O)C=2)N=C(C)C=1>>[Br:27][C:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[N:18]=[C:17]([CH3:22])[CH:16]=1
Reactant: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: Cc1cc(Br)c2cc(O)ccc2n1
Product: Cc1cc(Br)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
Synthesized as per 6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline using 4-Bromo-2-methyl-quinolin-6-ol as starting material. ESI-MS (M+H+): 378.1.