Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.Cl[C:53]1[C:58]([O:59][CH3:60])=[CH:57][N:56]=[C:55]([S:61][CH3:62])[N:54]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)(Cl)Cl>O1CCOCC1.O>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:53]1[C:58]([O:59][CH3:60])=[CH:57][N:56]=[C:55]([S:61][CH3:62])[N:54]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: COc1cnc(SC)nc1Cl
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2B2OC(C)(C)C(C)(C)O2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(SC)ncc2OC)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (300 mg) is dissolved in 1,4-dioxane (5 ml) and thereto are added 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (117 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (33 mg) and cesium carbonate (199 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added chloroform and water, and the insoluble materials are removed by filtration through Celite™. The filtrate is separated, and the organic layer is dried and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(5-methoxy-2-methylsulfanyl-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (165 mg). MS (m/z): 764 [M+H]+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:25])([CH3:24])[CH2:14][C:15]([C:20]([F:23])([F:22])[F:21])([OH:19])[CH2:16][C:17]#[CH:18])[CH:10]=[CH:11][CH:12]=1.[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1I)([CH3:29])([CH3:28])[CH3:27]>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.C(N(CC)CC)C.CN(C=O)C.C(OCC)C.[Cu]I>[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[C:18]#[C:17][CH2:16][C:15]([OH:19])([C:20]([F:21])([F:22])[F:23])[CH2:14][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:2]2[O:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:8]=1)([CH3:25])[CH3:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Reactant: C#CCC(O)(CC(C)(C)c1cccc(C2OCCCO2)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnccc1C#CCC(O)(CC(C)(C)c1cccc(C2OCCCO2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
A mixture of 6-(3-[1,3]dioxan-2-ylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (300 mg, 0.84 mmol), (4-iodopyridin-3-yl)carbamic acid tert-butyl ester (270 mg, 0.84 mmol), bis(triphenylphosphine)palladium(II) chloride catalyst (29.6 mg, 0.04 mmol) and copper (I) iodide (16 mg, 0.08 mmol) in 4 mL of anhydrous triethylamine and 1 mL of anhydrous DMF was stirred at room temperature for 12 hours. The reaction mixture was then diluted with 30 nL of diethyl ether and washed with 20 mL of aqueous saturated ammonium chloride solution and 20 mL of brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Column chromatography over silica gel with hexanes-ethyl acetate (5:1 to 1:1) provided 250 mg of the title compound as a foam (54% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])C(=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:34]([O:37]CC)(=[O:36])[CH3:35].Cl.[C:41]([O:44]CC)(=[O:43])[CH3:42]>CC(O)C>[C:41]([OH:44])(=[O:43])/[CH:42]=[CH:35]/[C:34]([OH:37])=[O:36].[C:34]([O:23][CH2:22][C:19]1[O:18][C:17]([S:14]([N:5]2[CH:4]=[C:3]([CH2:24][NH:25][CH3:33])[C:2]([F:1])=[C:6]2[C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)(=[O:16])=[O:15])=[CH:21][CH:20]=1)(=[O:36])[CH3:35]
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(COC(C)=O)o2)c(-c2cccnc2F)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(hydroxymethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (223 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=2:3→ethyl acetate) to give the title compound as a free base (basic TLC:Rf=0.22 (hexane:ethyl acetate=1:1)) (yield 42.2 mg). A solution of the obtained free base (42.2 mg) in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (11.5 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 37.4 mg, 23%).
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[C:14]([F:24])[CH:13]=3)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH3:8].[F:24][C:14]1[CH:13]=[C:12]2[C:17]([N:18]3[C@H:10]([CH2:11]2)[CH2:9][NH:8][CH2:20][C@H:19]3[CH3:21])=[N:16][C:15]=1[CH2:22][OH:23]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c(CO)nc3N21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNC[C@H]2Cc3cc(F)c(CO)nc3N21
Product: N
Yield: 156.4 %

Procedure:
A solution of 0.020 g (4R,9aR)-7-fluoro-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2N hydrochloric acid in dioxane was kept at room temperature for 18 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:satd. ammonia (9:1:0.1) to yield 0.011 g (4R,9aR)-(7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-methanol as brownish crystals.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH2:15])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH:15][C:26](=[O:27])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2c(Cl)cc3c(c2O1)CCC3)OCc1ccccc1
Yield: 98.2 %

Procedure:
Treatment of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (1.11 g, 4.27 mmol) with diisopropylethylamine (1.65 g, 12.8 mmol) followed by benzyl chloroformate (0.87 g, 5.12 mmol) generally according to the procedure described for Intermediate 7 provided 1.5 g (98%) of (±)-benzyl (4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as a white solid. mp 127-130° C.; Anal. calcd. for C20H20ClNO3: C, 67.13; H, 5.63; N, 3.91. Found: C, 67.03; H, 5.42; N, 3.80. Chiral HPLC separation of (±)-benzyl (4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (Chiralcel OD, methanol:water 9:1) provided two fractions. Fraction 1 (Rt=12.714 min Chiralcel OD, methanol:water 9:1); Fraction 2 (Rt=16.644 min, Chiralcel OD, methanol:water 9:1).
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:15][CH:14]([O:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: CC(O)COc1ccc(Oc2ccccc2)cc1
Reactant: Clc1ccccn1
Product: CC(COc1ccc(Oc2ccccc2)cc1)Oc1ccccn1

Procedure:
The resulting oily substance containing 1-(4-phenoxyphenoxy)-2-propanol is reacted with 2-chloropyridine in the same manner as described in Example 9 to give 2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine.
Reaction SMILES: [NH2:1][Al]CCl.[F:5][C:6]([F:24])([C:20]([F:23])([F:22])[F:21])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:18]#[N:19])[N:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=12.CO>C1(C)C=CC=CC=1>[F:24][C:6]([F:5])([C:20]([F:21])([F:23])[F:22])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:18](=[NH:1])[NH2:19])[N:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=12
Reactant: N[Al]CCl
Reactant: N#Cc1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Solvent: Cc1ccccc1
Solvent: CO
Product: N=C(N)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Temperature: 107 °C
Reaction time: 0.5 h

Procedure:
A solution of amino(chloro)methylaluminum (0.5 M in toluene, 18.13 mL, 9.06 mmol) was added quickly to a stirred solution of the intermediate from Step F (0.3006 g, 1.036 mmol) in toluene (12.63 mL) and the mixture was heated at 107° C. overnight. The reaction mixture was cooled to room temperature, MeOH was added and the mixture was stirred for 30 min. The reaction mixture was filtered through a plug of Celite™ (diatomaceous earth), washed through with 2M NH3 in MeOH and the filtrate was concentrated in vacuo to give the crude product. This was purified by flash chromatography using a DCM/MeOH (2 N NH3 in MeOH) gradient to afford the desired product, as a yellow solid. m/z=308.0 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:17])[C:7]=2[CH:18]=1)#N.[OH-:19].[Na+].Cl.[OH2:22]>>[CH:5]1[C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:17])[C:7]=2[CH:18]=[C:3]([C:1]([OH:22])=[O:19])[CH:4]=1
Reactant: N#Cc1ccc2c(c1)S(=O)c1ccccc1C=C2
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1C=C2

Procedure:
925 Mg. 3-cyanodibenzo[b,f]thiepin 5-oxide are refluxed for 31/2 hours in a mixture of 60 cc. 10% aqueous sodium hydroxide solution and 60 cc. denatured alcohol. The mixture is diluted with 1/2 liter of water and acidified with concentrated HCl. The acid precipitates and is filtered and dried. The yield of white dibenzo[b,f]thiepin-3-carboxylic acid 5-oxide is 965 mg. (97%), m.p. dec. 249° C.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][CH:9]1[CH2:10][C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13]
Reactant: CN
Reactant: O=C1C=CC(=O)N1c1ccccc1
Product: CNC1CC(=O)N(c2ccccc2)C1=O

Procedure:
Furthermore, it is known that N-phenylmaleimide can be reacted with methylamine to give 3-methylamino-1-phenylpyrrolidine-2,5-dione which can be reduced with lithium aluminum hydride to give 3-methylamino-1-phenylpyrrolidine (J. Med. Chem. 10, 1015 (1967)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[S:9][CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1.I([O-])(=O)(=O)=[O:16].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[S:9](=[O:16])[CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1
Reactant: O=C(O)c1cc(Br)cc2c1NCCS2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2c1NCCS2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-1,4-benzothiazine-5-carboxylic acid (500 mg) in methanol 80 ml) was added 0.05M sodium metaperiodate solution (40 ml) The mixture was stirred for 5 hours at room temperature, then diluted with water (500 ml) and concentrated until crystals began to separate. The crystals were collected and dried to give the title compound (300 mg, 57.5% which was recrystallized from ethanol to give pale yellow crystals, mp 254°-255° C. (decompd.).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30]O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30][F:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To an ice cooled solution of DAST (2 equivalents) in methylene chloride under N2 was added the alcohol prepared in Step 4 in methylene chloride dropwise. The yellow solution was stirred at 0° C. to room temperature for 20 hours. The reaction was diluted with NaHCO3, and the organic layer was separated and dried over sodium sulfate. The crude product was chromatographed on silica gel eluting with 10-50% EtOAc/hexanes giving the desired title compound as a yellow oil (40%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[CH:25][CH:24]=2)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([NH:22][C:4]3[C:5]4[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]5[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=5)(=[O:14])=[O:13])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[N:3]=3)[CH:31]=2)[CH:27]=[N:28]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4c(C)cn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 115 °C
Yield: 17.7 %

Procedure:
To a mixture of 2-Chloro-N-(1H-indazol-6-yl)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.18 g, 0.4 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.22 g, 1 mmol) in n-butyl alcohol (2 mL) was added trimethylsilyl chloride (TMSCl) (0.026 mL, 0.2 mmol). After heating at 115° C. for 15 h, the mixture was purified by preparative HPLC to give 1-(4-(4-(4-(1H-indazol-6-ylamino)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (0.045 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(CCCCCl)c1cccc(C(F)(F)F)c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[3-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 473.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[N:15]1([CH2:21][CH:22]([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([N:18]3[CH2:17][CH2:16][N:15]([CH2:21][CH:22]([N:26]4[CH:30]=[C:29]([C:31]5[C:32]6[CH:39]=[CH:38][NH:37][C:33]=6[N:34]=[CH:35][N:36]=5)[CH:28]=[N:27]4)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19]3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CCC(CN1CCN(S(=O)(=O)c2ccc3[nH]ncc3c2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 16 h

Procedure:
1H-Indazole-5-sulfonyl chloride (26 mg, 0.12 mmol; from Step 1) was added to a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (24 mg, 0.041 mmol; from Example 12, Step 2) and triethylamine (57 uL, 0.40 mmol) in acetonitrile (0.30 mL). The mixture was stirred for 16 hours, then solvent was removed in vacuo. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product as the free base (5 mg, 24%). 1H NMR (300 MHz, d6-dmso): δ 12.08 (br s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.31-8.30 (m, 2H), 8.26-8.23 (m, 1H), 7.72 (d, 1H), 7.61 (dd, 1H), 7.52 (d, 1H), 6.87 (d, 1H), 4.93-4.81 (m, 1H), 3.39-2.41 (m, 12H); LCMS (M+H)+: 517.1.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([C:14]3[NH:22][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:23])[CH:5]=2)[CH2:3][CH2:2]1.[I:24][CH3:25]>ClCCl>[I-:24].[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:23])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][C:13]=2[C:14]2[NH:22][C:17]3[CH:18]=[N+:19]([CH3:25])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(-c2nc3ccncc3[nH]2)c(C2CC2)cc1C
Reactant: CI
Solvent: ClCCl
Product: COC(=O)c1cc(-c2nc3cc[n+](C)cc3[nH]2)c(C2CC2)cc1C
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 4-cyclopropyl-5-(3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoate (compound 87.2, 500 mg, 1.63 mmol) in dichloromethane (15 mL). Iodomethane (203 μL, 3.26 mmol) was added drop-wise and the resulting solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to yield 0.30 g (41%) of the title compound as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C@H:11]([C:17]([OH:19])=O)[CH2:12][CH2:13][C:14](O)=[O:15])=[O:9].C([N:22]([CH2:25]C)[CH2:23]C)C.C(Cl)(=O)OCC.Cl.[CH3:34][NH:35][CH3:36]>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][CH:11]([CH2:12][CH2:13][C:14]([N:35]([CH3:36])[CH3:34])=[O:15])[C:17]([N:22]([CH3:25])[CH3:23])=[O:19])=[O:9]
Reactant: CNC
Reactant: O=C(O)CC[C@H](NC(=O)C=Cc1ccco1)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)CCC(NC(=O)C=Cc1ccco1)C(=O)N(C)C
Yield: 55 %

Procedure:
In 100 ml of methylene chloride was suspended 5 g of the DL-N-[β-(2-furyl)acryloyl]glutamic acid, and 7 g of triethylamine was added to dissolve it. Subsequently, the resulting solution was cooled to -20° C. to -15° C., after which 4.6 g of ethyl chlorocarbonate was added dropwise, and the resulting mixture was subjected to reaction for 30 minutes. Thereafter, 3.1 g of dimethylamine hydrochloride was added, and the resulting mixture was subjected to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was washed successively with 50 ml of a 5% aqueous sodium hydroxide solution, 50 ml of diluted hydrochloric acid and 50 ml of water, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 3.5 g (yield 55%) of DL-2-[β-(2-furyl)acrylamido]-N1,N1,N5,N5 -tetramethyl-pentane-1,5-diamide having a melting point of 178°-180° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:35](=[O:36])[N:34]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C(Cl)(Cl)[Cl:43]>C(O)C>[ClH:43].[CH2:1]([O:3][C:4]([C:6]1[C:35](=[O:36])[N:34]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Solvent: CCO
Product: CCOC(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Product: Cl
Reaction time: 2 h

Procedure:
2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.40 g, 0.709 mmol, prepared as in Example 6) was dissolved in a mixture of chloroform (15 ml) and ethanol (15 ml) and the solution was purged with anhydrous hydrogen chloride gas. After 2 hours, the addition of ethyl acetate precipitated a solid which was filtered, washed with diethyl ether and dried in vacuo to yield 0.4 g of 8-cyclopentyl-7-oxo-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester hydrochloride as a yellow solid. MS (APCI); M++1: Calc'd, 464.53. Found, 464.4. Analyses for C24H29N7O3.0.75 H2O.2.0HCl. Calc'd: C, 52.41; H, 5.96; N, 17.83; Cl (ionic), 12.89; H2O, 2.46. Found: C, 52.25; H, 5.86; N, 17.85; Cl (ionic), 12.10; H2O, 1.52.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17](O)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]>>[CH3:19][C:13]1[C:12]2[N:11]=[C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=3)[O:8][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(O)c1N
Reactant: Nc1ccc(C(=O)O)cc1
Product: Cc1cccc2oc(-c3ccc(N)cc3)nc12
Temperature: 160 °C

Procedure:
To a suspension of 4-amino-benzoic acid (2.0 g, 14.5 mmol) in PPA (˜85 g) was added 2-amino-m-cresol (1.8 g, 15.3 mmol). The reaction was heated to 160° C. for 14 h, then carefully quenched in aqueous sodium carbonate (˜50% saturated) at room temperature. Ethyl acetate was added, and the organic layer was washed with water and brine, and dried over sodium sulfate. The crude product was obtained was subsequently purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes to afford the desired product, 4-(4-methyl-benzooxazol-2-yl)-phenylamine as a light pink solid, 1.8 g (56%). LC-MS m/z=225 [C14H12N2O+H]+.