Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.O1CCOCC1.Cl>CO>[ClH:24].[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Yield: 201.4 %

Procedure:
To a stirred mixture of glycine (30 g, 0.3996 mole) in 1N aqueous NaOH (39.96 g, 0.999 mole) was added tert-butanol (270 mL). The mixture was cooled to 0° C. and di-tert-butyl dicarbonate (96.42 g, 0.4395 mole) was added dropwise. The mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was acidified with citric acid. The product was extracted with ethyl acetate. the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 49 g (70%) of tert-butoxycarbonylamino-acetic acid. 1H NMR (DMSO-d6): δ 12.8-12.0 (bs, 1H), 7.1 (t, 1H), 3.6 (d, 2H), 1.4 (s 9H). To a stirred solution of tert-butoxycarbonylamino-acetic acid (0.2 g, 0.00114 mol) in DMF (5 mL) was added DIPEA (0.59 g, 0.00457 mol), HOBt (0.193 g, 0.001427 mol) and EDCI.HCl (0.274 g, 0.00143 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.283 g, 0.00114 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using basic aluminium oxide (60% ethyl acetate in hexane) to afford 0.41 g (98%) of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester. LCMS: 368.18 (M+1)+, 93.53%. A solution of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (0.41 g, 0.00111 mole) in methanol (10 mL) was added dioxane.HCl (5 mL) and the resulting mixture was stirred at ambient temperature for 10 minutes. The mixture was then concentrated under reduced and the resulting residue was washed with ether to afford 0.34 g (98%) of 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone hydrochloride. LCMS: 268.11 (M+1)+, 84.63%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:25]3[CH2:30][CH2:29][N:28]([C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])[CH2:27][CH2:26]3)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cccc(OCc4ccccc4)c3)c12
Product: CN(C)CC(=O)N1CCC(c2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 24 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 342 and using 5-(3-benzyloxyphenyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and N,N-dimethylglycine as starting material, 20 mg (24%) of the desired product was isolated. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.45-7.30 (m, 6H), 7.10 (s, 1H), 7.05-6.97 (m, 2H), 6.56 (s, 1H), 5.13 (s, 2H), 4.48-4.42 (m, 1H), 4.18-4.12 (m, 1H), 3.41-3.32 (m, 3H), 3.20-3.10 (m, 2H), 3.05-2.97 (m, 1H), 2.76-2.68 (m, 1H), 2.16 (s, 6H), 2.06-1.98 (m, 2H); LC-MS m/z [M+H]+ 485.3, RT 2.32 min.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCCC1C=CC=[C:20]2[C:21]([NH:23]C(=O)C=12)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:1]1([C:7]#[C:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:20][CH2:21][NH2:23])[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: C(#CC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCCN1CCC(C#Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
4-(Phenylethynyl)piperidine (0.5 mmol, 92 mg) was dissolved in acetonitrile (anhydrous 4 Å, 4 mL) together with bromoethylphtalimide (0.5 mmol, 128 mg) and K2CO3 (2 mmol, 276 mg). The reaction mixture was heated to reflux for 3 hours, diluted with ethyl acetate (50 mL) and washed with HCl/aq (1M, 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The protection group was removed by stirring the compound in methylamine (33% in ethanol, 5 mL) for another 3 hours. The mixture was evaporated, diluted with ethyl acetate (50 mL) and washed with NaOH (1M, 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCC1CCOCC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)tetrahydro-2H-pyran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: Br[C:2]([CH3:17])([CH2:15][CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([Cl:13])[C:6]=1[Cl:14])=[O:4].[Br-].[Li+]>CN(C=O)C>[CH:15](=[C:2]([CH3:17])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([Cl:13])[C:6]=1[Cl:14])=[O:4])[CH3:16]
Reactant: CCC(C)(Br)C(=O)c1ccc(OC)c(Cl)c1Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC=C(C)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
By following the procedure described in Example 5, Step C, using as the reactants 2-bromo-2-methyl-2',3'-dichloro-4'-methoxybutyrophenone (34 g., 0.1 mole), lithium bromide (17.4 g., 0.2 mole) and DMF (200 ml.), there is obtained 2-ethylidene-2',3'-dichloro-4'- methoxypropiophenone.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]=[C:11]=[O:12].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: CNCC=O
Reactant: O=C=Nc1nc2ccccc2s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzothiazol-2-yl isocyanate dimer prepared in Example 1, benzene (300 ml) and the dimethyl acetal of 2-methylaminoacetaldehyde (80 grams; 0.67 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about one hour. After this time the mixture is filtered to remove a yellow solid that has formed. The filtrate is then stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-(1-methyl-3-benzothiazol-2-ylureido)acetaldehyde as an oil.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C([O:31][C:32](=O)[C:33]2[CH:38]=[CH:37][C:36]([CH2:39][OH:40])=[CH:35][CH:34]=2)=C(F)C(F)=C(F)C=1F.CN1CCOCC1>ClCCl>[OH:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:23][CH2:22][CH2:21][S:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])=[CH:34][CH:35]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(CO)cc1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 57.3 %

Procedure:
To a solution of S-trityl cysteamine (1.60 g, 5.00 mmol) and 4-hydroxymethylbenzoic acid pentafluorophenyl ester (MilliGen, 1.51 g, 5.00 mmol) in dichloromethane (40 ml) was added N-methylmorpholine (0.55 ml, 5.0 mmol). The mixture was stirred at room temperature for 36 hrs. Precipitated material was filtered off, washed with dichloromethane and dried to give 1.30 g (57%) of white solid. NMR analysis was in accordance with the structure.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C([NH:65][CH2:66][CH2:67][N:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH:25][C:4]2[N:3]=[C:2]([NH:65][CH2:66][CH2:67][N:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46). MS (ES+) m/e 636.42 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(N(CC)CC)C.[F:39][C:40]([F:48])([F:47])[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[C:9]1[C:25]1[CH:26]=[CH:27][C:28]([O:31][S:43]([CH2:42][CH2:41][C:40]([F:48])([F:47])[F:39])(=[O:45])=[O:44])=[CH:29][CH:30]=1
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 8.8 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (0.54 g, 1.24 mmol) in dichloromethane (30 ml) at 0° C. was added triethylamine (0.20 ml, 1.50 mmol) followed by 3,3,3-trifluoropropane sulfonyl chloride (295 mg, 1.50 mmol). The reaction mixture was subsequently stirred at room temperature for 2.5 hours. Concentration and purification by flash chromatography (heptane:EtOAc gradient) afforded 65 mg (9%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:16][CH:15]=1)=O>C(O)C>[C:2]1([C:1]2[S:8][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:16][CH:15]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: CC(=O)NCCc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: CC(=O)NCCc1ccc(-c2csc(-c3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
In a round-bottomed flask, thiobenzamide (357 mg, 2.60 mmol) and N-[2-(4-bromoacetyl-phenyl)-ethyl]-acetamide (740 mg, 2.60 mmol) were combined in ethanol (30 ml) and heated to about 80° C. for about three hours. The reaction mixture was then concentrated in vacuo to yield an off-white solid. The resulting material (838 mg, 100% yield) was ascertained to be pure by NMR and was carried into the next step directly without further purification. LRMS ([M+H]+)=323.2.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:27][S:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:29][CH:28]=3)[CH2:14][CH2:13]2)=[O:16])=[CH:18][CH:19]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCOc3ccc(N)cc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of the amine (1.20 g, 2.88 mmol) prepared in the preceding paragraph in dichloromethane (20 mL) at 0° C. under nitrogen was added pyridine (0.47 mL, 5.76 mmol) and methanesulfonyl chloride (0.33 mL, 4.32 mmol). The mixture was stirred at 25° C. for 2 hours and was then partitioned between 5% aqueous sodium bicarbonate and 4:1 dichloromethane/isopropanol. The organic phase was dried (MgSO4), decolorized (charcoal) and concentrated to afford a residue which was triturated with ethyl acetate/diethyl ether/hexane to give the title compound as a white solid: 0.92 g (65%). mp 168°-172° C.; 1H NMR (DMSO-d6): δ 10.28 & 9.35 (2s, 2H), 7.94 (d, J=8.87 Hz, 2H), 7.27 (d, J=8.85 Hz, 2H), 7.13 (d, J=9.00 Hz, 2H), 6.92 (d, J=9.01 Hz, 2H), 4.05 (t, J=5.61 Hz, 2H), 3.32 (m, 1H), 3.09 (s, 3H), 3.00 (m, 2H), 2.86 (s, 3H), 2.75 (m, 2H), 2.30 (m, 2H), 1.75-1.50 (m, 4H). IR (KBr): 3220, 1660 cm-1 ; MS (m/z) 496 (MH+), 217,91.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][C:34]2[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=2)=[CH:31][CH:30]=1>CN(C)C=O.C(Cl)Cl>[Br:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][C:34]2[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=2[C:9]([C:8]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:11])=[CH:31][CH:30]=1
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C1CCCC1
Yield: 78.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (2.04 g, 9.24 mmol, RN-59216-82-9), oxalyl chloride (0.887 mL, 10.2 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (1.19 mL, 10.2 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (2.45 g, 9.24 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave 3.39 g (78%) of the title compound. 1H NMR (DMSO-d6) δ 1.38-1.47 (m, 2 H), 1.60-1.73 (m, 4 H), 1.79 (s, 3 H), 1.90-1.94 (m, 2 H), 2.18 (s, 3 H), 3.21 (quintet, 1 H), 3.82 (s, 2 H), 3.88 (s, 3 H), 7.02-7.08 (m, 3 H), 7.44 (d, 2 H), 7.55-7.61 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]2)=[CH:37][C:38]([O:42][CH2:43][CH3:44])=[C:39]([NH2:41])[CH:40]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:39]3[CH:40]=[C:35]([CH3:34])[C:36]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]4)=[CH:37][C:38]=3[O:42][CH2:43][CH3:44])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (100 mg, 0.217 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (Example 248, Step B) (100 mg, 0.293 mmol) in trifluoroethanol (5 mL) was added p-toluene sulfonic acid (100 mg, 0.526 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and silica was added. The solvent was removed on a rotovap and the product purified on a 12 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (25 mg, 0.032 mmol, 15%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 9.36 (d, J=7.5 Hz, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 8.23 (d, J=5.1 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.48-7.32 (m, 2H), 7.17 (t, J=8.1 Hz, 2H), 6.95 (t, J=6.3 Hz, 1H), 6.71 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.36-3.24 (m, 2H), 3.03 (s, 3H), 2.86-2.79 (m, 4H), 2.74 (t, J=7.0 Hz, 2H), 2.64-2.50 (m, 4H), 2.10 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). MS (ESI) m/z=384 [M+2H]+2.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:40])=[C:25]([NH:27][C:28](=[O:39])[C:29]3[CH:34]=[C:33](F)[CH:32]=[CH:31][C:30]=3[N+:36]([O-:38])=[O:37])[CH:26]=2)=[O:20])[CH2:17][CH2:16]1>>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:33]2[CH:32]=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[C:29]([C:28]([NH:27][C:25]3[CH:26]=[C:21]([C:19]([NH:18][CH:15]4[CH2:17][CH2:16]4)=[O:20])[CH:22]=[CH:23][C:24]=3[CH3:40])=[O:39])[CH:34]=2)[CH2:3][CH2:2]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN(CC(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting materials, tert-butyl piperazin-1-ylacetate was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give tert-butyl(4-{3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-4-nitrophenyl}piperazin-1-yl)acetate; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 1.43 (s, 9H), 2.32 (s, 3H), 2.66 (m, 4H), 2.86 (m, 1H), 3.21 (s, 2H), 3.53 (m, 4H), 7.09 (m, 2H), 7.30 (m, 1H), 7.59 (m, 1H), 7.99 (s, 1H), 8.07 (m, 1H), 8.38 (m, 1H), 9.93 (s, 1H); Mass Spectrum: M+H+ 538.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8](S)=[N:9][C:10](C)=[C:5]2[C:4]([C:13]2[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:3]1.[CH3:21][NH2:22]>C(O)C.C(OCC)(=O)C>[CH3:21][NH:22][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12
Reactant: Cc1nc(S)nc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 3.0 grams of 1-methyl-4-methyl-mercapto-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, 50 milliliters of a 33 % solution of methylamine in ethanol and 20 milliliters of ethyl acetate was heated at reflux for 1 hour and cooled. The crystalline product formed was collected, washed with ethanol and dried. Recrystallisation from ethyl acetate gave 4-methylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having melting point 280°C. identical to the product obtained in Example 13.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[N:25]1([C:2]2[N:7]=[C:6](/[CH:8]=[C:9]3/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/3)[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1NC(=O)/C(=C/c2cccc(N3CCCCC3)n2)S1
Temperature: 110 °C
Reaction time: 24 h
Yield: 13 %

Procedure:
A 2 dram round-bottomed vial was charged with (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (60 mg, 0.210 mmol, 1 equiv.), DMSO (1 mL, 0.08 M), diisopropylethylamine (34 μL, 0.2 mmol, 1 equiv.), and piperidine (21 μL, 0.21 mmol, 1 equiv.), and the reaction was heated with shaking at 110° C. for 24 h. The solvent was removed under reduced pressure (Genvac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide (Z)-5-((6-(piperidin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (7.9 mg, 60.9 mg theoretical, 12.9%). LC-MS m/z 290.1 (M+1).
Reaction SMILES: CN.O1CCCC1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1.COC1C=CC([CH2:30][NH:31]C2C3C(=CC=C(C(O)=O)C=3)C=CN=2)=CC=1>>[CH3:30][NH:31][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Reactant: CCOC(=O)c1ccc2ccnc(Cl)c2c1
Agent: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2ccnc(NC)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of methylamine in tetrahydrofuran (30 mL, 60 mmol, 2 M) was added to ethyl 1-chloroisoquinoline-7-carboxylate (formed in Step 3 of Intermediate 27) (705 mg, 2.99 mmol) in a sealed tube. The reaction was heated to 60° C. and stirred overnight. LCMS indicated the reaction was not complete. Additional methylamine (10 mL, 20 mmol, 2 M in THF) was added and the reaction was heated to 60° C. for another 18 hours. The reaction was cooled to room temperature and concentrated. The residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulphate, filtered, and concentrated. Purification by flash column chromatography (25-65% ethyl acetate/heptanes) gave the title compound (584 mg, 85%) as a yellow oil that solidified upon standing. +ESI (M+H) 231.1; 1H NMR (400 MHz, DMSO-d6, δ): 8.83-8.94 (m, 1H), 8.07 (dd, J=8.58, 1.56 Hz, 1H), 7.99 (d, J=5.85 Hz, 1H), 7.89 (d, J=4.49 Hz, 1H), 7.77 (d, J=8.58 Hz, 1H), 6.92 (d, J=5.07 Hz, 1H), 4.38 (q, J=7.02 Hz, 2H), 2.97 (d, J=4.49 Hz, 3H), 1.38 (t, J=7.12 Hz, 3H).