Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Mg+2].[Cl-].[CH2:15]=[O:16].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]=[O:16])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)(C)c1ccccc1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C=O)c1O
Yield: 90 %

Procedure:
To a stirred suspension of 2-tert-butylphenol (6)(4.55 g, 30 mmol), magnesium chloride (5.71 g, 60 mmol) and paraformaldehyde (2.08 g, 66 mmol) in THF (120 mL) at room temperature, was added triethylamine (8.35 mL, 60 mmol) dropwise. The reaction was heated to reflux for 3 hours to give an orange suspension. The crude was extracted using EtOAc (3×50 mL). A small amount of diluted HCl can be added if a permanent emulsion is formed. The organic layers were dried over MgSO4 and the volatiles evaporated under low pressure to yield a pale yellow oil which did not need any further purification. It can become dark green on storage. Yield: 90%. Pale yellow oil. 1H-NMR δH (CDCl3, 300 MHz): 1.44 (9H, s, 3×CH3), 6.97 (1H, t, J=7.5 Hz, HAr), 7.41 (1H, dd, J=1.5 Hz, J=7.5 Hz, HAr), 7.54 (1H, dd, J=1.2 Hz, J=7.5 Hz, HAr), 9.88 (1H, s, CHO), 11.82 (1H, s, OH).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:19])[C:3]=1[NH2:4].[CH:20](O)=[O:21]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:19])[C:3]=1[NH:4][CH:20]=[O:21]
Reactant: Nc1c(Cl)cccc1Sc1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=CO
Product: O=CNc1c(Cl)cccc1Sc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 2-chloro-6-(2-chloro-6-nitrophenylthio)aniline (689 mg, 2.18 mmol) in formic acid (5 mL) was heated at reflux for 16 hours. The mixture was allowed to cool to room temperature and the solvent was evaporated. The residue was used without purification.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[O:31])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(SC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of 9-{[4-(1-methylethyl)phenyl]sulfanyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (137.4 mg) in dehydrated DMF (3 mL) was added a mixture of 3-chloroperbenzoic acid (75%, 99 mg) in dehydrated DMF (3 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (67.6 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[NH:25][C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[CH2:31]=[O:32]>C(#N)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[N:25]([CH2:31][OH:32])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1
Reactant: C=O
Reactant: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)N1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (500 mg, 1.17 mmol) in acetonitrile (15 mL) and pyridine (1.5 mL) was added formaldehyde (37% aq) (5.0 mL). The reaction mixture was stirred at 65° C. for 5 minutes. Cooled to room temperature and filtered off the resulting solid. Washed with water and dried under vacuum to provide 450 mg (84%) of (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione as a yellow solid. LCMS (ES): >95% pure, m/z 458 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[I:12].[CH3:13]O.Cl>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: Nc1ccc(CC(=O)O)cc1I
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C

Procedure:
The crude (4-amino-3-iodophenyl)acetic acid (about 40 g, about 171 mmol) in methanol (110 mL) was added 100 mL of 4 M MeOH/HCl and the solution was stirred at ambient temperature over night. Distilled the solution under reduce pressure, and the residue was purified by silica gel cloumn chromatography to give methyl (4-amino-3-iodophenyl)acetate. 1H-NMR (300 MHz, CDCl3) δ ppm 7.54 (s, 1H), 7.04 (d, J=7.9 Hz, 1H), 6.68 (d, J=7.9 Hz, 1H), 3.67 (s, 3H), 3.46 (s, 2H).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26](O)[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([S:3][CH:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH2:23][O:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=4)[N:13]=3)=[CH:19][C:20]1=2)(=[O:4])[CH3:2]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: CC(O)=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 0 °C

Procedure:
Under ice cooling and stirring, 1.25 ml of thioacetic acid was added to 7.03 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 36 dissolved in a mixed solution of 58 ml of trifluoroacetic acid and 30 ml of methylene chloride and the mixture was stirred at the same temperature for 3 hours. 300 ml of ice water was added to the reaction mixture, crystals precipitated by neutralization with a 1N-sodium hydroxide aqueous solution were collected by filtration and these crystals were dissolved in methylene chloride. Then, this organic layer was washed with water and dried over anhydrous sodium sulfate and then the solvent was removed. The resulting residue was applied to silica gel column chromatography to obtain 4.6 g of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.Br[CH2:33][CH2:34][OH:35]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH2:33][CH2:34][OH:35])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Product: Cc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In a manner similar to that previously described (e.g. Scheme 3/Step 1 and the synthesis of Intermediate 20B/Step 6), 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (4B) was reacted with 2-bromoethanol (K2CO3, DMF. 2-bromoethanol. RT, 18 h) to provide 2-((6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)oxy)ethanol (66B). MS: [M+H]+ m/z 470.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O>CN(C=O)C>[C:30]([C:6]1[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]=2[CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)[NH:8][CH:7]=1)#[N:29]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCc1cc(C)c2[nH]cc(C#N)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-((5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (15 mg, 0.048 mmol) in DMF (1 mL) was added chlorosulfonyl isocyanate (17 μL, 0.191 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1.5 h. The mixture was allowed to warm up to room temperature with stirring. After 13.5 h, the reaction was quenched by 28% aq. NH4OH. The mixture was stirred for 0.25 h and then extracted with EtOAc/2,2,2-trifluoroethanol (c.a. 9/1). The organic layer was washed with H2O and brine, dried over Na2SO4, and filtered. After concentration, the resulting residue was purified by silica gel flash column chromatography [CH2Cl2/(2M NH3 in MeOH)=98/2, isocratic] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 10.22 (br. s., 1H), 8.07 (dd, J=1.00, 1.10 Hz, 1H), 7.91 (d, J=3.16 Hz, 1H), 7.71-7.85 (m, 2H), 7.15 (s, 1H), 5.02 (s, 2H), 2.71 (q, J=7.60 Hz, 2H), 2.54 (d, J=0.63 Hz, 3H), 1.14 (t, J=7.58 Hz, 3H). HRMS calcd. for C21H17N5 (M+H)+ 340.1557. found 340.1556.
Reaction SMILES: [CH:1]([S:4][C:5]1[NH:6][C:7](=[O:24])[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]=1[C:10]#[N:11])([CH3:3])[CH3:2].[H-].[Na+].Cl.[CH3:28][N:29]([CH2:31][CH2:32][CH2:33]Cl)[CH3:30]>O1CCOCC1>[CH:1]([S:4][C:5]1[N:6]([CH2:33][CH2:32][CH2:31][N:29]([CH3:30])[CH3:28])[C:7](=[O:24])[C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]=1[C:10]#[N:11])([CH3:3])[CH3:2]
Reactant: CN(C)CCCCl
Reactant: CC(C)SC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)SC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1CCCN(C)C
Reaction time: 1 h

Procedure:
A suspension of 10.0 g 2-isopropylthio-5-oxo-4,4-diphenyl-2-pyrroline-3-carbonitrile and 0.9 g sodium hydride (80%) in 150 ml dioxan is boiled for one hour, with stirring. Thereafter, one mixes with a further 0.9 g sodium hydride and 5.2 g dimethylaminopropyl chloride hydrochloride and boils further for 30 hours.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].O>C(#N)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)N1CCN(CCC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Isopropylpiperazine (650 mg) is dissolved in acetonitrile (7 ml) and thereto is added t-butyl acrylate (743 μl) under ice-cooling. The reaction solution is warmed to room temperature and stirred for 4 hours, and thereto is added additional t-butyl acrylate (148 μl), and then the mixture is stirred at room temperature for another 10 hours. Additional t-butyl acrylate (222 μl) is added to the reaction solution, and the mixture is stirred for 6 hours, thereto is poured water and the solution is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 followed by 10/1) to give t-butyl 3-(4-isopropylpiperazin-1-yl)propionate (1.18 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34](OCC)[O:35]CC)=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=[O:35])=[CH:4][N:3]=1
Reactant: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of Example 176B (90 mg, 0.16 mmol) in acetone (9 mL) and water (1 mL) was treated with p-toluenesulfonic acid (5 mg, 0.016 mmol) then stirred for 30 minutes. The solvent was evaporated under reduced pressure then the residue was partitioned between dichloromethane and water. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel to provide the desired product (77 mg). 1H NMR (DMSO-d6, 400 MHz) δ 9.67 (d, 1H), 9.52 (s, 1H), 8.34 (s, 1H), 8.03 (d, 1H), 7.91 (d, 1H), 7.75 (s, 1H), 7.75 (s, 1H), 7.70 (d, 1H), 7.32 (m, 2H), 7.25 (s, 1H), 7.10 (m, 3H), 6.69 (m, 1H), 4.04 (s, 3H), 3.92 (s, 3H); MS m/e 483.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (2.68 g) of Preparation 2 and 4-chloroaniline (1.28 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl8 (0.69 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.97 g of the title product as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[NH2:15][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[C:6]([CH2:5][C:4]3[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=4)=[O:36])[CH:25]=[CH:24][CH:23]=3)[C:14]=12
Reactant: Nc1cccc(Cc2nn(Cc3ccccc3)c3ncnc(N)c23)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: Nc1ncnc2c1c(Cc1cccc(NC(=O)Nc3cccc(C(F)(F)F)c3)c1)nn2Cc1ccccc1

Procedure:
To 3-(3-aminobenzyl)-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, molar equivalents of 3-(trifluoromethyl)phenyl isocyanate (Sigma-Aldrich) were added drop wise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to yield final Cmpd BB6 1-(3-((4-amino-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 518.4, calculated 518.2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15]Br)[C:6]=1[F:17])(=[O:4])=[O:3].[CH3:18][S-:19].[Na+]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15][S:19][CH3:18])[C:6]=1[F:17])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1CSC

Procedure:
44.6 g (0.14 mol) of methyl 4-methylsulfonyl-3-fluoro-2-bromomethylbenzoate were dissolved in THF. 10.58 g (0.15 mol) of sodium thiomethoxide were added at RT and the mixture was then heated under reflux for 5 h. It was then poured onto ice-water and extracted with EE. The combined organic phases were dried over MgSO4 and concentrated to completion.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[OH:18][C@@H:17]([CH2:19][NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]1)[CH2:16][O:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: Oc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: Oc1ccc2[nH]c3ccccc3c2c1OC[C@@H](O)CNCC1CCN(CCC(F)(F)F)CC1
Yield: 16.6 %

Procedure:
Prepared from 3-hydroxy-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.260 g, 1.09 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.229 g, 1.09 mmol) according to the procedure used for Example 2 without heating to give 0.084 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])(C#N)[C:10]([CH3:23])([CH3:22])[CH:11]=[C:12]([O:19]CC)[N:13]2CCOCC2)[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.N.[C:38](O)(=[O:40])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:10]([CH3:23])([CH3:22])[CH2:11][C:12](=[O:19])[NH:13][C:38]2=[O:40])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=CC(C)(C)C(C#N)(CCCN(C)C)c1cccc(OC)c1)N1CCOCC1
Reactant: CC(=O)O
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cccc(C2(CCCN(C)C)C(=O)NC(=O)CC2(C)C)c1

Procedure:
The but-1-ene product above is dissolved in acetic acid (45 ml) and sulphuric acid (30 ml) added. The resultant mixture is maintained at 100° until cyclisation is complete, as determined by working-up an aliquot and studying the infra-red spectrum of the product. The solution is cooled and poured into excess ammonia/ice, the pH adjusted to about 8 with aqueous ammonia and the solution extracted with chloroform (three times). The organic solutions are combined, dried, filtered and the solvent removed. The residual dione is crystallised and recrystallised from ethanol to give white crystals of 3-(m-methoxyphenyl)-3-(γ-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxo-piperidine, m.pt. 167°-9°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34]([NH2:36])=[NH:35])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:35]=[C:34]([NH:33][C:27]4[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)[N:36]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: COc1cc(NC(=N)N)cc(OC)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc(OC)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3,5-dimethoxy-phenyl)-guanidine nitrate were converted to I-55 (62%): HRMS Calcd. for C20H17ClN4O3: 397.1067, Found 397.1056.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([O:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:18]1[CH:19]=[C:20]([S:24][CH2:25][CH2:26]OS(C)(=O)=O)[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:32][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH2:25][CH2:26][N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[CH:19]=2)[C:9]2[S:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:34][CH2:35]1
Reactant: c1c[nH]nn1
Reactant: CN1CCC(OC(c2cccc(SCCOS(C)(=O)=O)c2)c2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(OC(c2cccc(SCCn3nccn3)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,3-triazole (36.5 mg) in N,N-dimethylformamide (1 mL) is added a dispersion of sodium hydride 60% in mineral oil (1 molar equivalent). The reaction mixture is stirred at room temperature for 15 minutes, then a solution of methanesulfonic acid 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester (85 mg) in N,N-dimethylformamide (1 mL) is added. The reaction mixture is stirred at 60° C. overnight. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia 100/0/0 to 90/10/1) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1)(O)[CH2:6][CH2:5]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:12]1[S:13][CH2:14][CH2:15][CH2:16][S:17]1)[CH2:6][CH2:5]2
Reactant: OC1(C2SCCCS2)CCc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)CCC2=C1SCCCS1
Temperature: 25 °C

Procedure:
A mixture of (rac)-5-bromo-1-[1,3]dithian-2-yl-indan-1-ol (2.15 g, 6.49 mmol) and p-toluenesulfonic acid monohydrate (309 mg, 1.62 mmol) in benzene (30 ml) was heated to reflux for 2 h using a Dean-Stark trap to remove water. The brown solution was allowed to cool to room temperature and was diluted with sat. NaHCO3 solution. The layers were separated and the organic layer was washed with brine, dried with Na2SO4 and evaporated. The title compound was obtained as brown gum (2.024 g, 99%) and was used without purification for the next reaction step.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), N,N-dimethylglycine hydrochloride (31 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (44 mg). MS found for C28H32F2N6O2 as (M+H)+ 523.5. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 7.33 (2H, d, J=8.8 Hz), 7.26 (1H, m), 7.17 (1H, m), 7.14-7.07 (3H, m), 5.80 (1H, s), 4.68 (1H, m), 4.55 (2H, s), 4.37 (1H, d, J=16.0 Hz), 4.27 (1H, d, J=16.0 Hz), 3.81 (1H, m), 3.27 (1H, m), 2.97 (6H, s), 2.92-2.83 (2H, m), 1.95 (2H, m), 1.71 (2H, m) ppm.