Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[C:14]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[N:13]=1>CN(C)C=O>[NH2:11][C:12]1[N:16]([C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[N:15]=[C:14]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[N:13]=1
Reactant: Nc1nc(-c2ccc(CN3CCCCCC3)s2)n[nH]1
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(CN3CCCCCC3)s2)nn1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
5 ml of N,N-dimethylformamide solution containing 331 mg (2.49 mmol) of benzyl isocyanate was added to 75 ml of N,N-dimethylformamide solution containing 690 mg (2.49 mmol) of the compound of Example 38, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the resulting residue was dissolved in chloroform, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (75:1) to give 1.07 g of the title compound. This was crystallized by adding an appropriate amount of diethyl ether and then recrystallized from ethyl acetate-n-hexane to give 564 mg of the compound of interest.
Reaction SMILES: C([O:8][C:9](=O)[CH:10]([NH:19][C:20](=[O:38])[CH:21]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.[NH3:40].CO>>[C:9]([CH:10]([NH:19][C:20](=[O:38])[CH:21]([CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:8])[NH2:40]
Reactant: O=C(NC(CCN1CCCCC1)C(=O)OCc1ccccc1)C(CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: N
Solvent: CO
Product: NC(=O)C(CCN1CCCCC1)NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To 2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-4-piperidin-1-yl-butyric acid benzyl ester (0.10 g, 0.18 mmol) was added NH3/MeOH (2.0 M, 10 mL) in a sealed tube and the mixture was stirred at room temperature for 3 days. The solvent was evaporated to give the title compound in 50% yield.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][O:15][C:16]2=[O:19])=[CH:12][CH:11]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[C:1]1([S:7][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([CH2:8][CH3:9])=[CH:18][C:17]=2[C:16]([OH:19])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1ccc2c(c1)C(=O)OC2
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(CSc2ccccc2)c(C(=O)O)c1
Temperature: 110 °C

Procedure:
Thiophenol (0.128 ml) was added to a mixture of 6-ethyl-3H-isobenzofuran-1-one (Intermediate 18, 0.202 g) and potassium carbonate (0.344 g) in dry DMF (1.3 ml). The resultant mixture was stirred and heated at 110° C. for 2 hours. After cooling, the mixture was diluted with water and acidified by addition of hydrochloric acid (1M). The resultant solid was collected by filtration, washed with water and dried under vacuum to give 2-(phenylthiomethyl)-5-ethylbenzoic acid (0.288 g) as a white solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[F:9][CH:10]([F:19])[O:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([I:1])[CH:17]=1
Reactant: Oc1ccc(OC(F)F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(OC(F)F)cc1I
Reaction time: 16 h
Yield: 42 %

Procedure:
To a suspension of N-iodosuccinimide (1.12 g, 0.005 mol) in acetic acid (15.0 mL) was added 4-(difluoromethoxy)phenol (0.8 g, 0.005 mol) under nitrogen. Sulfuric acid (0.147 g, 0.0015 mol) was added and the resulting dark brown suspension was stirred at room temperature for 4 hours before the addition of N-iodosuccinimide (0.6 g, 0.0025 mol). The mixture was stirred for 16 hours before diluting with citric acid (1.0 M aqueous solution, 20.0 mL) and water (20.0 mL). The aqueous layer was extracted with dichloromethane (2×30.0 mL). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to afford a dark purple oil. This was concentrated in vacuo from toluene (3×20.0 mL) to afford a brown oil. The aqueous layer was concentrated in vacuo. Both organic and aqueous crude residues were purified by flash column chromatography on the ISCO™ (40 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 1:1, by volume) to afford the title compound as a yellow oil, 0.604 g, 42% yield.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.CS([Cl:34])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:34][C@@H:6]1[CH2:7][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:14][CH:15]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCCN1CCc1ccc(N2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cl[C@@H]1CCCN(CCc2ccc(N3CCCC3)cc2)C1
Reaction time: 2 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-pyrrolidinophenethyl)pyrrolidine (4.96 g, 19.1 mmol) was dissolved in 70 ml of dichloromethane. 3.21 g (24.8 mmol) of diisopropylethylamine and 2.84 g (24.8 mmol) of methanesulfonyl chloride were added to the obtained solution under stirring under cooling with ice. They were stirred under cooling with ice for 1 hour and then at room temperature for 2 hours. The reaction mixture was distributed into dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-pyrrolidinophenethyl)piperidine in the form of a light yellow solid (3.23 g, 61%).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:16][C:17]1[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14].[C:26](=[O:28])=[O:27]>C(OCC)C>[CH2:12]([O:16][C:17]1[C:25]2[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COc1cccc2sccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)COc1cccc2sc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.6 M solution of n-butyl lithium in hexane (18 ml, 28.8 mmol) is dissolved under an argon atmosphere in 100 ml of dry diethyl ether, followed by dropwise addition of a solution of 4-Isobutoxy-benzo[b]thiophene (201, 5.4 g, 26.1 mmol) in 40 ml of diethyl ether. The reaction mixture is refluxed for 45 min, then cooled down and transferred via syringe to a mixture of excess dry ice (115 g, 2.61 mol) in diethyl ether (the dry ice is washed before twice with diethyl ether). The mixture is allowed to stir overnight at room temperature, then distributed between diethyl ether and water. The ether layers are reextracted with water. The aqueous layers are acidified with 2M aqueous HCl solution, and the precipitate is filtered off, washed with water and dried under high vacuum.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=[S:22])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:22][CH3:23])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)[nH]1
Yield: 29.9 %

Procedure:
By following the same procedure as in Example 10 using 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, 10 ml of dry acetone, 0.15 g of potassium carbonate, and 0.15 g of methyl iodide and recrystallizing the product from cyclohexane, 0.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:21]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][CH:9]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: ClCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)cc1

Procedure:
A solution of 11.64 g (40 mmol) of N-(4-carboxyphenyl)-4-toluenesulfonamide, 5.06 g (40 mmol) of benzyl chloride and 5.20 g (44 mmol) of di-i-propylethylamine in 100 ml of dimethylformamide is heated at 140° C. for 4 hours. After the reaction is complete, the mixture is evaporated in vacuo, the residue is taken up in propyl acetate, and the solution is washed 2× with 2N hydrochloric acid and ##STR22## 2× with saturated NaHCO3 solution, dried over sodium sulfate and evaporated. 11.8 g (78% of theory) of N-(4-benzyloxycarbonylphenyl)-4-toluenesulfonamide, which are recrystallized from methanol, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][CH2:22][OH:23])[CH:18]=3)[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(NC1Cc2ccc(CCO)cc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
[2-[(4-Chlorophenyl)sulfonylamino]indan-5-yl]acetic acid (600 mg) is dissolved in tetrahydrofuran (20 ml) and thereto is added dropwise 7.8M borane-1,4-oxathiane complex (1 ml). The mixture is stirred at room temperature for one hour and thereto is added methanol to terminate the reaction, and then, the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution and saline solution, dried and then distilled under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform) to give 2-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]ethanol (542 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.C([O:16][C:17](=O)[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21])C>C(O)(=O)C>[CH3:1][N:2]1[C:6]2[NH:7][C:17](=[O:16])[CH:18]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:5]=2[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:3]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cn1nc(-c2ccccc2)cc1N
Solvent: CC(=O)O
Product: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Temperature: 150 °C
Yield: 24.3 %

Procedure:
A mixture of 1-methyl-3-phenyl-1H-pyrazol-5-amine (1.7 g, 9.815 mmol) and 4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (2.168 g, 11.776 mmol) in acetic acid (3.0 mL) was heated at 150° C. for 10 h in a sealed tube under constant stirring. The reaction mixture was cooled to rt and poured into rapidly stirred ice-cold water to obtain the crude product as a solid. The product was collected by filtration and dried under vacuum. The product was purified by flash-chromatography (eluent: 35% EtOAc in hexane) to yield the title compound as a white solid (0.7 g, 24%). [1H-NMR (CDCl3, 300 MHz) δ 13.65 (s, 1H), 7.52-7.37 (m, 5H), 6.78 (s, 1H), 4.20 (s, 3H); LCMS RtC=1.430 min; [M+H]+=294.0]
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22]O.S(Cl)([Cl:39])=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22][Cl:39]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3cccc(CC(=O)OC)c3)c2n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCCl)Cc3cccc(CC(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-hydroxypropyl)amino]methyl}phenyl)acetate (described in WO2007/1031726, Example 1 step (ix)) (534 mg) was suspended in DCM (5 mL) and thionyl chloride (0.09 mL) added. The reaction mixture was stirred at 25° C. overnight. The reaction was concentrated in vacuo to give the subtitle product (0.55 g); MS multimode (+) 520
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(4-trifluoromethyl-phenyl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 399(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](N(OC)C)=[O:12])=[CH:5]2.[CH2:17]([Li])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5]2
Reactant: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [Li]CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a cooled (−78° C.) solution of the title compound of Example 1 Step A (ca. 42.6 mmol) in THF (100 mL) was added n-hexyllithium (74 mL, 2.3 M in hexanes, 170.4 mmol) dropwise. The mixture was stirred at −78° C. for 2 h, then was quenched by addition of 2 N aqueous hydrochloric acid. The resulting suspension was allowed to warm to room temperature, then was extracted with ethyl acetate. The organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc in hexanes) provided the title compound: LCMS B, tr=2.70 min, m/z 264.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.37 (br s, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.29 (dd, J=9.0, 2.0 Hz, 1H), 7.13 (s, 1H), 2.94 (t, J=7.5 Hz, 2H), 1.78 (quint., J=7.5 Hz, 2H), 1.43-1.29 (m, 6H), 0.89 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)OCC[O:10]1.Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:10])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: Clc1ccc(C2(Cn3cncn3)OCCO2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1Br

Procedure:
A mixture of 456 parts of 1-[[2-(2-bromo-4-chlorophenyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole and 1584 parts of concentrate hydrochloric acid was stirred and refluxed for 4 hours. The whole was treated with a sodium hydroxide solution 50%. After stirring for a while, the precipitated product I was filtered off, washed with water and set aside. The filtrate was extracted first twice with 4-methyl-2-pentanone and then three times with trichloromethane. The 4-methyl-2-pentanone layers were dried, filtered and evaporated. The residue was stirred in 2-propanol. The precipitated product II was filtered off and set aside. The trichloromethane-layers were dried, filtered and evaporated. The residue was stirred in 2-propanol. The precipitated product was filtered off and purified, together with product I and product II which were set aside, by column chromatography over silica gel using a mixture of dichloromethane, ethanol and ammonium hydroxide (98.5:1:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2' -oxybispropane and 2-propanol. The product was filtered off and dried, yielding 17 parts of 1-(2-bromo-4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (62).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14](Cl)[N:13]([CH2:18][CH3:19])[C:12]2=[O:20].C(Cl)Cl>O>[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:13]([CH2:18][CH3:19])[C:12]2=[O:20]
Reactant: CCn1c(Cl)nc2c(Br)cccc2c1=O
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CCn1c(NC(C)(C)C)nc2c(Br)cccc2c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butylamine (1.1 mL, 10.43 mmol) and 8-bromo-2-chloro-3-ethylquinazolin-4(3H)-one (100 mg, 0.348 mmol, 481c) was sealed and set stirring for 3 h at 80° C. The reaction was cooled to RT, diluted with water, and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure giving a pale yellow solid. The material was taken up DCM, adsorbed onto silica, and purified on 4 g SiO2 (eluent: 0-100% EtOAc/hexanes over 20 min, RediSep Gold). The product containing fractions were combined and concentrated under reduced pressure to a colorless residue (52 mg, 46%). m/z (ESI, +ve) 323.9 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1.ClCCl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:8][CH:7]=3)=[CH:10][N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CNC(=O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of trans-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.119 mmol) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0° C. then treated with benzoyl chloride (19 mg, 0.13 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The solvents were removed under reduced pressure then the residue was purified by preparative reverse phase chromatography to give trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzyl)benzamide (50 mg) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.08(t, 1H), 8.13(s, 1H), 7.91(m, 2H), 7.4-7.54(m, 8H), 6.0(bs, 2H), 4.53(m, 3H), 2.30-2.40(m, 5H), 2.15(s, 3H), 1.85-1.89(m, 10H), 1.43-1.46 (m, 2H); RP-HPLC (Hypersil HS C18, 5μm, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 18.20 min.; MS:MH+ 524.3.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.Cl.N1C2=NC=CC(OC3C=CC(N[C:37]4[N:53]=[CH:52][CH:51]=[CH:50][C:38]=4[C:39]([NH:41][C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=4[F:49])=[O:40])=CC=3F)=C2C=C1>>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:37]3[N:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=3[F:49])=[O:40])=[CH:3][C:4]=2[F:18])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(Nc1ccc(F)cc1F)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Product: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Yield: 37 %

Procedure:
4-(4-Amino-2-fluorophenoxy)picolinamide (0.12 g, 0.50 mmol) was converted to the desired compound (0.088 g, 37%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-nicotinamide (Example 2). HRMS(ESI+), 480.1283 (M+H)+ calc, 480.1281 (M+H)+ found.
Reaction SMILES: [OH-].[K+].[I-].[NH2:4][N+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O.ClCCl>[F:11][C:12]([F:20])([F:21])[C:13]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: N[n+]1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nn2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
A mixture of 2.1 g (37.6 mmol) of potassium hydroxide and 6.7 g (30.1 mmol) of aminopyridinium iodide in 20 ml of water is added to a solution of 2.5 g (15.1 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in 25 ml of dichloromethane. After stirring for 5 h at ambient temperature, water is added and the mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated to dryness. The crude product is purified by chromatography over silica gel eluted with an 80/20 heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl 2-trifluoromethylpyrazolo[1,5-a]pyridine-3-carboxylate are obtained in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.N1CCC[CH2:13]1>CN(C=O)C.C(OCC)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:13][NH:9]2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1ccc2cc[nH]c2c1
Temperature: 110 °C

Procedure:
To a solution of 4-bromo-2-nitrotoluene (4.3 g., 20 mmol.) in DMF (40 mL.) was added DMF dimethylacetal (7.15 g., 60 mmol.) and pyrrolidine (1.4 g., 20 mmol.). The solution was heated to 110° C. for 4 hr. then cooled to rt. and diluted with ethyl ether. The mixture was washed 3× with water, dried with Na2SO4, filtered and the solvent evaporated. The residue was dissolved in 80% aqueous acetic acid (125 mL.) and heated to 75° C. Zinc dust (9.75 g., 150 mmol.) was added gradually over 20 min. The reaction mixture was heated to 85° C. for 2 hr. then cooled to ~35° C. and filtered to remove unreacted zinc. The filtrate was diluted with ethyl ether, washed 3× with water then with saturated aqueous NaHCO3. The solution was dried with Na2SO4, filtered and concentrated in vacuo to ~30 mL. then diluted with hexanes and filtered. The filtrate was concentrated to an off-white solid which was dissolved in hexane, filtered, and concentrated to give 1.65 g. of the title compound as a light green solid.