Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.[N+]([O-])([O-])=O.[Ag+:42]>CO.C(Cl)(Cl)Cl>[Ag:42].[SH:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1
Reactant: c1ccc(C(SCCn2cnc3ccccc32)(c2ccccc2)c2ccccc2)cc1
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: SCCn1cnc2ccccc21
Product: [Ag]
Temperature: 25 °C
Reaction time: 3 h
Yield: 159.9 %

Procedure:
To a solution of 1-(2-tritylthioethyl)benzimidazole (7.0 g, 16.6 mmol) in a mixture of methanol (50 ml) and chloroform (80 ml), were added pyridine (1.32 ml, 16.3 mmol) and then silver nitrate (2.9 g, 17.1 mmol). The mixture was stirred for 3 hours at room temperature. Precipitates then separated out were collected and washed with methanol and then with ethyl ether to give silver salt of 1-(2-mercaptoethyl)benzimidazole (4.73 g, 99%). The silver salt (4.73 g, 16.6 mmol) was suspended in dichloromethane (250 ml), which was bubbled with hydrogen sulfide at 0° C. for one hour. Precipitates were filtered off, and the filtrate was concentrated to give 1-(2-mercaptoethyl)benzimidazole (2.35 g, 79%) as colorless powder (2.35 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[O:36][C:35]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])=[N:34][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[O:36][C:35]([Si:37]([CH:41]([CH3:43])[CH3:42])([CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:39])[CH3:40])=[N:34][CH:33]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](c1ncc(-c2cc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)oc3cn2)o1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole (0.35 g), 2 M aqueous Na2CO3 solution (0.8 mL), and N,N-dimethylformamide (3 mL) is sparged with argon for 10 min. PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (0.15 g) is added and the mixture is stirred at 80° C. overnight. The mixture is concentrated, diluted with water and methanol, and purified by HPLC on reversed phase (methanol/water) to give the title compound. LC (method 4): tR=2.07 min; Mass spectrum (ESI+): m/z=526 [m+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[C:17]([CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)#[N:18].[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1.O>[C:17]([CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:11]([NH:14][C:15]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)=[O:16])(=[O:13])=[O:12])#[N:18]
Reactant: Cc1cc(C)nc(N)n1
Reactant: N#CCCn1cccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccn2CCC#N)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
To a stirred suspension of 2.59 g (0.021 mole) of 2-amino-4,6-dimethylpyrimidine in 80 ml dry tetrahydrofuran at -70° C. under nitrogen was added dropwise via syringe 2.0 ml (0.023 mole) of chlorosulfonyl isocyanate at such a rate to maintain the temperature of the reaction mixture below -55° C. The resulting solution was stirred 0.5 hour at -70° C., then treated dropwise with a solution of 2.4 ml (0.021 mole) of N-(2-cyanoethyl)pyrole in 10 ml dry THF. A catalytic amount (approximately 0.2 to 0.3 gm) of aluminum (III) chloride was added and the reaction mixture allowed to warm to ambient temperatures and stirred for an additional 18 hours. The reaction mixture was poured into 300 ml of H2O and extracted with three portions of dichloromethane. The organic solutions were washed with water, dried over MgSO4 and evaporated. Trituration with a small volume of CH2Cl2 afforded 1.2 g of the desired product as a white microcrystalline solid, m.p. 158°-159° C. The infrared spectrum of the product included absorptions at 3250 and 3110 (NH), 2240 (C≡N), 1685 (C=O), 1350 and 1160 cm-1 (SO2).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)[CH:10]=1)=[O:28]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: CCCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(ethyl(propyl)amino)phenyl)isonicotinamide (150 mg, 0.30 mmol, 1.00 equiv, 90%) in dichloromethane (8 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (144 mg, 0.44 mmol, 1.50 equiv, 90%), EDC.HCl (126 mg, 0.66 mmol, 2.00 equiv), 4-dimethylaminopyridine (80 mg, 0.66 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of NH4Cl aq. and 1×20 mL of sodium bicarbonate (10%). The resulting mixture was washed with 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (250 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 39% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 183.7 mg product was obtained. This resulted in 183.7 mg (56%) of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(ethyl(propyl)amino)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 731 [M+H]+; H-NMR (300 MHz, DMSO, ppm): 9.83 (s, 1H), 9.52 (t, J=18 Hz, 1H), 8.89 (d, J=3 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.99 (m, 2H), 7.82 (d, 1H), 7.54-7.69 (m, 6H), 6.95-7.54 (m, 2H), 4.60 (s, 2H), 3.85-4.02 (m, 4H), 3.64 (m, 4H), 3.36-3.47 (m, 6H), 3.18 (m, 2H), 2.95 (s, 3H), 1.60 (m, 2H), 1.09-1.13 (m, 3H), 0.87-0.92 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:10]([CH3:16])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:12]1[C:13](=[O:14])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH3:17])[N:10]([CH3:16])[C:11]=1[CH3:15]
Reactant: BrBr
Reactant: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)n1C
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)c(=O)c(-c2ccc(Cl)cc2)c(C)n1C

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-1,2,6-trimethylpyridin-4-one (0.5 g) in acetic acid (5 ml) was added dropwise a solution of bromine (0.1 ml) in acetic acid (1 ml). After 5 min the mixture was poured into water. The solid was filtered off, washed with water and recrytallised from ethanol (10 ml) to give the desired compound (0.25 g), m.p. 264°-266°, NMR δH (CDCl3) 7.3-7.4 (2H, m), 7.05-7.2 (2H, m), 6.95-7.12 (4H, m), 3.65 (3H, s), 2.7 (3H, s), 2.2. (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11].[Br:30][CH:31]([CH3:35])[C:32](Br)=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CCOCC>[Br:30][CH:31]([CH3:35])[C:32]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:6]2=[O:11])=[O:33]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: CC(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C(C)Br)c3C2=O)ccc1OC
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A solution of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (500 mg, 1.20 mmol) and 2-bromopropionyl bromide (0.140 mL, 1.34 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight. An additional 0.1 mL of 2-bromopropionyl bromide (1 mol) was added and the mixture stirred overnight. To the mixture was added brine (4 mL), Sodium bicarbonate (sat, 10 mL) and methylene chloride (15 mL). The organic layer was separated, was washed with brine (10 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give a yellow oil. The oil was slurried in ether (10 mL). The resulting suspension was filtered and the solid washed with ether to give 2-bromo-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide as a white solid (500 mg, 76% yield): 1H NMR (CDCl3) δ1.46 (t, J=6.9 Hz, 3H, CH3), 1.97 (d, J=6.9 Hz, 3H, CH3), 2.86 (s, 3H, CH3), 3.75 (dd, J=4.5, 14.4 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.49-4.59 (m, 2H, CHH, CH), 4.09(q, J=6.9 Hz, 2H, CH2), 5.87 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.09-7.13 (m, 2H, Ar), 7.53 (d, J=7.3 Hz, 1H, Ar), 7.68 (t, J=7.5 Hz, 1H, Ar), 8.73 (d, J=8.4 Hz, 1H, Ar), 10.19 (s, 1H, NH); 13C NMR (CDCl3) δ14.61, 22.42, 41.54, 43.78, 48.67, 54.44, 55.87, 64.45, 111.39, 112.3, 116.10, 116.79, 120.35, 124.76, 129.14, 131.13, 136.02, 136.82, 148.55, 149.70, 167.28,168.42, 169.11.
Reaction SMILES: NCCN1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(N(CC)CC)C.[NH2:30][CH2:31][C@@H:32]([OH:34])[CH3:33]>C(O)C>[OH:34][C@@H:32]([CH3:33])[CH2:31][N:30]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: C[C@H](O)CN
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](O)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C

Procedure:
A mixture of 5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate A, Step 3) (200 mg 0.59 mmol), triethylamine (82 μl, 0.59 mmol) and (S)-1-aminopropan-2-ol (44.6 mg 0.59 mmol) in ethanol (2 ml) was heated under microwave radiation for 1 hour. The reaction mixture was filtered and the residue rinsed with ethanol to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: Oc1ccccc1Br
Reactant: O=C(O)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1ccccc1Br

Procedure:
A solution of 2-bromophenol (17.3 g, 100 mmol) in 50 mL of H2O was added NaOH (8 g, 200 mmol), 3-bromopropanoic acid (15.3 g, 100 mmol), and the mixture was stirred at reflux overnight. The reaction solution was diluted with H2O, extracted with EtOAc. The aqueous layer was acidified to pH=1˜2 and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford 3-(2-bromophenoxy)propanoic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(COC(=O)NCC)CC1>ClCCl>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[C:8]=1[O:7][CH2:6][C:3]1([CH2:2][O:1][C:43](=[O:44])[NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)CC2)c1OC
Reactant: O=C=NCc1ccccc1
Agent: CCNC(=O)OCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(COC(=O)NCc3ccccc3)CC2)c1OC

Procedure:
To a stirring solution of 4-[2-(1-Hydroxymethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 177) (150 mg, 0.407 mmol) in dichloromethane (15 mL), were added triethylamine (123 mg, 1.222 mmol) and benzyl isocyanate (105 mg, 0.812 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 179 to afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](NN)=[N:5][CH:6]=[N:7][C:8]=1[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].C(#N)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>O>[CH2:1]([C:3]1[C:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[N:7][CH:6]=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1c(NN)ncnc1-c1ccco1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CCc1cncnc1-c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a mixture of [5-ethyl-6-(furan-2-yl)-pyrimidin-4-yl]-hydrazine (2.85 g), acetonitrile (50 ml), and para-toluensulfonyl chloride (2.86 g), pyridine (2.37 g) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture, water (50 ml) was added, and the precipitated solids were collected by filtration. The solid was sequentially washed with water (20 ml) and acetonitrile (20 ml), and dried. To the resulting solid, sodium hydroxide (8.1 g), ethylene glycol (100 ml), and water (50 ml) were added, and stirred under reflux for 3 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.03 g of 5-ethyl-4-furan-2-yl-pyrimidine.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[C:11]([C:15]([C:18]([C:21](Cl)=[O:22])([F:20])[F:19])([F:17])[F:16])([F:14])([F:13])[F:12]>[Pd]>[C:18]([CH:21]=[O:22])([C:15]([C:11]([F:12])([F:13])[F:14])([F:17])[F:16])([F:20])[F:19]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Product: O=CC(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A 3-necked round bottom flask fitted with with dropping funnel, dry-ice condenser, and gas inlet was charged with 10% Pd/C (0.35 g) and cooled to 0° C. Triisopropylsilane (7.29 g, 46 mmol) was added, and CF3CF2CF2C(O)Cl (9.30 g, 40 mmol) was added dropwise over a 10 min period. The reactor was connected to a cold trap (-78° C.) while the mixture was stirred for 18 hr. Transfer from the trap and reaction vessel gave a total of 5.1 g (62%) of colorless liquid. 1H NMR (CD2Cl2): 9.62 (m). 19F NMR: -81.24 (t, J=8.3 Hz), -126.4 (quartet of doublets, Jq =8.3, Jd =3.2), -127.9 (s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Sn](C)(C)C>CN(C)C=O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH3:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 120 °C

Procedure:
A solution of Intermediate 1 (228 mg) obtained in Example 1, Step A and tetramethyltin (0.69 ml, Tokyo Kasei Kogyo) in N,N-dimethylformamide (4 ml) is added with tetrakis(triphenylphosphine)palladium(0) (29 mg, Kanto Chemicals), and the mixture is stirred at 120° C. with heating for 12 hours. The reaction mixture is cooled to room temperature, then added with saturated brine (5 ml), and extracted 3 times with ethyl acetate (5 ml for each time). The combined organic layer is washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and then the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (176 mg (predictive yield)).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)[CH:9]=2)[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:3]=1.[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([C:8]3[CH:9]=[C:10]4[C:2]([I:1])=[N:3][N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[C:5]4=[N:6][CH:7]=3)[CH:12]=2)=[O:16])[CH2:34][CH2:33]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccc(C(=O)O)c3)cnc21
Reactant: CN(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1CCN(C(=O)c2cccc(-c3cnc4c(c3)c(I)nn4COCC[Si](C)(C)C)c2)CC1
Yield: 42.9 %

Procedure:
A mixture of crude 3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid (200 mg, 0.404 mmol), N,N-dimethyl-2-(piperazin-1-yl)ethanamine (76 mg, 0.485 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (185 mg, 0.485 mmol), triethyl amine (0.700 ml, 0.485 mmol) and in DMF (2 ml) was stirred at 90° C. in Personal Microwave for 1 hour. Water was then added to the mixture and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (110 mg, 43% yield) as off-white solids. MS: m/z 635.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([NH2:16])=O)=[C:7]2[N:6]=[N:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](=[S:18])[NH2:16])=[C:7]2[N:6]=[N:5]1
Reactant: COCn1nnc2c(C(N)=O)ncn2c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: COCn1nnc2c(C(N)=S)ncn2c1=O
Reaction time: 24 h
Yield: 67 %

Procedure:
3-(Methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.100 g, 0.446 mmol), phosphorus pentasulfide (27 mg; 0.06 mmol), and hexamethyldisiloxane (87 mg; 0.114 mL; 0.535 mmol) were stirred in DCM under reflux for 24 hours. After 24 hours, a second portion of P2S5 (27 mg; 0.06 mmol) was added, and reflux continued for a further 24 hours, after which time the reaction mixture was filtered, and the precipitate was washed with EtOAc, Et2O and air dried to yield the title compound as an orange solid (67% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm 9.95 (1H, bs), 9.47 (1H, bs), 8.85 (1H, s), 5.74 (2H, s) and 3.40 (3H, s).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[CH3:33]>>[CH3:33][C:32]1[CH:31]=[CH:30][C:29]([S:34](=[O:36])(=[O:35])[NH2:37])=[CH:28][C:27]=1[NH:26][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(S(N)(=O)=O)cc1N
Product: Cc1ccc(S(N)(=O)=O)cc1NC(=O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-4-methyl-benzenesulfonamide [CAS-No. 6274-28-8; commercially available] according to general procedure II. Light brown solid. MS (ISP) 524.0 [(M−H−]; mp 293° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21](Br)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[OH:45].O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:41]3[CH:42]=[CH:43][C:44]([OH:45])=[C:39]([F:38])[CH:40]=3)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: CCC1(CC)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(CC)CN(Cc2cc(-c3ccc(O)c(F)c3)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 33.5 %

Procedure:
To a solution of 150 mg 4-[6-Bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2-diethyl-5,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 48 mg 3-fluoro-4-hydroxy-phenylboronic acid in 8 ml of DEM and 0.45 ml of water were added 40 mg of potassium carbonate. To the degassed reaction mixture 4 mg of bis(tri-tert-butyl-phosphin)palladium(0) were added. The reaction was heated to 120° C. in a microwave reactor for 2 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate twice. The combined organic layers were dried and concentrated in vacuo. The resulting residue was purified by HPLC. 53 mg (34%) of the title compound were obtained.