Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.O=[Mn]=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[CH:18][N:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
A mixture of (6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl)methanol (0.96 g) and MnO2 (2.951 g) in AcOEt (50 ml) was refluxed under stirring for 1.5 hour. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3): δ 3.01 (s, 3H), 7.36-7.37 (d, J=2.4 Hz, 1H), 7.43 (m, 1H), 7.54 & 7.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.70-7.73 (m, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.90 (m, 4H), 8.59 (d, J=2.0 Hz, 1H), 8.80 & 8.82 (dd, J=4.8 Hz, 1.6 Hz, 1H), 9.98 (s, 1H). MS: M/z 450.9 (M++1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[C:22]2[C:17](=[N:18][C:19]([NH2:23])=[N:20][CH:21]=2)[N:16]([CH3:24])[N:15]=1.B(Br)(Br)Br.C(Cl)Cl>>[NH2:23][C:19]1[N:18]=[C:17]2[N:16]([CH3:24])[N:15]=[C:14]([C:4]3[CH:5]=[CH:6][C:7]([O:9][C:10]([F:11])([F:13])[F:12])=[CH:8][C:3]=3[OH:2])[C:22]2=[CH:21][N:20]=1
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nn(C)c2nc(N)ncc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2O)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(2-Methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 123) (50 mg, 0.147 mmol) and 1M BBr3 in DCM (3 ml, 2.94 mmol) is stirred at room temperature for 30 minutes. The reaction mixture is quenched with water (5 ml) and stirred for a further 30 minutes. The resulting precipitate is collected by filtration, washed with water and dried under vacuum (50° C.) to afford the title compound as the hydrobromide salt.
Reaction SMILES: [F:1][B-](F)(F)F.[C:6]([OH:14])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:6]([F:1])(=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: F[B-](F)(F)F
Reactant: O=C(O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(F)c1ccccc1
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (344 mg, 1.5 mmol) in dichloromethane (3.0 mL) at room temperature is added benzoic acid (122 mg, 1.0 mmol) and DBU (224 μl, 1.5 mmol). The reaction mixture is stirred for 4 hours, then an 10% aqueous solution of HCl is added and stirring is continued for 15 minutes. The resulting mixture is extracted twice using dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated. The crude material is diluted with pentane and the solution is passed through a pad of silica gel with pentane elution. Solvent are evaporated in vacuum to provide benzoyl fluoride (90 mg, 74%) as a clear liquid. 1H NMR (CDCl3, 300 MHz) δ 7.94 (d, J=7.8, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.43 (t, J=8.2 Hz, 2H); 19F NMR (CDCl3, 282 MHz) δ 17.5 (s, 1F); 13C NMR (CDCl3, 75 MHz) δ 157.3 (d, 1JC-F=344.3 Hz), 135.5, 131.5 (d, 3JC-F=4.0 Hz), 129.2, 125.0 (d, 2JC-F=60.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][OH:14].CCOC(C)=O.C1COCC1>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([OH:9])[CH2:10][NH:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: Clc1ccc(C2CO2)cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCNCC(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-chloro-5-(oxiran-2-yl)pyridine (4.0 g) in THF (15 ml) was added 2-aminoethanol (15.4 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and the mixture was washed with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(6-chloropyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (5.05 g) as a yellow solid which was used in the next step without further purification. MS (ISP): 219.3 ([{37Cl}M+H]+), 217.2 ([{35Cl}M+H]+), 201.3 ([{37Cl}M+H—H2O]+), 199.1 ([{35Cl}M+H—H2O]+).
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(Cl)Cl.S(=O)(=O)(O)O>O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:17]1[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[O:19][CH3:20])[CH2:8]2
Reactant: COc1ccc(Br)cc1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Br)cc1C1C2CC3CC(C2)CC1C3

Procedure:
In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to separating funnel and the organic layer collected, which is neutralized by two portions of 100 mL 10% sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72%) with m.p. 140-141° C. is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(N2CCNCC2)n1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol), piperazine (1.4 g, 16.0 mmol), and triethylamine (1.5 mL, 11.0 mmol) were mixed in DMF (10 mL) in a dealed tube. The mixture was heated at 100° C. overnight. The reaction mixture was concentrated and chromatographed on silica gel (ethyl acetate to EA/MeOH/Et3N=9:1:0.5) to give 1.05 g of the desired product. MS calculated for C10H12F3N3: (M+H) 232.1; found 232.1.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6](COCC[Si](C)(C)C)[N:5]=[C:4]2[CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[C:22]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[CH:21][C:20]=3[N:3]12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[C:22]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:31][CH2:30]4)=[CH:21][C:20]=3[N:3]12
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of tert-butyl 4-(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.07 g, 0.117 mmol) in THF (2 mL) was added a solution of TBAF in THF (1M, 0.58 mL, 0.585 mmol) and the reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled to rt and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 23) to give tert-butyl 4-(1-methyl-2-oxo-8-(trifluoromethyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.04 g, 73%). LC/MS (Table 1, Method 3) Rt=1.665 min; MS m/z: 469 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:26])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.CO[CH:29]1[CH2:33][CH2:32][CH:31](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:26]2[CH:29]=[CH:33][CH:32]=[CH:31]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12
Solvent: CC(=O)O
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1-n1cccc1
Temperature: 110 °C
Yield: 88 %

Procedure:
6-Chloro-2-{4-[2-(4-morpholinyl)ethoxy]phenyl}-1H-imidazo[4,5-b]pyridin-7-amine (Example 212) (17 mg, 45 μmol) was dissolved in acetic acid (5 ml). 2,5-Dimethoxytetrahydrofuran (0.20 ml) was added and the mixture heated (110° C., 3 h) and then allowed to cool and the solvents and excess reagents were removed in vacuo. The residual brown oil was dissolved in acetonitrile (1 ml) and subjected to semi-preparative HPLC-C18. The appropriate fractions were pooled and evaporated in vacuo. The residue was dissolved in EtOAc (5 ml). This solution was washed with saturated aqueous NaHCO3 (5 ml) and brine (2 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to afford the pure product (17 mg, 88%) as a beige powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37][CH2:38]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(N3CCN(c4ccccc4)CC3)n2)cc1
Yield: 73 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (40 mg, 73% yield.) MS/ES+: m/z=476.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:38]([CH:35]1[CH2:37][CH2:36]1)=[O:39]
Reactant: O=C(Cl)C1CC1
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNC(=O)C1CC1)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (60 mg, 0.155 mmol), triethylamine (17 mg, 24 μL, 0.170 mmol), cyclopropane carbonyl chloride (16 mg, 14 μL, 0.155 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-28 (66 mg, 93%). 1H NMR (600 MHz, CDCl3): δ 8.33 (s, 1H), 7.40 (t, J=6.1 Hz, 1H), 6.77 (s, 1H), 6.52 (s, 1H), 6.40 (br s, 2H), 5.90 (s, 2H), 4.29 (t, J=6.2 Hz, 2H), 3.11 (q, J=6.0 Hz, 2H), 2.68 (s, 6H), 1.87-1.91 (m, 2H), 1.45-1.49 (m, 1H), 0.98-0.96 (m, 2H), 0.77-0.74 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 173.7, 154.9, 153.0, 151.8, 148.3, 147.5, 146.6, 144.7, 119.9, 119.5, 109.6, 102.5, 101.7, 45.3, 40.6, 35.3, 29.1, 14.9, 7.1 HRMS (ESI) m/z [M+H]+ calcd. for C21H26N7O3S, 456.1818. found 456.1812.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:25][O:24]2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>C(O)C>[CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][NH2:27])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCc1ccc(OCC2CO2)cc1)OCc1ccccc1
Reactant: N
Solvent: CCO
Product: NCC(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
An ethanol solution of 39 (0.86 g, 2.42 mmol) was saturated with ammonia and stirred overnight at room temperature. The solvent was evaporated and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 40 (0.75 g, 87%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.40 (m, 2H), 1.51 (m, 2H), 2.50 (m, 2H), 2.58 (m, 1H), 2.68 (m, 1H), 3.00 (m, 2H), 3.69 (m, 1H), 3.80 (m, 1H), 3.90 (m, 1H), 5.08 (s, 2H), 6.82 (d, 2H), 7.06 (d, 2H), 7.35 (br s, 5H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]c(=O)[nH]c4c3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (63.3 mg, 0.243 mmol), DMSO(2 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 35 mg (40%). LCMS E-S (M+H)=472.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 4.41 (d, J=4.8 Hz, 2 H), 5.30 (quin, J=6.6 Hz, 1 H), 5.91 (s, 1 H), 7.07 (d, J=8.3 Hz, 1 H), 7.86 (s, 1 H), 7.92 (dd, J=8.3, 1.8 Hz, 1 H), 8.10 (s, 1 H), 8.30-8.41 (m, 1 H), 8.98 (t, J=4.8 Hz, 1 H), 10.82 (s, 1 H), 10.89 (s, 1 H). 11.58 (s, 1 H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([O:12]C(=O)C)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>O.CO>[Br:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(OC(C)=O)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(O)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
A solution of potassium hydroxide (290 mg, 5.19 mmol) in water (2.5 mL) was added to a solution of acetic acid 3-bromo-4-methoxy-phenyl ester (1.2 g, 4.9 mmol) in methanol (18.5 mL). Mixture was stirred at ambient temperature for 30 min, then solvents were removed in vacuo and water (40 mL) added. The mixture was made acidic by drop-wise addition of 1.2 M aq HCl solution (4.3 mL) and the mixture extracted with dichloromethane (2×40 mL). Combined organics were dried over sodium sulphate, filtered and filtrate solvents evaporated in vacuo to give the title compound (976 mg, 98%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: BrCc1cccnc1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccnc4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3-bromomethyl-pyridine gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH:16]12[CH2:22][CH:20]([O:21]1)[CH2:19][NH:18][CH2:17]2>>[CH:20]12[CH2:22][CH:16]([O:21]1)[CH2:17][N:18]([C:13]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])[CH2:19]2
Reactant: C1NCC2CC1O2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CC4CC(C3)O4)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 6-oxa-3-azabicyclo[3.1.1]heptane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[C:27]([CH3:33])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:30]([C:28]2[C:27]([CH3:33])=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:31])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1nn(C)cc1C(=O)O
Product: Cc1nn(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.69 min; [M+H]+=455.2.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1ccccc1
Reactant: OB(O)c1ccco1
Product: O=C(Nc1nc2cccc(-c3ccco3)n2n1)c1ccccc1
Yield: 26 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B1), 75 mg; 0.24 mmol; 1.0 eq.) and 2-furanboronic acid (53 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, 45:55) gave the title compound as an off-white powder (19 mg, 26%). HPLC, Rt: 3.24 min. (purity 97.9%). LC/MS, M+(ESI): 305.3, M−(ESI): 303.2.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[CH3:24][NH:25][CH3:26]>C(O)C.C(O)(=O)C>[CH3:24][N:25]([CH2:2][CH2:1][S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:16][CH2:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[N:13]2)=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:26]
Reactant: C=CS(=O)(=O)c1ccc(N2CCC(c3ccc(Cl)cc3)=N2)cc1
Reactant: CNC
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCS(=O)(=O)c1ccc(N2CCC(c3ccc(Cl)cc3)=N2)cc1
Temperature: 25 °C

Procedure:
6.9 g of 1-(p-vinylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline are stirred in 5.5 g of a 33% solution of dimethylamine in ethanol and 15 ml of ethanol. The solution is heated gradually over one hour to 78° C. and stirring is continued until the starting material is dissolved and a concentrated sample is soluble in dilute acetic acid. The solution is allowed to cool to room temperature, whereupon a dense precipitate of the reaction product forms. This precipitate is collected by suction filtration, washed with ethanol and dried, affording 6.7 g of 1-(p-dimethylaminoethylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline (formula 103). 1-(p-Diethylaminoethylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline (m.p. 104°-107° C.) is obtained in analogous manner using diethylamine in isopropanol instead of dimethylamine in ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:25])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([O:17][CH3:25])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c2c(nn1-c1ccc(Cl)cc1F)CCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.1 parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one, 25 parts of tetrahydrofuran and 5 parts of 10% aqueous sodium hydroxide was reacted with 1.29 parts of dimethyl sulfate. The reaction was stirred at ambient temperature for 20 hours and evaporated at 25° and 100 mm. Hg to yield 2.8 parts of a glass. This glass was chromatographed on 75 parts of Mallinckrodt Silicar CC-7 Special silica gel. The benzene eluent gave a solid which was recrystallized from etherhexane at -70° to yield 0.2 part of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-3-methoxy-2H-indazole melting at 100°-102°. The infrared spectrum contained no absorptions for a carbonyl, NH, or OH and the nuclear magnetic reasonance spectrum contained singlet absorption at 4.0 δ characteristic of a methoxy moiety.