Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH:5]([OH:7])[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>O.C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[CH2:6][CH:5]([OH:7])[CH2:4][N:3]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)(=[O:24])=[O:25])[CH2:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CNCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(O)CN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of hexahydro-5-pyrimidinol (1.0 g, 9.8 mmol) and sodium carbonate (1.04 g, 9.8 mmol) in 10 mL of water in a 250 mL round bottom flask was stirred with a magnetic stir bar for 10 minutes. A solution of 4-nitrobenzenesulfonyl chloride (4.4 g, 19.8 mmol) in 10 mL of toluene was added dropwise over a period of 30 minutes. The reaction mixture formed a white suspended solid. A mixture of 100 mL of water and 20 mL of toluene was added to the reaction mixture and stirred overnight. The reaction mixture was filtered and the solid was washed with 100 mL of toluene, then with 100 mL of water. The solid was dried at room temperature under reduced pressure to give 4.4 g (95%) of crude product, hexahydro-1,3-bis(4-nitrobenzenesulfonyl)-5-pyrimidinol. [1H NMR (DMSO-d6): δ 2.29 (s, 1 H), 2.84, 3.47 {AB q of d, J=12.4(3.8) Hz, 12.4(7.9) Hz, 4 H}, 3.30 (m, 1 H), 4.46, 5.07 (AB q, J=12.5 Hz, 2 H), 5.31 (s, 1 H), 8.11, 8.41 (AB q, J=8.7 Hz, 8 H); 13C NMR (DMSO-d6): δ 50.0, 59.8, 60.6, 124.6, 128.9, 143.3, 150.1].
Reaction SMILES: [CH3:1][C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:7][C:6](=[O:8])[N:5]([C@H:9]([C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15]C(OCC)=O)[CH3:10])[CH2:4][CH2:3]1.C[Mg]Br>C1COCC1>[OH:7][C:2]([CH3:3])([CH3:1])[CH2:15][O:14][C:13]1[CH:12]=[C:11]([C@@H:9]([N:5]2[CH2:4][CH2:3][C:2]([CH3:1])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:7][C:6]2=[O:8])[CH3:10])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)COc1cccc([C@H](C)N2CCC(C)(c3ccccc3)OC2=O)c1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H](c1cccc(OCC(C)(C)O)c1)N1CCC(C)(c2ccccc2)OC1=O
Reaction time: 1 h
Yield: 150.6 %

Procedure:
To a solution of ethyl 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate (0.0369 g, 0.0928 mmol) in THF (5 mL) was added methylmagnesium bromide (1.4 M in toluene/THF, 1.0 mL, 1.4 mmol) at rt under nitrogen. After stirring for 1 h, the mixture was quenched with saturated NH4Cl (1 mL), diluted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.0268 g (75%) of (R/S)-3-((S)-1-(3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1, tR=1.64 min, m/z=384 (M+1). 1H NMR (CDCl3) 7.41-7.23 (m, 6H), 6.92-6.88 (m, 2H), 6.84-6.81 (m, 1H), 5.77 (q, J=7.0 Hz, 1H), 3.78 (s, 2H), 2.70-2.67 (m, 2H), 2.29-2.24 (m, 1H), 2.23 (s, 1H), 2.06-1.98 (m, 1H), 1.64 (s, 3H), 1.35 (s, 6H), 1.27 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH:3]([C:5]1[CH:41]=[CH:40][CH:39]=[CH:38][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[CH:24]=2)[N:10]=1)[CH3:4].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[NH:28]1[CH2:27][CH2:26][CH:25]([N:23]2[CH:24]=[C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:38]=[CH:39][CH:40]=[CH:41][C:5]=4[CH:3]([CH3:4])[C:2]([NH2:1])=[O:42])[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=3)[CH:21]=[N:22]2)[CH2:30][CH2:29]1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A66 (3.41 g, 5.80 mmol) in DCM (50 mL) was cooled to 0° C. and treated with TFA (4.44 mL, 0.058 mol). The mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. An extra aliquot of TFA (2.2 mL, 0.029 mol) was added to the mixture and stirring was continued for 2 hours at room temperature. Sat. aq. NaHCO3 (˜50 mL) was carefully added, followed by aq. NaOH (2 M, ˜50 mL). DCM was removed in vacuo and the resultant aqueous mixture was diluted with H2O (˜50 mL). The white suspension was sonicated for 10 minutes and vacuum filtered. The isolated solid was washed with water and air dried to give the title compound 56 as a white solid (2.8 g, 99%). 1H NMR (400 MHz, d6-DMSO) δ 10.20-10.08 (m, 1H), 8.69-8.56 (m, 1H), 8.02-7.93 (m, 1H), 7.58 (s, 1H), 7.44-7.35 (m, 1H), 7.27-7.14 (m, 4H), 6.92-6.80 (m, 1H), 4.21-4.08 (m, 1H), 3.91-3.79 (m, 1H), 3.18-2.91 (m, 6H), 2.61-2.50 (m, 2H), 1.92-1.86 (m, 2H), 1.81-1.68 (m, 2H), 1.33 (d, J=6.9 Hz, 3H). LCMS-A: rt 4.79 min; m/z 488 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)#[N:39]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:44](=[O:45])[C:43]4[CH:47]=[CH:48][C:40]([C:38]#[N:39])=[CH:41][CH:42]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-c2cn(C3CCN(C(=O)c4ccc(C#N)cc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and p-cyanobenzoyl chloride (496.5 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=15:1) to yield the target product as white solid powder.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[CH3:21][NH:22][S:23]([O-:26])(=[O:25])=[O:24].B.[Na]>O1CCCC1.CO>[CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[CH3:21][NH:22][S:23](=[O:25])(=[O:24])[O-:26]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: B
Agent: CNS(=O)(=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Estrone-(N-methyl)amidosulphonate (1 g) is reduced with sodium boron hydride (624.2 mg) in a mixture of tetrahydrofurane (20 ml) and methanol (20 ml). The crude product, following work-up, is recrystallised from acetone/n-hexane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:29](=[O:30])[N:11]3[C:12](=[O:28])[NH:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1>ClCCl.CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:29](=[O:30])[N:11]3[C:12](=[O:28])[NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2nc3c4cc(C#Cc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-n2nc3c4cc(CCc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Reaction time: 12 h
Yield: 79.2 %

Procedure:
A catalytic amount of 10% Pd/C and 13a (20.0 mg, 0.0510 mmol) in a mixture of 2 mL of dichloromethane and 2 mL of methyl alcohol was stirred during 12 h under H2 at atmospheric pressure. The mixture was filtered through celite, washed with additionally methyl alcohol and triturated from ethyl alcohol to afford 14a (16 mg, 0.0404 mmol, 79%) as a white solid. mp: 303° C.;
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4].C(N(CC)CC)C.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>CN(C)C=O.C(Cl)Cl>[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([O:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4])(=[O:24])=[O:25]
Reactant: CCO/C(C)=N/O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO/C(C)=N/OS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
The ethyl (1E)-N-hydroxyethanimidoate (4.72 g, 45.7 mmol) was dissolved in N,N-dimethylformamide (12.0 mL) and triethylamine (6.37 mL, 45.7 mmol) and cooled in an ice bath. The mesitylenesulfonyl chloride (10.0 g, 45.7 mmol) was added portion wise over 5 minutes and the reaction was stirred vigorously for 30 minutes. The reaction mixture became a thick syrup. The reaction was diluted with methylene chloride (100 mL) and was washed with water 3×, brine, dried over magnesium sulfate and concentrated to give ethyl (1E)-N-[(mesitylsulfonyl)oxy]ethanimidoate (11.2 g, 86%) as a semi-solid residue. LCMS calculated for C13H20NO4S (M+H)+: m/z=286.1. found: 285.9.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18]Br)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:20])[CH:17]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)OC(C)(C)C)n1ccc([N+](=O)[O-])n1
Yield: 53.9 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 2.00 g, 17.70 mmol) in anhydrous N,N-dimethylformamide (30 mL), a 60% dispersion of sodium hydride in mineral oil (778 mg, 19.50 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 3-bromo-propionic acid tert-butyl ester (3.25 mL, 19.50 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) to afford (3-nitro-pyrazol-1-yl)-propionic acid tert-butyl ester (2.30 g, 57%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:33]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:28]=[C:29]([Br:31])[CH:30]=2)=[CH:17][C:16]=1[CH3:33]
Reactant: C#CCN1CCCCC1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-prop-2-ynyl-piperidine (53 mg, 0.44 mmol), {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (204 mg, 0.44 mmol, intermediate 2), Pd(PPh3)4 (50 mg, 0.044 mmol), CuI (23 mg, 0.12 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 30 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 105 mg (47%) yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[O:17]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a solution of 4-fluoronitrobenzene (0.50 mL) and phenol (443 mg) in 5.0 mL of dimethylformamide was added K2CO3 (1.27 g). The reaction was warmed to 70° C. for 20 h, then cooled to room temperature and poured into ethyl acetate and water. The organic layer was washed with water, sat. aq. NaHCO3 solution, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>CCOC(C)=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1ccccc1Cl
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)NCc1ccccc1Cl
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl dimethoxyacetate (1.41 g, 10.4 mmol) and 2-chlorobenzylamine (1.45 g, 9.73 mmol) in a microwave vial was sealed and heated in the microwave reactor to 130° C. for 30 min and then to 140° C. for 40 min. The reaction solution was dissolved in EtOAc (≈60 mL) and washed with dil. HCl, water, sat. Na2CO3 solution, and brine, and dried over MgSO4. The EtOAc extract was filtered, concentrated, and dried in vacuo overnight, giving the title compound as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.41-7.35 & 7.27-7.22 (AA′BB′, 4H), 6.98 (brs, 1H), 4.74 (s, 1H), 4.58 (d, J=6.0 Hz, 2H), 3.40 (s, 6H). MS(ES+): m/z=266.05/268.01 (41/13) [MNa′], 244.07/246.02 (86/58) [MH+], 212.03/214.02 (56/21) [MH+-MeOH], 180.07/182.05 (63/26) [MH+-2 MeOH]. HPLC: tR=2.87 min (polar—5 min, ZQ3).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6](Cl)[N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24]>>[NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6]([NH:37][C:34]2[CH:35]=[N:36][C:31]([N:28]3[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]3)=[CH:32][CH:33]=2)[N:7]=1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Product: CCN1CCN(c2ccc(Nc3nc(N)c4scc(-c5cccc(NS(C)(=O)=O)c5)c4n3)cn2)CC1
Yield: 74.9 %

Procedure:
The target compound of Example 27 (22 mg, 74% yield) was prepared in the same manner as Step 9 of Example 1 using N-(3-(4-amino-2-chlorothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (20 mg, 0.056 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (31 mg, 0.17 mmol).
Reaction SMILES: Br[C:2]([F:26])([F:25])[C:3](F)([F:23])[O:4][C:5]1[CH:10]=[C:9]([O:11][C:12](F)([F:17])[C:13]([F:16])([F:15])Br)[CH:8]=[CH:7][C:6]=1[S:19]([F:22])(=[O:21])=[O:20].C(#N)C1C=CC=CC=1>[Cu]Cl.[Zn].C(Cl)Cl>[F:23][C:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]([F:17])=[C:13]([F:16])[F:15])[CH:8]=[CH:7][C:6]=1[S:19]([F:22])(=[O:21])=[O:20])=[C:2]([F:26])[F:25]
Reactant: O=S(=O)(F)c1ccc(OC(F)(F)C(F)(F)Br)cc1OC(F)(F)C(F)(F)Br
Agent: Cl[Cu]
Agent: [Zn]
Solvent: ClCCl
Solvent: N#Cc1ccccc1
Product: O=S(=O)(F)c1ccc(OC(F)=C(F)F)cc1OC(F)=C(F)F
Temperature: 110 °C
Reaction time: 48 h

Procedure:
Into a 250 ml of round bottom flask were placed 16.5 g (0.03 mol) of the 2,4-di(2-bromotetrafluoroethoxy)benzenesulfonyl fluoride, 5.94 g (0.06 mol) of copper(I) chloride and 6.54 g (0.1 mol) of activated zinc powder. Then 120 mL of well-dried benzonitrile was added to the mixture. The solution was stirred at 110° C. for 2 days with the protection of dry nitrogen gas. After being cooled down to room temperature, 120 mL of methylene chloride was added to the flask and the mixture was stirred at that temperature for eight hours, followed by filtration to remove the solid materials. Then 5 g of active carbon was added to the filtrate and the mixture was refluxed for overnight. After being cooled down to room temperature, the mixture was filtered to remove active carbon and the solvents were removed under the reduced pressure. The crude material was purified by sublimation at 120° C. oil bath temperature at 10−2 torr to give 2,4-di(trifluorovinyloxy) benzenesulfonyl fluoride, identified by 19F and 1H NMR.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[N:10]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:18]2[CH2:19][CH2:20][CH:15]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][CH2:17]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: ClCCl
Product: Brc1cccc(CN2CCC(N3CCCC3)CC2)n1

Procedure:
7] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 4-(1-pyrrolidinyl)-piperidine (500 mg, 3.22 mmol) in dry CH2Cl2 (15 mL) to give 2-bromo-6-[4-(1-pyrrolidinyl)-piperidinylmethyl]pyridine as a pale yellow solid. MS m/z: 326.1(M+2H). Calc'd for C15H22BrN3: 324.26.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[C:10]2[CH:9]=[N:8]1.C1(C)C=CC=CC=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[S:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH2:37][C:38]([NH:40][C:41]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]4[N:7]([CH:2]5[CH2:3][CH2:4][CH2:5][CH2:6][O:1]5)[N:8]=[CH:9][C:10]=34)=[CH:18][CH:19]=2)=[S:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-phenylamine (0.199 g, 0.63 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) and phenyl-acetyl isothiocyanate (0.33 g, 2.0 mmol, 3.0 eq). The reaction mixture was stirred at room temperature overnight. After removal of solvent in vacuo, the product was separated by flash chromatography using a 3:1 hexane/ethyl acetate solution as the eluent to give 2-phenyl-N-{[(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)amino]carbonothioyl}acetamide (0.17 g, 54% yield). 1H NMR (400 MHz, DMSO): 12.39 (s, 1H), 11.78 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.71 (d, 2H), 7.53 (t, 1H), 7.34 (m, 5H), 7.26 (m, 1H), 5.97 (d, 1H), 3.94 (d, 1H), 3.73 (s, 2H), 3.72 (m 1H), 3.40 (s, 2H), 2.05 (m, 1H), 1.93 (m, 1H), 1.77 (m, 1H), 1.58 (m, 1H); MS (ESI) for C25H24N6O3S: 489 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:70][O:71][C:72]1[CH:73]=[C:74]([CH:76]=[CH:77][C:78]=1[O:79][CH3:80])[NH2:75]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:13]2[CH:12]=[C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:75][C:74]5[CH:76]=[CH:77][C:78]([O:79][CH3:80])=[C:72]([O:71][CH3:70])[CH:73]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[S:15][C:14]=2[CH:16]=1
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc2cc(-c3cnc4ccc(Cl)nn34)sc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc2cc(-c3cnc4ccc(Nc5ccc(OC)c(OC)c5)nn34)sc2c1
Temperature: 110 °C
Yield: 75 %

Procedure:
To a solution of 6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (82 mg, 0.260 mmol, 1.0 equiv), xantphos (30 mg, 0.0519 mmol, 0.2 equiv), palladium acetate (6 mg, 0.0260 mmol, 0.1 equiv), and potassium carbonate (718 mg, 5.19 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (48 mg, 0.312 mmol, 1.1 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 77 mg, 0.195 mmol of the yellow solid, 75%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14](=O)/[N:15]=[CH:16]/[N:17](C)C)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:24]N.CCOC(C)=O.O>CC(O)=O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14]2[NH:15][CH:16]=[N:17][N:24]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1(c2nnc[nH]2)CC1)OCc1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
To a solution of (1-{[1-dimethylamino-meth-(E)-ylidene]-carbamoyl}-cyclopropyl)-carbamic acid benzyl ester (1.11 g, 3.83 mmol) in AcOH (6 ml) was added hydrazine dihydrochloride (803 mg, 7.65 mmol). The reaction mixture was stirred at 90° C. for 1.5 h. The reaction mixture was poured into EtOAc/water. The organic phase was separated, washed with water, sat. NaHCO3, brine, dried over anhydrous Na2SO4, filtered, concentrated and dried under high vacuum to afford 677 mg of [1-(4H-[1,2,4]triazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester as a off-white solid, m/z 259.6 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:13].[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH:8][CH3:13])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1ncc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 5-bromo-3-methylpyridin-2-amine (B-4-1) (3.7 g, 0.02 mol) in THF (50 mL) was added portionwise NaH (0.8 g, 0.02 mol) at 0° C. After the addition, the mixture was stirred at room temperature for about 0.5 hr, and cooled to 0° C. again. Iodomethane (2.8 g, 0.02 mol) was added slowly. The resulting mixture was allowed to rise to room temperature and stirred for 1 hr. TLC (EtOAc: Petroleum ether=1:4) showed that the reaction was complete. Saturated aqueous NaCl (10 mL) and EtOAc (10 mL) were added. The organic layer was concentrated and the residue was purified via a silica gel column eluted with EtOAc/Petroleum ether (1:8) to give 5-bromo-N,3-dimethylpyridin-2-amine (B-4-2) (2.3 g, 57.8%) as a white solid.