Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.I[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N:18]1[CH:19]=[CH:20][C:15]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=3)[CH:7]=[CH:8]2)=[CH:16][CH:17]=1
Reactant: Ic1ccncc1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Product: FC(F)(F)c1ccc2ccn(-c3ccncc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-(trifluoromethyl)-1H-indole and 4-iodopyridine: ESMS m/e: 262.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]#[N:8])[CH:3]=1.F[C:10]1C=CC(C2OC3C=CC(C4C=CC(C5C=CC=C(C(O)=O)C=5)=C(C(=O)NCC(C)C)C=4)=CC=3C=2C(=O)NC)=C[CH:11]=1.CC[Mg+].[Br-].[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2([NH2:8])[CH2:11][CH2:10]2)[CH:3]=1
Reactant: Cc1cc(C#N)no1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4cccc(C(=O)O)c4)c(C(=O)NCC(C)C)c3)cc12
Agent: CC[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C2(N)CC2)no1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Methylisoxazole-3-carbonitrile (1.0 g, 1 mmol) was dissolved in THF. Ti (Oi-Pr) 4 (1.2 mmol) was added dropwise over a period of 5-10 min and the reaction mixture was stirred at r.t for 15 min. It was then cooled down to 0° C. and EtMgBr (2.5 mmol) was added dropwise over a period of 10-15 min. It was stirred at 0° C. for 15 min. and then stirred at rt for 1 hr. The mixture was cooled again to 0° C. and BF3OEt2 (2 mmol) was added dropwise over a period of 5-10 min at 0° C. After the mixture was stirred for 10 min at 0° C. and 1 hr at rt, 1 N NaOH was added at 0° C. DCM was added to the reaction mixture which was then stirred for 5-10 min. This alkaline solution was filtered through celite and washed with DCM. The organic layer was concentrated and residue purified by flash chromatography on silica gel using 10% chloroform/methanol. Yield: 0.6 g 1H NMR (400 MHz, CDCl3): δ 0.96-1.05 (m, 4H), 2.36 (s, 3H), 5.59 (s, 1H). LCMS: (ES+) m/z observed 138.7.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]3=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[C:11]3=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Brc1cccnc1
Reactant: CC1(C)CN(c2ccc3ncsc3c2)C(=O)N1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)CN(c2ccc3ncsc3c2)C(=O)N1c1cccnc1

Procedure:
1-Benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-201b: 100 mg, 0.4048 mmol) was reacted with 3-bromo-pyridine (83 mg, 0.525 mmol), 1,4-dioxane (10 mL), copper iodide (7 mg, 0.036 mmol), trans-1,2-diamino cyclohexane (17 mg, 0.119 mmol) and potassium phosphate (214 mg, 1.009 mmol) to afford the crude product.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(c3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc3c(N4CCN(c5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 18 h
Yield: 36 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-phenylpiperazin-1-yl)pyridin-2-amine (75 mg, 0.20 mmol), DMF (1.5 mL), 1M Na2S2O4 (3 eq, 0.60 mmol, 0.60 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.21 mmol, 31 mg). After 18 h, filtration of the precipitate and trituration with Et2O gave the product (34 mg, 36%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 3.00 (s, 6H, N(CH3)2), 3.36-3.38 (m, 4H, piperazine N(CH2)2), 3.78-3.80 (m, 4H, piperazine N(CH2)2), 6.80-6.83 (m, 1H, phenyl H-4), 6.82 (d, J=8.7 Hz, 2H, N,N-dimethylaminophenyl), 7.03 (d, J=8.0 Hz, 2H, phenyl H-2 & H-6), 7.25 (t, br, J=8.0 Hz, 2H, phenyl H-3 & H-5), 8.02 (d, J=8.8 Hz, 2H, N,N-dimethylaminophenyl), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.14 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[CH2:9][CH:8]=[C:7]([CH3:11])[CH2:6][C:5]=2[C:4]([CH3:13])([CH3:12])[CH2:3]1.P([O-])([O-])(O)=[O:16].[Na+].[Na+].C(OO)(C)(C)C>ClCCCl.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[O:16]1[CH:8]2[C:7]1([CH3:11])[CH2:6][C:5]1[C:4]([CH3:13])([CH3:12])[CH2:3][C:2]([CH3:14])([CH3:1])[C:10]=1[CH2:9]2
Reactant: O=P([O-])([O-])O
Reactant: CC1=CCC2=C(C1)C(C)(C)CC2(C)C
Agent: [Mo]
Agent: CC(C)(C)OO
Agent: [C-]#[O+]
Solvent: ClCCCl
Product: CC1(C)CC(C)(C)C2=C1CC1OC1(C)C2
Yield: 57.2 %

Procedure:
44.5 g of a hydrocarbon mixture containing (according to GC) about 85.4% of 1,1,3,3,5-pentamethyl-4,7-dihydroindane (IIc) are dissolved in 200 ml of 1,2-dichloroethane and treated in accordance with method C described in Example 1 with 0.53 g of molybdenum hexacarbonyl, 0.2 g of disodium hydrogen phosphate and 140 ml of 2.85 molar tert.butyl hydroperoxide solution. After working-up and high vacuum distillation, there are obtained 23.6 g (corresponding to 57.2% yield based on IIc) of 5,6-epoxy-1,1,3,3,5-pentamethyl-4,5,6,7-tetrahydroindane with the following data:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
A mixture of 5-phenyl-2-oxindole (39 mg, 0.18 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (48 mg, 0.18 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 44 mg (54%) of the title compound as a red solid.
Reaction SMILES: [F:1][C:2]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([F:7])[CH2:3][CH2:4][CH2:5]I.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:16]([CH2:5][CH2:4][CH2:3][C:2]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([F:7])[F:1])=[N+:17]=[N-:18]
Reactant: CCOP(=O)(OCC)C(F)(F)CCCI
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)CCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethyl 1,1-difluoro-4-iodobutylphosphonate (1 eq) in DMF (0.27 M) was added sodium azide (3 eq). The reaction mixture was stirred at room temperature for 90 minutes. The mixture was diluted with ethyl acetate and washed with water. The aqueous phase was back extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-50% EtOAc/Hex to give the product as a yellowish oil.
Reaction SMILES: [Mg].II.Br[C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][O:14][CH3:15])=[CH:7][C:6]=1[O:16][CH3:17].[B:18]([O:23]C)([O:21]C)[O:19]C.[Cl-].[NH4+]>O1CCCC1.CO>[CH3:17][O:16][C:6]1[CH:7]=[C:8]([CH2:13][O:14][CH3:15])[CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[O:19][B:18]([OH:23])[OH:21]
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
To a suspension of magnesium turnings (97.5 mg, 4.01 mmol) in tetrahydrofuran (0.5 mL) containing a small amount of added iodine, was added approximately a tenth part of a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (1.0 g, 3.82 mmol) in tetrahydrofuran (1 mL) under a nitrogen atmosphere, and the mixture was heated in an oil bath at 70° C. The heating was terminated upon gentle reflux of the reaction mixture and fading of the iodine color. To continue the reflux, the remaining solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene in tetrahydrofuran was added dropwise to the reaction mixture. Upon completion of the dropwise addition, the reaction mixture was further heated to reflux for 1 hour and then cooled to room temperature. The reaction mixture was then added dropwise to an ice-cooled solution of trimethyl borate (0.57 mL, 4.97 mmol) in tetrahydrofuran (0.5 mL). Upon completion of the dropwise addition and stirring for 40 minutes while cooling with ice, the mixture was stirred overnight at room temperature. An aqueous ammonium chloride solution and methanol were then added to the reaction mixture. Quantitation by liquid chromatography confirmed that the title compound had been obtained at an 89% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:21](Cl)(=[O:23])[CH3:22]>CC(N(C)C)=O>[C:21]([NH:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:23])[CH3:22]
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c1I
Yield: 87 %

Procedure:
Analogously to Example 3, 5-amino-N-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid and acetyl chloride are reacted in dimethylacetamide. Yield: 87%, m.p. 276°-278° C., with decomposition.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].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>[N+:11]([C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc(C)c1O
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of 4-bromo-2,6-dimethylphenol (2.58 g, 12.8 mmol) and 3-nitrophenylboronic acid (2.08 g, 12.5 mmol) in toluene (50 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) and 2M sodium carbonate (6.3 mL, 13 mmol). The mixture was stirred at 100° C. for 22 hours at which time additional palladium catalyst (150 mg) was added. The mixture was heated for another 20 hours and then cooled to room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was dried and concentrated. The residue was purified on silica gel, eluting with 12% ethyl acetate in hexanes, to provide 4-(3-nitrophenyl)-2,6-dimethylphenol as a yellow solid (0.932 g, 31%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7]2([CH2:12][CH:11]([OH:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:7]2([CH2:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCC=CC12CCCC(O)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC=CC12CCCC(=O)C2
Yield: 91.6 %

Procedure:
To a solution of 11,11-dimethyl-spiro[5.5]undec-7-en-2-ol (320 mg) obtained in Step 4 in chloroform (10 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-on e (Dess-Martin periodinane; 735 mg) under ice-cooling, followed by stirring the reaction mixture under ice-cooling for 3 hours. Then, after addition of aqueous sodium sulfite solution to the reaction mixture, chloroform was evaporated off in vacuo. To the residue was added aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=20:1) to give 11,11-dimethyl-spiro[5.5]undec-7-en-2-one (290 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:32][C:33]1[S:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1>>[CH3:32][C:33]1[S:34][C:35]([S:39]([N:5]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]2)(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(C)c(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)s1

Procedure:
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and (2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl chloride (275 mg), the title compound was obtained as an oil (yield 27.8 mg, 8%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[N:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][O:32][C:5]1[CH:4]=[N:3][C:2]([NH:40][C:37]2[CH:38]=[CH:39][N:34]=[CH:35][N:36]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])[C:6]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1cnc(Nc2ccncn2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 115 °C
Yield: 4 %

Procedure:
A suspension of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.195 mmol), pyrimidin-4-amine (55.7 mg, 0.586 mmol), Tris(dibenzylideneacetone)dipalladium(0) (8.94 mg, 9.76 μmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (11.29 mg, 0.020 mmol) and Cesium carbonate (127 mg, 0.390 mmol) in Dioxane (2 mL) was heated at 115° C. for 4 hours. After cooling to rt, the mixture was diluted with MeOH and filtered. The filtrate was concentrated and purified by prep. HPLC to give 1-(4-methoxy-7-(pyrimidin-4-ylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (4.1 mg, 7.79 μmol, 3.99% yield). LCMS: m/e 527.3 (M+H)+, ret time 1.02 min. 1H NMR (500 MHz, MeOD) δ ppm 8.87 (s, 1H) 8.61 (d, J=3.66 Hz, 1H) 8.49 (d, J=6.10 Hz, 1H) 8.42 (s, 1H) 8.03-8.10 (m, 1H) 7.83 (d, J=7.94 Hz, 1H) 7.67 (s, 1H) 7.51-7.56 (m, 2H) 4.02 (s, 3H) 3.83-3.90 (m, 2H) 3.62-3.67 (m, 2H) 3.43-3.56 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[O:13]1[C:17]2([CH2:22][CH2:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:20]2[CH2:21][CH2:22][C:17]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:18][CH:19]=2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)ccc1N
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1cc(C2=CCC3(CC2)OCCO3)ccc1N

Procedure:
2-Amino-5-bromo-N-methyl-benzamide (Compound 106A, 645.0 mg, 2.816 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester (899.2 mg, 3.379 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (229.9 mg, 0.2816 mmol) were added to a 20 mL microwave tube and taken up in 1,4-Dioxane (8 mL, 100 mmol). This mixture was treated with a solution of potassium carbonate (1167 mg, 8.447 mmol) in H2O (3 mL, 200 mmol). After sparging the mixture with N2 for 1 minute, the tube was sealed and irradiated in the Biotage microwave reactor for 30 minutes at 100° C. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to a black goo. This was taken up in DCM, treated with silica and concentrated to a plug. This plug was loaded into a sample cartridge and purified on an ISCO Combiflash unit (0-40%-70% EtOAc/Hexane) to isolate the desired product as 359 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.78 (t, J=6.44 Hz, 2H), 2.33 (br. s., 2H), 2.50-2.51 (m, J=1.80 Hz, 2H), 2.72 (d, J=4.55 Hz, 3H), 3.91 (s, 4H), 5.85 (t, J=3.92 Hz, 1H), 6.41 (s, 2H), 6.63 (d, J=8.59 Hz, 1H), 7.23 (dd, J=8.59, 2.02 Hz, 1H), 7.48 (d, J=2.27 Hz, 1H), 8.23 (d, J=4.29 Hz, 1H). MS (ES+): m/z=289.06 (100) [M+1]. HPLC: tR=2.62 min (ZQ3, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH2:10][CH:11]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:12]([C:16]([O:18][CH3:19])=[O:17])[C:13](=O)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].P(OCC)(OCC)[O:39]CC>O1CCCC1.O=O>[N+:1]([C:4]1[C:9]2[CH2:10][CH:11]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:12]([OH:39])([C:16]([O:18][CH3:19])=[O:17])[CH2:13][NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1C(=O)Nc2cccc([N+](=O)[O-])c2CC1c1ccc(OC)cc1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(O)CNc2cccc([N+](=O)[O-])c2CC1c1ccc(OC)cc1
Yield: 166.9 %

Procedure:
6-Nitro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (5.05 0.014 mol) in 250 ml of tetrahydrofuran was treated with 10.9 g (0.055 mol) of potassium hexamethyldisilazide at -70° C., then with 9.6 ml (0.056 mol) of triethyl phosphite and oxygen gas at -70 to 0° C. as described in Example 1, Method II, part D. The solution became very dark on adding the base and did not lighten on passing in oxygen. Workup according to the reference procedure gave 8.7 g of a deep red oil which did not crystallize following trituration with hexane. The final yield of a deep red oil was 5.3 g.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.[OH:21][C:22]1[CH:23]=[C:24]([CH2:28][CH:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[P:1]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH:29]=[O:30])[CH:23]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCCCCSP(=O)(Cl)SCC
Reactant: O=CCc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCSP(=O)(Oc1cccc(CC=O)c1)SCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of S-ethyl S-hexyl chlorodithiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 3-hydroxylphenylacetaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed, the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product S-ethyl S-hexyl O-(3-formylmethylphenyl) dithiophosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.O1CCOCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Solvent: CCO
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A Raney nickel suspension (“R-100”, product of Nikko Rika Corporation) was washed sequentially with water and ethanol to give a corresponding ethanol suspension. The resulting ethanol suspension (1 ml) was added to a solution of methyl(E)-3-[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]acrylate (290 mg, 0.602 mmol) in a mixture of ethanol (6 ml) and 1,4-dioxane (4 ml). The resulting mixture was stirred vigorously for 30 minutes under a hydrogen atmosphere of 1 atmospheric pressure. The reaction mixture was filtered, followed by concentration under reduced pressure. The residue thus obtained was dissolved in dichloromethane. The resulting solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was washed with hexane to give the title compound (252 mg, 0.521 mmol, 87%) as a white powder.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(Cl)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 15, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (50 mg, 20%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=475. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.40-5.56 (m, 2H), 7.65 (m, 1H), 7.79-7.95 (m, 4H), 8.10 (m, 1H) and 8.95 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.05 (s, 3F).