Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc(N)c1C#N

Procedure:
A stirred solution of 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid (commercially available), 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-[3,5-di(trifluoromethyl)phenyl]pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[N:24]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[N:24]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cn(C)c(Br)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: Cc1cn(C)c(-c2cc(C)c(Cl)c(C)c2)n1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-1,4-dimethyl-imidazole following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.82 min; Mass spectrum (ESI+): m/z=235/237 (Cl) [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][CH2:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: NCC(F)(F)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCC(F)(F)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 130 °C
Yield: 51 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-Amino-2,2-difluoro-propionic acid hydrochloride (122 mg, 0.75 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5M; 3 mL, 1.5 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 150 minutes. The reaction mixture was diluted with water and treated with 1N hydrochloric acid and extracted three times with ethyl acetate then dried over sodium sulfate. The solvent was removed in vacuo to provide the title compound as an orange solid in 51% yield. MS ESI(−) m/e: 412.1027 (M−1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.[CH3:16][C:17]([CH:19]([O:22][CH3:23])[O:20][CH3:21])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:21][O:20][CH:19]([O:22][CH3:23])[C:17]1([CH3:16])[CH2:12][C:11](=[O:13])[C:6]2[CH:5]=[C:4]([O:3][C:2]([F:14])([F:15])[F:1])[CH:9]=[CH:8][C:7]=2[O:10]1
Reactant: COC(OC)C(C)=O
Reactant: CC(=O)c1cc(OC(F)(F)F)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2cc(OC(F)(F)F)ccc2O1
Yield: 64.6 %

Procedure:
To a solution of 0.5 g (2.27 mmole) of the compound obtained in step 2 dissolved in 10 ml of toluene were added 0.55 ml (4.54 mmole) of pyruvic aldehyde dimethyl acetal and 80 mg (1.14 mmole) of pyrrolidine. The reactants were heated to reflux for about 12 hours using Dean-Stark apparatus. After completion of the reaction, toluene solvent was removed therefrom under reduced pressure. The residue so obtained was extracted with ethyl acetate and concentrated to give residue, which was purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate of 10:1 to obtain 0.470 g (yield 65%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.CN([CH:26]=[O:27])C.Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([CH:6]=1)[CH:26]=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(F)c(C=O)c1
Temperature: -45 °C
Reaction time: 5 h

Procedure:
A solution of 1-tert-butyl-4-fluoro-benzene (4.54 g, 30 mmol) in THF (100 mL) cooled at −78° C. was treated dropwise with a 2.5M solution of nBuLi in hexane (24 mL, 59 mmol). The reaction mixture was stirred for 5 h at −45° C. then DMF (3.5 mL, 44 mmol) was added at −75° C. and the reaction mixture was stirred for 0.5 h at −75° C. The reaction mixture was poured onto 1N aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi Flash, 40 g silica gel, hexane to hexane-EtOAc 10:1) as a light yellow oil: TLC (hexane-EtOAc 10:1) Rf=0.48, HPLC RtA=2.10 min; 1H NMR (400 MHz, CDCl3): δ10.36 (s, 1H), 7.85 (dd, 1H), 7.62 (m, 1H), 7.08 (dd, 1H), 1.32 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH:23][C:32](=[O:33])[CH2:31][Cl:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(N)N=Nc1ccccc1C(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(N=Nc1ccccc1C(=O)c1ccccn1)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
To a solution of 12.5 g. of ethyl [2-(2-pyridinecarbonyl)phenyl]azo-aminoacetate in 400 ml. of anhydrous benzene are added 11.4 g. of potassium carbonate and 8.0 ml. of chloroacetyl chloride. The resulting mixture is refluxed with stirring for 30 minutes, and then cooled. The resulting precipitate is collected by filtration, and partitioned between saturated aqueous sodium hydrogen carbonate solution and chloroform. The chloroform layer is separated, washed with water, dried over sodium sulfate, followed by evaporation of the solvent to give ethyl [2-(2-pyridinecarbonyl)phenyl]azo-(2-chloroacetamido)-acetate as crystals. Recrystallization from acetone-n-hexane gives yellow needles, melting at 160 to 162° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15]I.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:14])[N:10]([CH:11]1[CH2:12][CH2:13]1)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of cyclopropyl-carbamic acid benzyl ester (11.8 g) and methyl iodide (excess) in THF (80 mL) and DMF (20 mL) at 0° C. was added NaH (2.20 g, 91.6 mmol) and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched at 0° C. by sat. NaHCO3. The separated aqueous phase was extracted several times with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 20% EtOAc/hexanes) to give cyclopropyl-methyl-carbamic acid benzyl ester (11.32 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]=O)=[C:5]([CH3:11])[N:4]([CH:12]([CH3:14])[CH3:13])[C:3]1=[O:15].BrBr.C(O[CH2:22][CH3:23])(=O)C>C(Cl)(Cl)Cl.ClCCl>[CH2:13]1[C:22]2[C:23](=[CH:11][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH:12]1[N:4]1[CH:9]=[C:6]2[C:5]([N:4]([CH:12]([CH3:14])[CH3:13])[C:3](=[O:15])[N:2]([CH3:1])[C:7]2=[O:8])=[CH:11]1
Reactant: Cc1c(C=O)c(=O)n(C)c(=O)n1C(C)C
Reactant: CCOC(C)=O
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C)c(=O)c2cn(C3Cc4ccccc4C3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,6-Dimethyl-5-formyl-1-(1-methylethyl)pyrimidine-2,4-dione (J. Med. Chem., 1995, 38, 2557, 1.70 g) was dissolved in chloroform (25 ml) and the solution was heated to 50° C. A solution of bromine (0.413 ml) in chloroform (20 ml) was added dropwise to the aldehyde solution over 24 minutes. The reaction was maintained at 50° C. for a further 15 minutes, then allowed to cool to ambient temperature. The reaction mixture was diluted with dichloromethane and was washed successively with water, dilute sodium thiosulphate solution (twice) and brine. The resultant solution was dried, filtered and evaporated to a crude oil which was dissolved in ethanol (50 ml). Triethylamine (3.38 ml) was added to the solution followed by 2-aminoindane (1.49 g) and the mixture was stirred under nitrogen overnight. The reaction mixture was filtered, the white solid collected was washed with a little ethanol and the filtrate was evaporated to give a brown oil. Ethyl acetate was added to the oil and the resultant precipitate was collected by filtration and was washed with a little ethyl acetate. The filtrate was washed with hydrochloric acid (HCl) (2.5 M) and then brine. The resultant ethyl acetate phase was dried, filtered and evaporated to an oil. The oil was purified by chromatography, eluting with isohexane:acetone (4:1) to give a solid which was triturated with hot ethyl acetate:isohexane (3:1) to give the subtitle compound (0.50 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([NH2:19])[C:16]([C:20]#[N:21])=[C:15](Cl)[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:25]([NH2:28])([CH3:27])[CH3:26]>CN(C)C(=O)C.C(#N)C>[NH2:19][C:17]1[C:16]([C:20]#[N:21])=[C:15]([NH:28][CH:25]([CH3:27])[CH3:26])[N:14]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:23]=[CH:24][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:12])[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(CNC(=O)c2cc(N)c(C#N)c(Cl)n2)cc1
Reactant: CC(C)N
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C#N
Yield: 20.6 %

Procedure:
A mixture of Example 181F (36 mg, 0.1 mmol), isopropylamine (85 μL, 1.0 mmol) in N,N-dimethylacetamide (500 μL) was heated at 190° C. for 80 minutes in a microwave reactor. The crude mixture was diluted with 1 mL acetonitrile and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate), followed by second purification via silica gel chromatography, eluting with hexane/ethyl acetate (1:1 to 100% ethyl acetate) to provide the titled compound (8 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.02 (t, J=6.4 Hz, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 6.89 (bs, 2H), 6.69 (s, 1H), 6.15 (d, J=8.1, 1H), 4.58-4.46 (m, 3H), 3.17 (s, 3H), 1.16 (t, J=6.8 Hz, 6H). MS (m/e) 388 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]1([CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][O:33][CH:28]([CH2:27][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CCN(CC2CNCCO2)CC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN4CCCCC4)C3)c(F)cc2c1=O

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro -4-oxoquinoline-3-carboxylic acid and 2-(piperidinomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(piperidinomethyl)morpholino]quinoline-3-carboxylic acid 1/2 hydrate, melting at 160°-162° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[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][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=1)CCC>O1CCOCC1.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>[F:32][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 100 °C

Procedure:
To a sealed tube containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (Compound B-1) (1.24 g, 2.48 mmol) in 1,4-dioxane (20 mL) was added ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (1.12 g, 2.61 mmol) and Pd(PPh3)4 (0.87 g, 0.75 mmol). The mixture was flushed with N2, and was sealed and heated to 100° C. After 14 h of heating, the mixture was cooled to rt, was diluted with MeOH, and was filtered through a pad of celite to remove any solids. The solution was concentrated under reduced pressure, and was re-dissolved in DMF. The DMF solution was loaded on the prep HPLC for purification. After purification, the title product was isolated as an off-white solid (0.901 g). LCMS: m/e 559.6 (M+H)+, ret time 2.283 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.52 (s, 1H) 12.35 (s, 1H) 8.26-8.41 (m, 2H) 7.36-7.76 (m, 6H) 4.29-4.47 (m, J=6.71 Hz, 2H) 3.09-3.80 (m, 8H) 1.36 (s, 3H).
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[N:1]1[C:2]([CH:10]=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12
Reactant: CCOC(=O)c1cn2c(n1)SCCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cn2c(n1)SCCC2
Temperature: -70 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
Ethyl 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine-2-carboxylate (2.12 g, 10 mmol) was dissolved in dry dichloromethane (40 ml) under argon and cooled to -70%. Diisobutylaluminium hydride (1.5M in toluene, 12 ml, 18 mmol) was added below -68° C. and the reaction mixture stirred at -70° C. for 1 h. Water was added carefully and the cooling removed. The reaction mixture was stirred vigorously at ambient temperature for 15 minutes and Celite (2 g) added. The mixture was filtered through Celite, the filter bed washed with dichloromethane and water, the filtrate and the washings combined and evaporated to dryness under reduced pressure. The residue was evaporated from ethanol (2×) to give the title compound as a white solid (1.31 g, 78%); nmax (CH2Cl2) 1685, 1543 and 1453 cm-1 ; dH (250 MHz; CDCl3) 2.34-2.43 (2H, m); 3.20 (2H, t, J 6 Hz), 4.17 (2H, t, J 6 Hz), 7.58 (1H, s), 9.75 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10].OS([O-])(=O)=O.[K+].C(C1C=CC=C(O)C=1O)(C)(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(C)cc(C(C)O)cc1C
Agent: CC(C)(C)c1cccc(O)c1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1cc(C)c(OC(C)=O)c(C)c1
Yield: 81.8 %

Procedure:
(36.6 g, 0.30 mol) of 2,6-dimethylphenol are mixed in an Hastelloy C autoclave with 0.315 mol of acetic anhydride and 9 mols of hydrogen flouride. The temperature is raised to 50° C. and the reaction runs for 3 hours. After extraction and wash, 47.4 g of a gray to purple solid mass of 3,5-dimethyl-4-hydroxyacetophenone is obtained. This solid is then esterified by refluxing with 4 mols of acetic anhydride for 19 hours. After removal of acetic acid and acetic anhydride by vacuum distillation the 3,5-dimethyl-4-acetoxyacetophenone is flash distilled to yield 47.7 g of a slightly yellow liquid. 0.1 mol of the 3,5-dimethyl-4-acetoxyacetophenone, 1.2 g of 5% Pd/C as catalyst and 100 ml ethanol are mixed in an autoclave and the autoclave is charged with hydrogen gas at a pressure of 215-220 mm Hg and the reaction is run for about 2 1/2 hours at a temperature of about 25°-30° C. Additional catalyst is added as needed. The catalyst is then removed and the ethanol evaporated to yield 21.5 g of a colorless oil which is (3,5-dimethyl-4-acetoxyphenyl)ethanol. 0.168 mol of (3,5-dimethyl-4-acetoxyphenyl)ethanol is added to a flask with 0.35 g KHSO4 and 0.5 g t-butyl catechol. The flask is heated to 185° to 190° C. at 1.5 to 2.0 mm Hg. A colorless liquid is distilled. After the addition of 0.15 g of t-butyl catechol, and redistillation, 26.1 g of 3,5- dimethyl-4-acetoxystyrene monomer is produced. The compound has a boiling point of 90-91°-91° C. at 0.5 mm of Hg and the yield is 81.8%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][N:29]([S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH2:30][CH2:31]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a CEM microwave tube containing {5-[(ethylamino)methyl]-2-thienyl}boronic acid (47 mg, 0.254 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), dioxane (1.5 mL), H2O (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. (This run was aborted prior to 30 min due to excessive pressure build-up). The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C., and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 60° C. to give 8.8 mg of the title compound (10%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14])#[N:10].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([NH:12][CH2:11][C:9]#[N:10])=[O:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: N#CCNC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (3.2 g, 0.22 mmol) and 4-(cyanomethylcarbamoyl)phenylboronic acid (3.0 g, 15 mmol) in toluene (146 mL) were added n-propanol (44 mL), aqueous sodium bicarbonate (2M, 22 mL) and tetrakis(triphenylphosphine)palladium[0] (850 mg, 0.7 mmol). The reaction was heated at 90° C. for 24 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions washed with brine, dried (Na2SO4) filtered and concentrated. Silica gel chromatography using 30-70% ethyl acetate/petroleum spirit as eluent provided 4-(2-chloropyrimidin-4-yl)-N-(cyanomethyl)benzamide as a pale yellow waxy solid (1.35 g, 33%). 1H NMR (300 MHz, d6-DMSO) δ 9.40 (t, J=5.4 Hz, 1H), 8.88 (d, J=5.2 Hz, 1H), 8.32 (d, J=8.7 Hz, 2H), 8.23 (d, J=5.1 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 4.36 (d, J=5.4 Hz, 2H); LC-ESI-MS (method B): rt 5.3 min.; m/z 273.2/275.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH2:11]O)=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH2:11][Br:22])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COC(=O)c1cc(I)c(CO)cc1-c1ccccc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(CBr)cc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.9 %

Procedure:
To a −10° C. solution in dichloromethane of the product of Example 319E (830 mg, 2.17 mmol) and carbon tetrabromide (864 mg, 2.60 mmol) was added triphenylphosphine (626 mg, 2.39 mmol) and the reaction mixture was warmed to 0° C. over 1 hour. The cold bath was then removed and stirring was continued for 2 hours. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (5% ethyl acetate-hexanes) to give the desired compound (1.1 g) which also contained some triphenylphosphine.