Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=3)=[CH:19][C:18]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1cc(F)cc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(CC#N)c3)cc21

Procedure:
The title compound was prepared according to the procedure B from 3-bromo-5-fluorophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. A white solid was obtained and recrystallized from ethanol/ether. mp 218-220. 1H NMR (DMSO-d6) δ 1.67 (s, 6H), 4.11 (s, 2H), 6.98(d, 1H, J=8.92 Hz), 7.18(d, 1H, J=9.26 Hz), 7.52-7.62 (m, 3H), 10.37 (s, 1H); MS(EI) (M−H)−m/z 309; Anal. Calcd. For C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.78; H, 4.97; N, 8.36.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N+:10]([C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)[CH:3]=1)([O-:12])=[O:11]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ncc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 105.5 %

Procedure:
To a solution of 5-bromo-3-nitropyridine-2-carbonitrile (2.00 g, 8.77 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.68 g, 9.65 mmol) in 10 ml of ethylene glycol dimethyl ether were added bis(triphenylphosphine)palladium(II) chloride (0.31 g; 0.44 mmol) and 9 ml of 2 M sodium carbonate-solution. The reaction mixture was heated at 50° C. for 2 h. Cooled reaction mixture was filtered, the solids were washed with water and dried in vacuum to give 2.77 g (105%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.50-1.66 (m, 3H), 1.81-2.04 (m, 2H), 2.29-2.47 (m, 1H), 3.66-3.79 (m, 1H), 3.97-4.07 (m, 1H), 5.37 (dd, 1H), 6.99 (d, 1H), 7.74 (d, 1H), 8.92 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1Br
Temperature: 70 °C
Yield: 99 %

Procedure:
A solution of 2-bromo-4-methylbenzoic acid (10.0 g, 46.5 mmol) in MeOH (50 mL) was cooled to 0° C., then concentrated sulfuric acid (10 mL) was carefully added. The mixture was heated at 70° C. for 2 hours. After cooling to room temperature, the volatile organics were removed under reduced pressure, and the residue was poured onto ice-water (100 mL). The mixture was extracted with EtOAc (×2) and the combined organic extracts were washed with aq. NaHCO3, brine, dried (MgSO4), filtered, and concentrated to yield 10.5 g (99%) of the title compound as a clear oil. 1H NMR (400 MHz, Chloroform-d) δ 7.73 (d, 1H), 7.50 (d, 1H), 7.19-7.11 (m, 1H), 3.92 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][CH2:37][CH:38]1[CH2:40][O:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:40][CH:38]([OH:39])[CH2:37][O:36][CH3:35])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: COCC1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Solvent: CCO
Product: COCC(O)CN1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 140 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.20 g, 0.40 mmol) in ethanol was added 2-(methoxymethyl)oxirane (0.04 mL, 0.40 mmol). The reaction mixture was heated in a microwave reactor at 140° C. for 5 minutes. The reaction was evaporated to dryness and the resulting residue was purified via silica gel chromatography (0-10% MeOH: CH2Cl2) to afford the desired product (1d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28].C1(C2OC3C=CC=CC=3C=2C(=O)C2C=CC(O)=CC=2)C=CC=CC=1.C(N(CC)CCCCl)C>>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([C:13]2[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[O:10][C:9]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:22])=[CH:20][CH:19]=1)[CH3:28]
Reactant: CCN(CC)CCCl
Reactant: Cc1cc(C)cc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)c1
Agent: CCN(CC)CCCCl
Agent: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(3,5-dimethylphenyl)-3-(4-hydroxybenzoyl)benzofuran with 2-diethylaminoethyl chloride by the procedure described in Example 1 for 2-phenyl-3-(4-hydroxybenzoyl)benzofuran and 3-diethylaminopropyl chloride gives 3-[4-(2-diethylaminoethoxy)benzoyl]-2-(3,5-dimethylphenyl)-benzofuran.
Reaction SMILES: Br[C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[CH2:35][CH2:34]1.ClCCl.P([O-])([O-])([O-])=O.[K+].[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].O1CCOCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([C:42]4[CH:41]=[CH:40][C:39]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)=[CH:44][CH:43]=4)[N:22]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:5]3=[N:6][CH:7]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(CCc2cnc3c(cc(-c4ccc(N5CCN(C)CC5)cc4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 636.6 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (from Example 1, step 4, 30.0 mg, 59.7 μmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (from Alfa Aesar, cat# H51659, 19.8 mg, 6.57 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (4.9 mg, 5.97 mmol), and potassium phosphate (25.4 mg, 119 μmol) in water (0.2 mL)/1,4-dioxane (1 mL) was heated at 88° C. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated to give the desired product (25 mg, 70%). LCMS calculated for C33H36N5O4S (M+H)+: m/z=598.3. Found: 598.3.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:19][CH2:20][CH3:21])[C@H:14]([OH:18])[C:15](O)=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C>[CH:1]1([NH:4][C:15](=[O:16])[C@@H:14]([OH:18])[C@@H:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:19][CH2:20][CH3:21])[CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1

Procedure:
Cyclopropylamine (55 mg, 0.97 mmol) was dropwise added to an ethyl acetate (5 mL) solution of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxyhexanoic acid (200 mg, 0.81 mmol), and the mixture was cooled by ice. HOBt monohydrate (130 mg, 0.85 mmol) and EDC hydrochloride (171 mg, 0.89 mmol) were added thereto, and the mixture was stirred with cooling by ice. As a result, the solid in the mixture aggregated to form a hard lump after about 5 minutes, and the mixture became impossible to be stirred.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[C:4](=[O:14])[CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[C:4](=[O:14])[CH2:3][CH2:2]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc2c(c1)NCCC2=O
Solvent: O
Product: CC(=O)N1CCC(=O)c2ccc(C(=O)O)cc21

Procedure:
5.0 g of 2,3-dihydro-4-quinolone-7-carboxylic acid and 22.5 g of acetic anhydride were heated to 100° C. for 1 hour. After cooling, water was added and the mixture was extracted with methylene chloride. The organic phase was dried and concentrated.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:17][CH2:16]1)=[O:14].[CH:32]1([O-:37])[CH2:36][CH2:35][CH2:34][CH2:33]1.[Na+]>>[CH:32]1([O:37][C:4]2[C:3]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=4[F:31])[CH2:19][CH2:20]3)=[O:14])=[C:2]([F:1])[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: [O-]C1CCCC1
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(F)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(OC4CCCC4)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1

Procedure:
The compound was prepared in analogy to example 358 from (2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone and sodium cyclopentanolate. MS (m/e): 560.5 (MNH4+, 43%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:24]=[CH:23][C:22]=2[CH3:33])=[O:19])=[N:16][CH:17]=1>CN1C(=O)CCC1>[CH:30]1([NH:29][C:27]([C:25]2[CH:24]=[CH:23][C:22]([CH3:33])=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:17][N:16]=3)=[O:19])[CH:26]=2)=[O:28])[CH2:32][CH2:31]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(Cl)cn1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2ccccn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To 2-pyridinylmethanol (300 μL) was added sodium hydride 60% dispersion in oil (20 mg, 1.39 mmol) under inert atmosphere and the mixture stirred at room temperature for 10 minutes. NMP (600 μL) was then added followed by 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-pyrazinecarboxamide (100 mg, 0.303 mmol) and the resulting mixture stirred for 48 hrs. The solvent was evaporated under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate and DCM. Evaporation of DCM, precipitation with diethyl ether and isohexanes and filtration gave the title compound as a solid (25 mg, 20%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.31 (s, 3H), 2.86 (m, 1H), 5.59 (s, 2H), 7.36 (m, 2H), 7.55 (m, 1H), 7.62 (d, 1H), 7.86 (m, 1H), 8.08 (m, 1H), 8.37 (m, 1H), 8.58 (m, 2H), 8.89 (s, 1H), 9.76 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>O1CCCC1>[CH2:3]([SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)[CH2:4][CH2:5][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: N#Cc1ccc(C2CC[SiH](Cl)CC2)cc1
Solvent: C1CCOC1
Product: CCCCCCC[SiH]1CCC(c2ccc(C#N)cc2)CC1
Yield: 92 %

Procedure:
3.6 g (20 mmol) of 1-bromo-n-heptane was dropped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of tetrahydrofuran (THF) to obtain Grignard reagent. This solution was then added to a mixture of 2.8 g of zinc chloride and 20 ml of THF to obtain the organozinc reagent. This solution was then dropped into a 50 ml THF solution of 4.7 g (20 mmol) of 4-(4-chloro -4-silacyclohexyl) benzonitrile to obtain 4-(4-n-heptyl -4-silacyclohexyl) benzonitrile.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33](OC)[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[C:37](CC)=[O:38].C1(C)C(C)=CC=CC=1>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([O:38][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(C)=O
Reactant: CCCCc1nc2c(OC)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: Cc1ccccc1C
Product: CCCCc1nc2cc(OC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-4-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene=1:2)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].F[C:11]1[C:16]([C:17]#[N:18])=[C:15]([F:19])[C:14]([C:20]#[N:21])=[C:13]([F:22])[C:12]=1[F:23].[F-].[K+]>C(#N)C.CC(C)=O.C1CCCCC1>[F:19][C:15]1[C:14]([C:20]#[N:21])=[C:13]([F:22])[C:12]([F:23])=[C:11]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: Cc1cccc(C)c1O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: Cc1cccc(C)c1Oc1c(F)c(F)c(C#N)c(F)c1C#N
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A solution of 1.2 g (10×10-3 mol) of 2,6-dimethylphenol in 40 ml of acetonitrile was dropwise added at a temperature of -10° C. to a solution of 2.0 g (10×10-3 mol) of tetrafluoroisophthalonitrile and 2.9 g (50×10-3 mol) of potassium fluoride. The mixture was allowed to stand at a temperature of -10° C. to 0° C. for 1 hour while stirring and the undissolved potassium fluoride was separated by filtration. The filtrate was concentrated to dryness in vacuo. The resultant residue was dissolved in a mixed solvent of acetone and cyclohexane and 2.3 g (77% yield) of the desired compound No. 37 was obtained as white crystal.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1Br.O1CCN([C:23](=[O:50])[CH2:24][O:25][CH:26]([CH:48]=[CH2:49])[CH2:27][O:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)CC1>C1COCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:23](=[O:50])[CH2:24][O:25][CH:26]([CH:48]=[CH2:49])[CH2:27][O:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Fc1cccc(Br)c1F
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)N1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1cccc(F)c1F
Reaction time: 1 h

Procedure:
Isopropylmagnesiumchloride-LiCl complex (1.30 M in THF, 155.0 mL, 0.0715 mol) under nitrogen was cooled to 0-5° C., and 2,3-difluorobromobenzene (13.8 g, 0.0715 mol, 1.50 equiv.) was added while T<10° C. After 1 h at 0-5° C., a solution of 1-morpholino-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone 14 (21.8 g, 0.048 mol, 1.0 equiv.) in THF (2.0 vols) was added while T<10° C. The reaction mixture was stirred for 2.5 hours and monitored for consumption of 1-morpholino-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone (target >97%). The reaction mixture was quenched by charging into cold sat. aq. NH4Cl (110 mL) and water (33 mL) while T<20° C. 2-Methoxy-2-methylpropane (218 mL) was added and the layers were separated. The organics were washed with sat. aq. NH4Cl (65 mL) and 18% aq. NaCl (44 mL). The organics were concentrated under vacuum T<25° C. to a light yellow oil of ketone 15 (21.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:11][C:3]4[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=4[F:1])=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc([N+](=O)[O-])cc4F)ncnc32)CC1
Temperature: 160 °C
Yield: 14.7 %

Procedure:
A mixture of 2-fluoro-4-nitro-phenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 32 mg, 0.074 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 25 mg, 0.074 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-[4-(2-fluoro-4-nitro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (5 mg, 15%) as a white solid. Mass spectrum MH+=459.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)[CH2:2][CH3:3].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][O:11][C:9]([C:7]1[N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][CH:20]=2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(Br)cc1
Yield: 88.3 %

Procedure:
A solution of 40.0 g (0.177 mole) of 2-propyl-4,5-bis(methoxycarbonyl)-imidazole and 44.6 g (0.178 mole) of 4-bromobenzyl bromide in 350 mL of DMF was stirred in the presence of 37.5 g (0.271 mole) of K2CO3 overnight at room temperature. The reaction mixture was then poured into 1200 mL of water and extracted with 3×300 mL of ether. The combined ether extracts were washed with 8×1000 mL of water and once with brine, then dried over MgSO4. The solvent was removed under reduced pressure to yield 61.8 g (88%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ0.94 (t, J=7.6 Hz, 3H); 1.73 (m, 2H); 2.63 (t, J=7.9 Hz, 2H); 3.81 (s, 3H); 3.93 (s, 3H); 5.37 (s, 2H); 6.86 (d, J=8.8 Hz, 2H); 7.45 (d, J=8.8 Hz, 2H). MS [DCI (NH3)]: m/z 395/397 (M+H, 1 Br).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9].[CH3:32][S:33]([CH2:36][C:37](O)=[O:38])(=[O:35])=[O:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:10][C:7]1[CH:6]=[C:5]([C:11]2([C:28]([F:30])([F:29])[F:31])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:25][N:26]([C:37](=[O:38])[CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:27]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:4]=[C:3]([Cl:2])[C:8]=1[F:9]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CN=C(c3ccc4c(c3)COC43CNC3)C2)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of 5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 9, 0.43 g, 0.87mmol) in THF (10 mL) was added TEA (1.20 mL, 8.67 mmol). Methane sulfonyl acetic acid (0.239 g, 1.74mmol) and T3P (2.74 mL, 4.34mmol) were added at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). Combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to get brown semi solid (0.46 g, crude). Crude compound was purified by column chromatography using Combiflash (redisep column, 12 g). Desired compound was eluted in 60% ethyl acetate in n-hexane to get off white solid (0.23 g. Impure). About 0.23 g was re-purified by preparative TLC to afford white solid (0.18 g). Compound was triturated with chloroform and n-Hexane and washed with distilled n-Hexane to get white solid (0.13 g, 25.9%). 1H NMR (400 MHz, CDCl3) δ: 3.19 (s, 3H), 3.43 (d, J=17.44 Hz, 1H), 3.78 (d, J=17.44 Hz, 1H), 3.86 (s, 2H), 4.34-4.46 (m, 3H), 4.64-4.69 (m, 2H), 4.87 (d, J=16.96 Hz, 1H), 5.16 (s, 2H), 7.32 (d, J=5.88 Hz, 2H), 7.58 (d, J=7.92 Hz, 1H), 7.77 (s, 1H), 7.83 (d, J=7.96 Hz, 1H), LC-MS (m/z): 576.9 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH:29]C(=O)C)[CH:11]=[C:12]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:13]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH:29][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:11]=[C:12]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(=O)Nc1cc(-c2ccncc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Product: CCS(=O)(=O)Nc1cc(-c2ccncc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Yield: 15.13 %

Procedure:
The compound was prepared from the compound of Example 277 (0.9 g, 2.11 mmol, 1 eq.) using the procedure of Example 2 and ethanesulfonyl chloride (60 mg, 0.46 mmol, 1.2 eq.) to give the product in 15.13% yield (28 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.69-8.68 (d, 1H), 8.58 (s, 1H), 8.54-8.52 (d, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.74-7.71 (t, 1H), 7.67-7.64 (d, 1H), 7.58-7.56 (d, 1H), 7.44-7.43 (t, 1H), 7.36-7.33 (d, 2H), 3.87 (s, 3H), 3.07-3.02 (quartet, 2H), 1.22-1.18 (t, 3H); LC-MS (ESI): Calculated mass: 476.14; Observed mass: 476.9 [M+H]+ (rt: 0.36 min).