Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([NH:12]C(=O)CCCCC)=[N:10][CH:11]=1.C[O-].[Na+]>CO>[CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([NH2:12])=[N:8][CH:7]=1
Reactant: CCCCCC(=O)Nc1ncc(OCCSC)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCCOc1cnc(N)nc1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
N-{5-[2-(Methylthio)ethoxy]pyrimidin-2-yl}hexanamide (6.8 g, 24 mmol) was suspended in methanol (68 mL), the suspension was added with sodium methoxide (1 M solution in methanol, 120 mL, 120 mmol), the substances in the suspension were dissolved on an oil bath at 60° C., and the solution was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was extracted with chloroform and water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was washed with ether-hexane, and taken by filtration to obtain 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (2.93 g, 59%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:16]=O)=[CH:4][CH:3]=1.[N:18]1([C:24]2[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH2:16][N:21]2[CH2:20][CH2:19][N:18]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(C)(C)C3)CC2)cc1

Procedure:
reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde, ethyl 4-piperazin-1-ylbenzoate and sodium triacetoxyborohydride and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate;
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].Cl([O-])(=O)(=O)=O.CS[C+:23]1[S:27][CH:26]=[CH:25][S:24]1>>[S:24]1[CH:25]=[CH:26][S:27][C:23]1=[C:11]([C:12](=[O:14])[CH3:13])[C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:15]
Reactant: CS[c+]1sccs1
Reactant: CC(=O)CC(=O)c1nc2ccccc2[nH]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(=O)C(C(=O)c1nc2ccccc2[nH]1)=C1SC=CS1
Yield: 29.1 %

Procedure:
By using 2.0 g of 1-(2-benzimidazolyl)-1,3-butanedione and 2.5 g of 2-methylthio-1,3-dithiolylium perchlorate, the treatment was conducted in the same manner as in Example 1. The product was purified by silicagel chromatography, whereby 0.87 g (yield: 29%) of 2-(1,3-dithiol-2-ylidene)-1-(2-benzimidazolyl)-1,3-butanedione was obtained as crystals having a decomposition point of 254° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([CH:9]=O)=[CH:7][C:6]2[O:11][CH2:12][O:13][C:5]=2[CH:4]=1.[CH3:14][C:15]([CH3:17])=[O:16]>O>[CH2:12]1[O:13][C:5]2[CH:4]=[CH:3][C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:7][C:6]=2[O:11]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc2c(c1)OCO2

Procedure:
An aqueous solution of 10% sodium hydroxide (3.5 ml) was added dropwise to a solution of piperonal (20.0 g) in acetone (27 ml) and water (14 ml), the temperature of the reaction mixture being maintained below 30° C. during the addition. On completion of the reaction (ca 2 hr) the reaction mixture was poured into water and the precipitate was filtered off and dried to give 1-(3,4-methylenedioxyphenyl)but-1-en-3-one as a crystalline solid, mp 108° C. (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:20](=O)[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH2:23][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:25][C:26]#[N:27].CC(C)([O-])C.[K+]>CC(O)C>[C:26]([C:25]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:21])[NH:23][C:24]=1[C:28]([F:31])([F:30])[F:29])#[N:27]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C#N)C1c1cccc2c(=O)cc(C)oc12

Procedure:
A solution of 310 mg (1.03 mmol) of ethyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate in 30 ml of 2-propanol is mixed with 140.47 mg (1.03 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation analogous to K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 17.38 mg (0.15 mmol) of potassium tert-butoxide and stirred under reflux for 12 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). After concentration of the product fractions, the residue is crystallized from diethyl ether. 50.9 mg (10.8% of theory) of the title compound are obtained as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[N:15]=2)[CH:5]=1.C(C1C=CC(C2N=C(CC3C=C(C=CC=3)C(N)=O)NC=2)=CC=1)#N.[OH-].[Na+]>C1COCC1.CO>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])[NH:12][CH:13]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cc2nc(-c3ccc(C#N)cc3)c[nH]2)c1
Agent: N#Cc1ccc(-c2c[nH]c(Cc3cccc(C(N)=O)c3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2c[nH]c(Cc3cccc(C(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve the mixture of crude 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzoic acid methyl ester and 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzamide (0.13 g) into 5 mL of 1:1 THF/MeOH. To this add 0.5 mL of 15% NaOH. Stir the mixture at room temperature for 2 h. Add 1 mL of 15% NaOH and stir an additional 2 h. Concentrate to dryness. Dissolve the residue into 5 mL of H2O and make acidic by the addition of 5% HCl. Extract with 3×10 mL of CH2Cl2 and dry with MgSO4. Concentrate to give 0.13 g of crude 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzoic acid and 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzamide as a purple residue.
Reaction SMILES: C(N(CC)CC)C.CC1C=CC([C:13]([NH:15][C:16]2[CH:21]=[C:20]([N:22]3[CH:26]=[CH:25][N:24]=[C:23]3[CH3:27])[CH:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=2)=[O:14])=CC=1NC1N=C(C2C=NC=CC=2)C=CN=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:64]([OH:68])([CH3:67])([CH3:66])[CH3:65]>>[CH3:27][C:23]1[N:22]([C:20]2[CH:21]=[C:16]([NH:15][C:13](=[O:14])[O:68][C:64]([CH3:67])([CH3:66])[CH3:65])[CH:17]=[C:18]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Triethylamine (5.23 mL, 37.5 mmol) is added to a stirred suspension of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 91 b; 6.8 g, 25 mmol) in t-butanol (200 mL). Diphenylphosphorylazide (7.6 g, 27.5 mmol) is added to the resulting solution and the mixture is heated 80° C. for 16 h. The solvent is evaporated off under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts are washed with brine (100 mL), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (silica gel, eluent 2% ethanol in ethyl acetate) and recrystallised from ether-hexane to afford the title compound as a colourless crystalline solid, m.p. 203–208° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.C[O:18][C:19]1[CH2:23][CH2:22][C:21](=O)[CH:20]=1>O1CCCC1>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH2:22][CH2:23][C:19](=[O:18])[CH:20]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: COC1=CC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C=C(c2ccc3ccccc3c2)CC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromonapthalene (8.03 g, 38.8 mmol) in anhydrous tetrahydrofuran (200 mL) at −78° C. was treated with a solution of n-butyllithium (1.6 M in hexane; 26.9 mL, 43.0 mmol, 1.1 eq.) such that the reaction temperature remained at −78° C. After 15 min, a solution of 3-methoxy-2-cyclopenten-1-one (5.0 g, 44.6 mmol, 1.1 eq.) in anhydrous tetrahydrofuran (50 mL) was added such that the reaction temperature remained below −78° C. The reaction was warmed to −20° C. over 2 h, quenched with a solution of 1N HCl (100 mL) and concentrated in vacuo to remove tetrahydrofuran. A solution of 1N HCl (100 mL) was added, stirred for 30 min and extracted with ethylacetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 mL), brine (100 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 3:7 ethyl acetate/petrol as the eluting solvent to afford (2.77 g, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.63-2.66 (2H, m, CH2), 3.17-3.20 (2H, m, CH2), 6.70 (1H, t, J 1.6 Hz, CH), 7.53-7.59 (2H, m, ArH), 7.75 (1H, dd, J 1.6, 8.5 Hz, ArH), 7.85-7.93 (3H, m, ArH), 8.12 (1H, s, ArH).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21](OC)=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Li+].C(OCC)(=O)C>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Yield: 97.3 %

Procedure:
A solution of (2S,4R)-1-tert-butyl 2-methyl 4-(tert-butyldimethylsilyloxy)pyrrolidine-1,2-dicarboxylate (5.34 g, 14.8 mmol) in THF (20 mL) was cooled to 0° C. and lithium borohydride (0.485 g, 22.2 mmol) in THF (10 mL) was added dropwise. The mixture was stirred for about 16 hours while the ice-salt bath gradually melted. Ethyl acetate (30 mL) was added followed by the addition of ice. The organic portion was separated and quenched by a dropwise addition of 1N aqueous phosphoric acid. The organic portion was separated and washed with water (120 mL), saturated sodium bicarbonate solution (2×120 mL), and brine (100 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure to yield (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.8 g, 14.4 mmol) as a colorless oil. RP-HPLC (Table 1, Method f) Rt 6.25 min; m/z: (M−H)− 390.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([C:29](=O)[CH3:30])=[CH:20][C:21]([Cl:28])=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:38].[Na+].O1CCCC1>CO.C(#N)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH:29]([NH2:38])[CH3:30])=[CH:20][C:21]([Cl:28])=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCN(C(C)=O)CC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CC(=O)N1CCC(C(=O)N2CCN(c3c(C(C)N)cc(Cl)c4cccnc34)CC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-(8-{4-[(1-acetylpiperidin-4-yl)carbonyl]piperazin-1-yl}-5-chloroquinolin-7-yl)ethanone (0.030 g, 0.068 mmol) and ammonium acetate (0.0522 g, 0.677 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.17 mL, 0.17 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C23H31ClN5O2 (M+H)+: m/z=444.2; Found: 444.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][CH:15]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]CC2C=CC(OC)=CC=2)[N:3]=1.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:1][C:2]1[N:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[C:7]=1[CH2:8][OH:9]
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(-c2ccccc2O)cc(C2=CCCNC2)c1CO
Yield: 87 %

Procedure:
tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1(2H)-carboxylate (25.0 mg, 0.05 mmol) was treated with 2N HCl in dioxane (4.0 mL) overnight at room temperature. The resulting solid was collected by filtration, washed with ether and dried under reduced pressure to give 2-[6′-amino-5′-(hydroxymethyl)-1,2,5,6-tetrahydro-3,4′-bipyridin-2′-yl]phenol hydrochloride. (14 mg, yield 87%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:17][CH:18]=C)[CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8].[O:21]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:17][CH:18]=[O:21])[CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=[O+][O-]
Reactant: C=CCC(C(=O)OC)C(CC(=O)O)c1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CC=O)C(CC(=O)O)c1cccc(F)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2-allyl-3-(3-fluoro-phenyl)-pentanedioic acid 1-methyl ester (2-5) (1.01 g, 3.28 mmol) and Sudan Red B (0.01 g) in 100 mL CH2Cl2 was treated with ozone at -78° C. for 20 min. Then excess ozone was purged with argon, followed with the addition of PPh3 (2.00 g, 7.63 mmol). The mixture was stirred for 30 min and concentrated under diminished pressure. The residue was purified by flash silica chromatography (EtOAc/Hexane, 1:3) to provide the desired product as two separated pairs of enantiomers (2-6A and 2-6B).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1(C)C(C)=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4]
Reactant: Nc1ccccn1
Reactant: CCc1ccc2c(c1)OCCC(C(=O)OC)C2=O
Solvent: Cc1ccccc1C
Product: CCc1ccc2c(c1)OCCC(C(=O)Nc1ccccn1)C2=O
Temperature: 25 °C
Yield: 5 %

Procedure:
8-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester (0.6 mmol) and 2-aminopyridin (0.6 mmol) were dissolved in 2.5 ml xylene. Reaction was performed by microwave irradiation for one hour at 150° C. The solution obtained from this reaction was cooled to room temperature and extracted by 2 mol/l hydrochloric acid and ethyl acetate. The ethyl acetate extract was dried over sodiumsulfate and the solvent removed in vacuo. After evaporation of the solvent in vacuo 8-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid pyridine-2-ylamide was obtained as a white powder in a yield of 5%. LC-MS: 1.8 min, 311.2 (MH+), 1H-NMR: (DMSO-d6, 500 MHz): □ [ppm]: 10.543 (s, 1H), 8.296 (s, 1H), 8.152 (d, 1H, J=8.1 Hz), 7.798 (t, 1H, J=7.2 Hz), 7.605 (m, 1H, J=8.1 Hz), 7.102 (t, 1H, J=6.3 Hz), 7.032 (m, 1H, J=8.1 Hz), 6.983 (s, 1H), 4.594 (m, 1H, J=3.0 Hz), 4.364 (t, 1H, J=4.8 Hz), 3.942 (m, 1H, J=5.2 Hz), 2.640 (q, 2H, J=7.7 Hz), 2.512 (t, 2H, J=1.7 Hz), 1.193 (t, 3H, J=7.5 Hz)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][CH:51]1[CH2:56][NH:55][CH2:54][CH:53]([CH3:57])[NH:52]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CS(C)=O.[Cl-].[Cl-].[Zn+2]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][CH:53]([CH3:57])[NH:52][CH:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Reactant: CC1CNCC(C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CC(C)NC(C)C4)c3)c2)c1
Reaction time: 12 h
Yield: 51.7 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (50.0 mg. 0.076 mmol) was diluted in DMSO (1.0 mL) and dispensed into a 1 dram vial containing 2,6-dimethylpiperazine (0.76 mmol), ZnCl2 (0.032 mmol, 4.2 mg), NaB(OAc)3H (0.76 mmol, 180 mg), with fitted magnetic stir bar, for 12 h. Purification was completed via a Gilson HPLC and desired product collected. The product was dissolved in dichloromethane (1 mL) and washed though 2 g of SPE-Amine in a column (EtOAc:MeOH=4:1, 5 mL) to afford 29.9 mg of the title compound (51.6%). LC-MS m/z 762 (M+H)+, 1.38 min (ret time).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:45])[NH:12][C@@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]([O:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([N:33]5[CH2:38][CH2:37][CH:36]([CH2:39]OS(C)(=O)=O)[CH2:35][CH2:34]5)=[N:31][N:32]=4)[CH:29]=3)[CH2:15][CH2:14]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][NH:47][CH3:48]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:12][C@@H:13]2[C:22]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:16]([O:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([N:33]5[CH2:34][CH2:35][CH:36]([CH2:39][N:47]([CH3:48])[CH3:46])[CH2:37][CH2:38]5)=[N:31][N:32]=4)[CH:29]=3)[CH2:15][CH2:14]2)=[O:45])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(COS(C)(=O)=O)CC5)n4c3)c3ccccc32)no1
Product: CN(C)CC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)on5)c5ccccc54)cn23)CC1

Procedure:
Intermediate 15c was reacted with dimethylamine in an analogous manner to that described in Example 14 step i to give the title compound. LCMS (Method 5): Rt: 3.30 min, m/z 587.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.33-1.47 (2H, m), 1.64-1.75 (1H, m), 1.75-1.84 (2H, m), 1.85-2.11 (4H, m), 2.13-2.20 (8H, m), 2.85-2.99 (2H, m), 3.35-3.47 (2H, m, obscured by water), 4.86-4.94 (1H, m), 5.56 (1H, t, J=4.5 Hz), 6.41 (1H, s), 7.01 (1H, d, J=8.4 Hz), 7.20 (1H, dd, J=9.8, 2.2 Hz), 7.27-7.34 (1H, m), 7.35-7.43 (3H, m), 7.62 (1H, d, J=10.2 Hz), 7.65 (1H, d, J=1.7 Hz), 8.20 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH:36]([CH3:38])[CH3:37])[N:28]=2)=[O:26])[CH2:19][CH2:18]1.[ClH:39]>C(O)C.C(OCC)(=O)C>[ClH:39].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH:36]([CH3:38])[CH3:37])[N:28]=3)=[O:26])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: CC(C)n1nc(C(=O)NCC2CCNCC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)n1nc(C(=O)NCC2CCN(CCc3ccc(O)cc3)CC2)c2ccccc21

Procedure:
2-(4-hydroxyphenyl)ethyl bromide (prepared as described in Acta Chem. Scand. 21 (1) 53-62, 1967) (3.4 g, 0.017 moles) and anhydrous potassium carbonate (4.6 g, 0.033 moles) in absolute ethanol (100 ml) were added to a solution of N-(4-piperidinylmethyl)-1-isopropyl-1H-3 indazolecarboxamide (4.2 g, 0.014 moles), prepared as described in EP-A-0 975 623 in absolute ethanol (80 ml). The suspension thus obtained was stirred continuously under reflux for 16 hours. The suspension was filtered and the filtrate evaporated under reduced pressure. The residue thus obtained was then transformed into the corresponding hydrochloride salt by dissolution in ethyl acetate, addition of ethanolic hydrogen chloride and recrystallisation from absolute ethanol to give the desired product (2.2 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[CH2:13]>C(OCC)C>[C:2]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: C=Cc1cccc(Br)c1
Solvent: CCOCC
Product: C=Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
The liquid temperature was increased until refluxing took place and then a solution of 7.37 g (0.07 mole) of bromobenzene in diethyl ether (70 ml) was gradually added dropwise taking 30 minutes. After completion of the dropwise addition, it was kept as such for 1 hour under reflux. The reaction solution was cooled to room temperature and it was added at room temperture to a solution of 6.51 ml (0.05 mole) of m-bromostyrene and 0.32 g (0.6 m mole) of a nickel chloride-(1,3-diphenyl phosphino propane) complex in diethyl ether (100 ml). After completion of the dropwise addition, refluxing was continued for 4 hours. The reaction solution was poured into 500 ml of ice water and the pH was adjusted to be weakly acidic. Extraction with hexane was undertaken and, through washing, drying, removal of the solvent by distillation and purification by the silica gel column chromatography, 7.32 g of m-phenyl styrene (yield 80%) were obtained.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3c(Br)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.9 %

Procedure:
1.00 g (5.02 mmol) of 6-bromo-9H-purine (purchased from Aldrich; cat. no. 104981) was suspended in 10 mL of DMF and potassium carbonate (2.08 g, 15.05 mmol) was added. The mixture was stirred at room temperature for 20 minutes and then 1-(chloromethyl)-4-methoxybenzene (1.40 mL, 10.06 mmol) were added. The reaction mixture was stirred at 45° C. overnight. Then the mixture was evaporated to dryness and the residue was partitioned between water and dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0% to 50% hexane/AcOEt) to yield 447 mg (28%) of the title compound.