Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH3:12])[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:4](=[O:5])[C:2]2=[O:3].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-].B(F)(F)F>CCOCC>[C:16]([CH:15]1[C:4](=[O:5])[CH:6]2[C:9]([CH3:10])([CH3:11])[C:1]([CH3:12])([CH2:8][CH2:7]2)[C:2]1=[O:3])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC12CCC(C(=O)C1=O)C2(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1C(=O)C2CCC(C)(C1=O)C2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (±) camphorquinone [(1,7,7) -trimethylbicyclo[3,2,1]-heptane-2,3-dione] (15.0 g, 90.24 mmol) and ethyl diazoacetate (11.8 g, 103.7 mmol) in 120 ml of ether is added, at 0°, BF3.ether (4 ml). The mixture is stirred at RT for 24 hr. The reaction mixture is extracted with 5% K2CO3 /H2O until no polar ethyl carboxyl dione remains. The combined aqueous extracts are acidified with conc. HCl and extracted with ether. The combined organic extracts are dried and evaporated to dryness to give crystalline 3-carboethoxy-1,8,8-trimethylbicyclo[3,2,1 ]octane-2,4-dione.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.C([N:13]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:14]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[C:17]([C:29]([O:31]CC)=[O:30])=[CH:18][N:19]2[CH:26]1[CH2:28][CH2:27]1)(=O)C>O>[CH2:35]([NH:13][C:14]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[C:17]([C:29]([OH:31])=[O:30])=[CH:18][N:19]2[CH:26]1[CH2:27][CH2:28]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(N(Cc3ccccc3)C(C)=O)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Yield: 81.1 %

Procedure:
Twenty milliliters of a mixture of conc. sulfuric acid, glacial acetic acid and water (1:8:6) was added to 4.4 g of ethyl 5-(N-acetylbenzylamino)-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, and the mixture was heated under reflux for 6 hours. After cooling, water was added to the reaction mixture, and the crystals were collected by filtration and successively washed with water and ethanol. The crystals were recrystallized from chloroform/ethanol to give 3.0 g of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 214°-216° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C([O:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]Br)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[Br-]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][OH:20])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: CC(=O)OCC(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OCC(C)(C)CO)cc(C(C)=O)cc1C(C)(C)C
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 42.2 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 2.00 g) and 3-bromo-2,2-dimethylpropyl acetate (2.54 g) were dissolved in DMF (15 ml), and cesium carbonate (3.69 g) was added. After stirring at 150° C. and max. 15 bar in a microwave for 2.5 h, a further 0.5 eq. of the bromide was added and the mixture was placed into the microwave at 150° C. for a further 2 h. Then the mixture was concentrated by rotary evaporation and the residue was partitioned between DCM and water. The DCM phase was removed, dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 0-50% within 60 min). 1.17 g of the title compound were obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([OH:9])[C:7]#[CH:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[CH2:6]([O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1)[C:7]#[CH:8]
Reactant: C1=COCCC1
Reactant: C#CCO
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of phosphoryl chloride (0.5 ml in 10 ml of dichloromethane [DCM])) was added with care to a solution of prop-2-yn-1-ol (7.00 g, 125 mmol) and dihydropyran (10.50 g, 125 mmol) in DCM (80 ml). The reaction mixture was stirred at room temperature for 16 h, washed with sodium hydrogen carbonate solution (3 times), dried (MgSO4) and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.43] to yield a colorless oil.
Reaction SMILES: [C:1]1([SH+]C2C=CC=CC=2)C=CC=C[CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]1[O:20][CH:1]1[CH3:2]
Reactant: c1ccc([SH+]c2ccccc2)cc1
Reactant: COc1cccc(C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(C2OC2C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) in tetrahydrofuran (one liter) is slowly added 3-methoxybenzaldehyde (1.0 mole). The reaction mixture is stirred at -78° C. for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether phase separated. The ether phase is washed with water, dried (MgSO4) and evaporated. Fractional distillation of the residue gives the title product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Product: O=Cc1ccc(Oc2ccc(Br)cc2C(F)(F)F)cc1

Procedure:
Prepared analogously to Example 78a) starting from 4-fluorobenzaldehyde and 4-bromo-2-(trifluoromethyl)-benzenol.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[OH:10].Cl.O>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C@H:11]2[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][CH2:16]2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=C1CCC(c2ccc(O)c(F)c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc([C@H]2CC[C@H](O)CC2)cc1F
Temperature: 0 °C

Procedure:
0.76 g (20 mmols) NaBH4 was suspended in 30 ml THF under nitrogen and cooled to 0° C. A solution of 4.16 g 4-(3-fluoro-4-hydroxyphenyl)cyclohexanone in 50 ml THF was added dropwise at the same temperature over a period of 15 minutes, and the resulting mixture was stirred at 0° C. until no more of the starting material was present. 10 ml 25% HCl was then added dropwise at a temperature of between 0-10° C., and stirred for a further 30 minutes. The reaction mixture was then poured into 100 ml of water and extracted three times with 50 ml of diethyl ether. The combined organic phases were washed twice with 50 ml of water, dried over magnesium sulphate and filtered. Removal of the solvent and recrystallisation of the residue from isopropanol gave 2-fluoro-4-(trans-4-hydroxycyclohexyl)phenol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: COc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-bromo-3-methoxyphenol (2.0 g, 0.0098 mol), phenylboronic acid (3.0 g, 0.025 mol), TEA (8.2 mL, 0.059 mol), cupric acetate (2.9 g, 0.016 mol) and DCM (100 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.81 (s, 3H), 6.45 (dd, J=8.72, 2.65 Hz, 1H), 6.61 (d, J=2.53 Hz, 1H), 7.01 (d, J=8.34 Hz, 2H), 7.12 (t, J=7.33 Hz, 1H), 7.34 (t, J=7.96 Hz, 2H), 7.42 (d, J=8.59 Hz, 1H).
Reaction SMILES: [N+]([C:4]1C=CC=CC=1O)([O-])=O.[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:21][CH3:4]
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The nitrophenol starting material C2 (1.3 g; 7.49 mmol) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 mmol), followed by MeI (1.4 mL; 22.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 mL), washed with water (150 mL), brine (4×100 mL), and then dried over (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole C3 (98%; 1.38 g) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=1)[C:28](=[O:29])[C:27]1[CH:26]=[C:25]([O:24][CH3:23])[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)CCCCCCCNc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1cc(OC)c(OC)c(OC)c1)c1cccc(C(F)(F)F)c1

Procedure:
As described in example 3(b), the reaction is carried out with 6.3 g (20 mmol) of 8-[3-(trifluoromethyl)-phenylamino]-caprylic acid methyl ester, 6.9 g (30 mmol) of 3.4.5-trimethoxybenzoic acid chloride, 2.5 g (25 mmol) of triethylamine and 150 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:19][C:20]2[C:25]3[C:26]4[CH2:34][CH2:33][C:32]5[C:28](=[CH:29][N:30]([CH2:35][CH2:36]O)[N:31]=5)[C:27]=4[S:38][C:24]=3[N:23]=[CH:22][N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.S(Br)([Br:41])=O>O>[Br:41][CH2:36][CH2:35][N:30]1[CH:29]=[C:28]2[C:32]([CH2:33][CH2:34][C:26]3[C:25]4=[C:20]([NH:19][C:7]5[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=6)=[C:5]([Cl:4])[CH:6]=5)[N:21]=[CH:22][N:23]=[C:24]4[S:38][C:27]=32)=[N:31]1
Reactant: O=S(Br)Br
Reactant: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: O
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)ccc1OCc1ccccn1
Yield: 93.5 %

Procedure:
To 60 mL CH2Cl2 cooled to 0° C. was added 2-(6-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl)ethanol (1.60 g, 3.2 mmol), followed by thionyl bromide (2.31 g, 11.1 mmol). The contents were then stirred with warming to it over a 24 h period, after which time water (5 mL) was added to quench the reaction mixture. The solvent was removed under reduced pressure. The crude residue was diluted with aq. 2M Na2CO3 and vigorously stirred for 1 h. The precipitate was collected by filtration and triturated with methanol (30 mL) to afford the desired product (1.70 g, 94%) as a light-brown solid. 1H-NMR (DMSO-d6) δ 8.59 (d, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.82 (dd, 1H), 7.78 (s, 1H), 7.47-7.60 (m, 2H), 7.30 (dd, 1H), 7.19 (d, 1H), 5.27 (s, 2H), 4.42 (t, 2H), 3.82 (t, 2H), 3.38 (t, 2H), 2.90 (t, 2H); LCMS RT=2.89 min; [M+H]+=567.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:14]=3)[CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:11]3[CH2:12][N:8]([C:4]4[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:36])[CH:7]=[CH:6][CH:5]=4)[C:9](=[O:27])[CH2:10]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OC1CCCC1
Solvent: ClCCl
Product: COc1ccc(C2CC(=O)N(c3cccc(NC(=O)Nc4ccccc4)c3)C2)cc1OC1CCCC1
Reaction time: 20 h

Procedure:
A solution of 1-(3-aminophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (8 mg, 0.022 mmol) in CH2Cl2 (0.5 mL) was created. Phenylisocyanate (0.023 mmol) was added, and the reaction mixture was stirred for 20 h. Concentration under reduced pressure and purification by column chromatography on silica gel (EtOAc:Hexane=1:2) gave the desired product.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:5]1([CH2:4][O:3][C:1]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([O:26][N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])=[O:25])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:14])=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 0 °C

Procedure:
A 7.17 g portion of carbobenzyloxy glycyl-L-phenylalanine and 2.30 g of N-hydroxysuccinimide were slurried in 100 ml of acetonitrile, cooled in an ice bath, with the addition of 5 ml of dimethylformamide, to obtain solution. A precooled solution of 4.12 g of dicyclohexylcarbodiimide in 50 ml of acetonitrile was added dropwise. The mixture was stirred in the ice bath for 2 hours, then refrigerated overnight, filtered and the filtrate concentrated in vacuo. The residue was taken up in 125 ml of ethyl acetate, washed with precooled 5% aqueous sodium bicarbonate, then twice with water, dried and concentrated in vacuo. The residue was dissolved in 125 ml of 2-propanol and refrigerated overnight. The resulting gum was taken up in tetrahydrofuran and concentrated in vacuo, giving 6.5 g of 1-[[N-[N-[(phenylmethoxy)carbonyl]glycyl]-L-phenylalanyl]oxy]-2,5-pyrrolidinedione.
Reaction SMILES: [N:1]1([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[N:1]1([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(NN1CCc2ccccc21)c1cnc(-c2cccc(F)c2)nc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(Nn1ccc2ccccc21)c1cnc(-c2cccc(F)c2)nc1
Yield: 54 %

Procedure:
A suspended solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (2,3-dihydro-indol-1-yl)-amide (0.39 mmol) and MnO2 (1.95 mmol) in DCM (10 mL) is stirred at rt for 40 min. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-40% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic indol-1-yl-amide (70 mg, 54%) as a solid. MS: 333 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.60 (s, H), 7.10 (d, H), 7.14-7.46 (m, 4H), 7.50 (br, H), 7.64 (d, H), 8.37 (d, 2H), 8.60-9.40 (br, 3H). IC50=5 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(OC)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(4-methoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13](B(O)O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:38][C:36]1[N:35]=[CH:34][N:33]=[C:32]2[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=[C:29]([C:13]3[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]4[C:11]([CH:12]=3)=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=4)[C:37]=12
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(OCc3ccccc3)ccc21
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cc3cc(OCc4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 5-Benzyloxy-1-BOC-indole-2-boronic acid (303 mg, 0.83 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [EtOAc-hexanes, 5:95] to yield BA24. ESI-MS (M+H)+ m/z calcd 499.2, found 499.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][N:22]1[CH:26]=[N:25][C:24]([NH2:27])=[N:23]1>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:27][C:24]2[N:25]=[CH:26][N:22]([CH2:21][C:20]3[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:32])([F:16])[F:31])[CH:19]=3)[N:23]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Nc1ncn(Cc2cccc(C(F)(F)F)c2)n1
Product: COc1cc(Nc2ncn(Cc3cccc(C(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(3-trifluoromethyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=63%). MS ISP (m/e): 429.3 (100) [(M+H)+].
Reaction SMILES: C[O:2][C:3]1[C:13]([CH:14]=[O:15])=[CH:12][C:6]2[C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[C:13]([CH:14]=[O:15])=[CH:12][C:6]2[C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1C=O)C(C)(C)CO2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)COc2cc(O)c(C=O)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
To a solution of 10.4 g (50.4 mmol) of 2,3-dihydro-6-methoxy-3,3-dimethyl-5-benzofurancarboxaldehyde in 250 ml of methylene chloride and cooled to -78° C. was added dropwise 51.0 ml (51.0 mmol, 1M in methylene chloride) of boron tribromide. The reaction mixture was warmed to ambient temperature and stirred for 1 day. The reaction mixture was poured into 500 ml of water. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel (250 g) using a gradient from 2:1 (v/v) hexane:methylene chloride to methylene chloride as eluent. There was obtained 5.77 g (30.0 mmol, 59%) of 2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde as a white solid mp 100°-102° C.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH3:12])[CH:11]=[CH:10][C:9]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:8][CH:7]=1
Reactant: Cc1ccccc1
Reactant: O=S(=O)(O)O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 115 °C
Reaction time: 5 h

Procedure:
560 g of 98% sulfuric acid was dropped into 600 g of toluene with stirring. Then, the temperature was raised at 110 to 120° C. while stirring, reacting for 5 hours. After the reaction, the temperature was decreased while distillation water was added, and upon the temperature reached at about 20° C., a small amount of a crystalline of p-toluenesulfonic acid (4-methylbenzenesulfonic acid) in the system, which was provided in advance, was put therein, generating crystalline deposition of p-toluenesulfonic acid. The crystalline as obtained was collected by filtering, into which distillation water was added. Then, the temperature of the liquid was raised into 60° C. again to dissolve. Then, the temperature was gradually decreased, and upon the temperature reached at about 20° C., a small amount of a crystalline of p-toluenesulfonic acid was added to deposit crystalline. The crystalline was collected by filtering to obtain toluenesulfonic acid in which the para compound was included at 99 mole % in the total of the toluenesulfonic acid. Note that the measurement of the concentration of the para compound was carried out by using HPLC (High Performance Liquid Chromatography) manufactured by Shimadzu Corporation. The same measure was used hereinafter.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[Br:16]Br>C(O)(=O)C.O>[ClH:1].[Br:16][C:9]1[CH:8]=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1[CH3:3]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N2CCNCC2)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 966 mg (4.0 mmol) of 1-(3-Methylphenyl)piperazine dihydrochloride in 9 mL of acetic acid and 1 mL of water at 0° C. was added 640 mg (4.0 mmol) of bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.37 (d, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 3.37 (m, 8H), 2.17 (s, 3H) ppm.