Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:29][S:26]([CH:23]2[CH2:25][CH2:24]2)(=[O:28])=[O:27])=[O:21])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1CC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with cyclopropanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C15H18FN2O6S: 373.1; found: 373.0. 1H NMR (500 MHz, CDCl3) δ: 1.13 (m, 2), 1.44 (m, 2), 2.95 (m, 1), 3.68 (s, 3), 4.79 (s, 2), 6.55 (s, 1), 7.02 (m, 2), 7.29 (m, 2), 8.95 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 6.45, 31.41, 48.31, 63.22, 92.45, 115.71, 115.88, 130.25, 130.32, 131.09, 159.44, 159.74, 161.70, 163.67, 170.98.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.CC(C)=O.O>[N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[O:14][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])([O-:3])=[O:2]
Reactant: BrCCCCBr
Reactant: CC(=O)Nc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(OCCCCBr)c([N+](=O)[O-])c1

Procedure:
39.2 g of 2-nitro-4-acetamino-phenol are dissolved in a mixture of 200 ml of dimethylsulfoxide and 400 ml of acetone and, after adding 23.8 g of 1,4-dibromobutane, 13.8 g of potassium carbonate and 0.1 g of potassium iodide, the solution is boiled under reflux cooling for 10 hours, whilst stirring, and the reaction mixture is discharged onto 5 times the volume of water. The resulting yellow precipitate is filtered off, washed first with 1% strength sodium hydroxide solution and then with water and dried in vacuo at about 60° C. A small amount of 4-(2'-nitro-4'-acetamino-phenoxy)-1-bromobutane, formed by condensation on one side, is removed by boiling up with ethyl acetate. A yellow crystalline powder remains which consists of 1,4-bis-(2-nitro-4-acetamino-phenoxy)-butane and melts at 224°-226° C., with partial decomposition. In order to split off the acetyl groups, 10 g of the resulting diacetyl compound are suspended in 200 ml of ethanol and the suspension is boiled under reflux for 5 hours, whilst passing a stream of hydrogen chloride through. The resulting white suspension is poured onto 2,000 ml of water, the mixture is heated to the boil, a slight residue is filtered off and the filtrate is rendered alkaline with sodium hydroxide solution, whilst still hot. The orange-colored precipitate is filtered off and dried in vacuo at about 70° C. An orange-colored powder is obtained which melts at 192°-194° C., with partial decomposition. Analytically pure 1,4-bis-(2-nitro-4-amino-phenoxy)-butane is obtained in the form of a yellow-red crystalline powder on dissolving and reprecipitating from dimethylformamide/methanol. It melts at 194°-196° C., with partial decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]O)[CH:7]=1.N1C=CC=CC=1.[Br:16]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][Br:16])[CH:7]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cncc(Br)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: BrCc1cncc(Br)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-hydroxymethylpyridine (16.1 mmol) [prepared according to the procedure of Ashimori et al, Chem. Pharm. Bull. 1990, 38(9), 2446] and pyridine (32.3 mmol) were dissolved in acetonitrile (32 mL) and cooled to 0° C. Dibromotriphenylphosphorane (20.9 mmol) added, and left reaction mixture to warm to room temperature in stoppered flask for 4 hours. The crude reaction mixture was purified by column chromatography directly on silica gel with diethyl ether:cyclohexane=1:1. 3-Bromo-5-bromomethylpyridine was isolated as a pale brown solid. 3-Bromo-5-bromomethylpyridine (7.7 mmol) and di-tert-butyliminodicarboxylate (10 mmol) were dissolved in tetrahydrofaran (20 mL), and sodium hydride (60% in mineral oil, 10 mmol) added at room temperature under argon. The reaction mixture was stirred at room temperature for 16 hours, quenched with saturated aqueous ammonium chloride, extracted into ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to dryness. The crude residue was purified by column chromatography on silica gel with cyclohexane:diethyl ether=2:1. 3-bromo-5-(N,N-bis-tert-butoxycarbonyl)aminomethylpyridine was isolated as a pale yellow solid. MS (EI) 387 and 389 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[C:12]([O-])([O-])=O.[K+].[K+].[OH-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(O)c(Cl)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(3-chloro-4-hydroxylphenyl)ethanone (1.7 g, 10 mmol) in DMF was added K2CO3 (1.52 g, 11 mmol), 2 N NaOH solution (5 ml), and Mel (0.68 ml). The reaction mixture was stirred at room temperature for 2 hours. Another 1.24 ml of Mel was added, and the reaction mixture was stirred for an additional 30 minutes. Water (50 ml) was added, and the product was extracted with 200 ml of EtOAc and 100 ml of benzene. The organic layer was washed with brine (50 ml), and dried with MgSO4, and the solvent was removed in vacuo to give the title compound in quantitative yield.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:32]([OH:33])=[C:31]([O:34][CH3:35])[C:30]([O:36][CH3:37])=[CH:29][C:28]=1C>O=O.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:32](=[O:33])[C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[C:3](=[O:4])[C:28]=1[CH3:29]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCO)c(O)c1OC
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCO)=C(C)C1=O

Procedure:
To a dimethylformamide solution (50 ml) of 6-(20-hydroxyeicosanyl)-2,3-dimethoxy-5-methylphenol (4.0 g) is added bis(salicylidene)ethylenediiminocobalt(II) (40 mg), and the mixture is stirred in oxygen streams at atmospheric temperature and pressure for 72 hours. The product is isolated as in Example 7 and recrystallized from ether. The above procedure yields 6-(20-hydroxyeicosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (3.28 g) as yellow needles melting at 85° C.
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]2[O:19][N:20]=[CH:21][C:7]1=2)[CH:2]=[CH2:3].Cl.[OH-].[NH4+]>C(OCC)(=O)C>[CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][CH2:9][C:8]2[O:19][N:20]=[CH:21][C:7]1=2)[CH:2]=[CH2:3]
Reactant: C=CCONC1CN(C(=O)OC(C)(C)C)Cc2oncc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=CCONC1CNCc2oncc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1.24 g of the compound obtained in Stage C (4.21 mmoles) and 8.7 cm3 of ethyl acetate are placed in a 50 cm3 three-necked flask equipped with a magnetic stirrer and a temperature detector. The solution is cooled down to 0° C. then 8.7 cm3 of a saturated solution of gaseous HCl in ethyl acetate is added dropwise. Agitation is maintained for 5 minutes at 0° C. then the temperature of the solution is taken to 20° C. After agitating for two hours at 20° C., the solvent is evaporated off under reduced pressure in order to obtain a white powder to which an ethyl acetate/water mixture is added and a 20% solution of ammonium hydroxide is added. After dissolution and agitation for 10 minutes, decanting is carried out, followed by extracting again with 3× ethyl acetate. The organic phase is dried over MgSO4, filtered and rinsed with ethyl acetate. Finally, the solvent is evaporated off under reduced pressure in order to obtain 0.740 g of 4,5,6,7-tetrahydro-4-[(2-propenyloxy)amino]-isoxazolo[5,4-c]pyridine, of molecular formula C9H13N3O2 is obtained (M=195.22 g).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2F)C1
Yield: 72.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-fluorophenylboronic acid (128 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (150 mg, 72.1%) as an oil.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[CH:11]([C:13]12[CH2:20][CH2:19][C:16]([C:21]([O:23][CH3:24])=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOC(C)=O>[CH:11]([C:13]12[CH2:20][CH2:19][C:16]([C:21]([O:23][CH3:24])=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=[CH2:1]
Reactant: COC(=O)C12CCC(C=O)(CC1)CC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC12CCC(C(=O)OC)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of methyltriphenylphosphonium bromide (9.1 g, 12.8 mmol) in THF (50 ml) at 0° C. was added potassium hexamethyldisilazide (0.5M in toluene, 48.6 ml), dropwise over 5 min. The resulting mixture was allowed to warm up to room temperature over 1 h, then cooled again to 0° C. and treated with methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (4-1) (Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (2.5 g, 12.8 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with EtOAc (350 ml). The organic phase was washed with aqueous HCl (1 N), saturated aqueous sodium bicarbonate, and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting solid was purified by flash silica gel chromatography, eluting with a gradient 0-4% EtOAc/hexanes. The resulting methyl 4-vinylbicyclo[2.2.2]octane-1-carboxylate (4-2) was isolated as a clear, colorless oil.
Reaction SMILES: C1OC2C(=CSC=2)[O:3]C1CO.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(C1C=CC(C2C=CC(OCC(O)=O)=CC=2)=CC=1)#N>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OCC1COc2cscc2O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: N#Cc1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.73 g of a mixture of 80% of EDT-methanol and 20% of hydroxy-PDT (corresponding to 8.08 mmol of EDT-methanol), 1.64 g of N,N′-dicyclohexyl-carbodiimide and 0.13 g of 4-(dimethylamino)pyridine are dissolved in 100 ml of CH2Cl2 and cooled to about 0° C. in an ice bath. 2.00 g of [(4′-cyano-1,1′-biphenyl-4-yl)oxy]acetic acid are added thereto a little at a time over a period of 1 hour while stirring and cooling in ice. The reaction is then continued at 23° C. for 42.5 hours. The N,N′-dicyclohexylurea formed is subsequently filtered off. The filtrate is washed in succession with 2×200 ml of 1 M HCl, 2×200 ml of saturated NaHCO3 solution and 2×200 ml of saturated NaCl solution. The organic phase is dried over MgSO4 and, after the magnesium sulphate has been filtered off, freed of solvent on a rotary evaporator. This gives 3.71 g of crude product which is purified by column chromatography using n-hexane/ethyl acetate 3:2. 0.39 g of the pure ester of EDT-methanol (I-a2) is obtained as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:61]1([CH2:66][C:67](O)=[O:68])[CH:65]=[CH:64][CH:63]=[N:62]1>CC(N(C)C)=O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:67](=[O:68])[CH2:66][N:61]2[CH:65]=[CH:64][CH:63]=[N:62]2)=[CH:7][C:6]=1[C:8]1[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: O=C(O)Cn1cccn1
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(N)ccc1Oc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Cn2cccn2)ccc1Oc1ccc(F)cc1F
Yield: 39 %

Procedure:
A solution of Example 1G and DIPEA (0.15 M and 0.43 M in DMA, respectively, 257 μL, 0.04 mmol Example 1G (1.0 equivalent) and 0.12 mmol DIPEA (3.0 equivalents)), HATU (0.2 M in DMA, 257 μL, 0.052 mmol, 1.3 equivalents), and 2-(1H-pyrazol-1-yl)acetic acid (0.40 M in DMA, 121 μL, 0.048 mmol, 1.2 equivalents) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0 2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6.5 min linear gradient 5-60% A, 6.5-7.0 min linear gradient 60-100% A, 7.0-8.9 min 100% A, 8.9-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to yield the title compound (7.33 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.76 (d, J=2.3 Hz, 1H), 7.60-7.45 (m, 4H), 7.37-7.28 (m, 1H), 7.07-6.87 (m, 3H), 6.31 (t, J=2.1 Hz, 1H), 5.82 (s, 1H), 5.00 (s, 2H), 3.93 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI) m/z 481.1 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:13]3[CH:12]=[CH:11][C:10]([CH:7]([C:8]#[N:9])[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:15][CH:14]=3)[C:34]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(C(C#N)c3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(C#N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 2-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (0.120 g, 0.000376 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.083 g, 0.000188 mol), tetrakis-(triphenylphosphine)palladium (0.013 g, 0.000011 mol) and sodium carbonate monohydrate (0.058 g, 0.00047 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl cyanide (0.025 g, 0.0000494 mol) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[O:20][C:19]([CH:21]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(-c2cccc(Cl)c2)o1
Reactant: Nc1ccccc1O
Product: Oc1ccccc1N=Cc1ccc(-c2cccc(Cl)c2)o1

Procedure:
Using 2-aminophenol and 5-(3-chlorophenyl)furan-2-carbaldehyde, 2.94 g of 2-{[5-(3-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1.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>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1OCCNC(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CC(=O)Nc2cccc(-c3ccccc3)c2)ccc1OCCNC(=O)OC(C)(C)C
Yield: 77.3 %

Procedure:
Intermediate 4 (500 mg) is dissolved in tetrahydrofuran (10 ml), and thereto are added tetrakis(triphenylphosphine)palladium (0) (110 mg), phenylboronic acid (230 mg), cesium carbonate (1.2 g) and water (2 ml), and the mixture is heated under reflux for 18 hours under argon atmosphere. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-(3-phenylphenyl)phenylacetamide (350 mg). This product is treated with 10% hydrogen chloride-methanol to give the desired compound (210 mg).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9]I>>[CH3:9][N:4]1[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1NC(=O)NC1=O
Reactant: CI
Product: CC1NC(=O)N(C)C1=O

Procedure:
Using 5-methylimidazolidine-2,4-dione (1.00 g) and methyl iodide (0.57 mL) and by the reaction and treatment in the same manner as in Preparation Example 214, the title compound (1.66 g, containing DMF) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)Cl.[NH3:6]>C1(C)C=CC=CC=1>[CH3:1][Si:2]1([CH3:5])[NH:6][Si:2]([CH3:5])([CH3:1])[NH:6][Si:2]([CH3:5])([CH3:1])[NH:6]1
Reactant: C[Si](C)(Cl)Cl
Reactant: N
Solvent: Cc1ccccc1
Product: C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N1
Yield: 42.1 %

Procedure:
A 500-ml, four-necked flask equipped with a stirrer, dry ice/acetone condenser, thermometer, and gas inlet tube was charged with 64.5 grams (0.5 mol) of dimethyldichlorosilane and 150 grams of toluene. Into the solution at 30° C., 52 grams (3.06 mol) of ammonia was blown over 2 hours for effecting reaction. At the end of reaction, the reaction solution was passed through a glass filter to remove ammonium chloride resulting from the reaction. The filtrate was subjected to vacuum distillation, obtaining 15.4 grams of hexamethylcyclotrisilazane (yield 42%).
Reaction SMILES: [CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21][CH3:22])=[O:20])[C@@H:8]([O:10]C(C3C=CC=CC=3)=O)[CH2:9][C@@H:3]1[CH2:4][CH2:5]2.Cl.Cl>O>[CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21][CH3:22])=[O:20])[C@@H:8]([OH:10])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Solvent: O
Product: COC(=O)[C@@H]1[C@H]2CC[C@@H](C[C@@H]1O)N2C
Temperature: 25 °C

Procedure:
Cocaine hydrochloride (2.0 g) was dissolved in distilled water (100 ml) and concentrated hydrochloric acid (8.0 ml) and refluxed for 19 hours. After cooling to room temperature, the benzoic acid precipitated and was filtered. The filtrate was washed with chloroform to remove any remaining benzoic acid. The aqueous solution was evaporated to dryness in vacuo. The residue (ecgonine hydrochloride) was esterified by refluxing in methanolic hydrogen chloride (150 ml) for 17 hours. The solvent was removed in vacuo to yield ecgonine methyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21]>CN(C=O)C>[CH3:23][N:22]([CH3:24])[C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C)C(=O)CCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Methyl 4-hydroxybenzoate (Fluka) (1.52 g, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) in DMF (10 mL) was treated with 2-chloro-N,N-dimethylacetamide (Merck) (1.03 ml, 10 mmol) and the mixture was stirred at RT overnight. The reaction mixture was worked up by partitioning between ethyl acetate and 2M hydrochloric acid, washing with HCl, brine, dried (MgSO4) and evaporating to dryness. The residue was dissolved in DMF (5 mL) and treated with potassium carbonate (1.38 g, 10 mmol) and 2-chloro-N,N-dimethylacetamide (Merck) (1.03 ml, 10 mmol). The mixture was stirred at RT over the weekend, and then worked up. Partitioned between ethyl acetate and 2M HCl and the organic solution was washed with HCl (×2), brine (×3), dried (MgSO4), and evaporated to give the title compound (1.62 g, 68%) as a white solid. LCMS (System A) RT=0.73 min, ES+ve m/z 238 (M+H)+.