Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13]C(SC)=[N:15][CH:16]=2)[N:11]([CH:21]([CH3:23])[CH3:22])[C:10]1=[O:24].ClC1C=CC=C(C(OO)=[O:33])C=1.[CH3:36][S:37]([CH3:39])=[O:38].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:36]([S:37]([CH3:39])(=[O:33])=[O:38])=[N:15][CH:16]=2)[N:11]([CH:21]([CH3:23])[CH3:22])[C:10]1=[O:24]
Reactant: CS(C)=O
Reactant: CSc1ncc2c(n1)N(C(C)C)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 60 mg (0.16 mmol) of 3-(2,6-dichlorophenyl)-1-isopropyl-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of dichloromethane was treated with 108 mg (0.32 mmol) of 3-chloroperbenzoic acid (50% w/w in water) and stirred for 18 hours. 0.2 ml of dimethyl sulfoxide was added. After a further 15 minutes 15 ml of saturated aqueous sodium bicarbonate solution were added and the phases were separated. The organic phase was washed with 30 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 65 mg (100%) of 3-(2,6-dichlorophenyl)-1-isopropyl-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =415].
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[CH:7]([C:1]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To 100 g. of cumene at 10° C. is slowly added over a period of 2.5hours to a mixture of 70.5 ml. of concentrated nitric acid and 109ml. of concentrated sulfuric acid. The reaction mixture is stirred at 5° to 10° C. for 1 hour following the addition. The reaction mixture is poured onto 250 ml. of ice water and extracted with ether. The ether is dried and evaporated in vacuo and the residue distilled at 9.5 to 10.5 mm./Hg. The fraction boiling at 130° C. is taken and used as is in the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH3:11])[N:9]=[CH:8][C:7]=2/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])=[CH:2]1.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH3:11])[N:9]=[CH:8][C:7]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:2]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1-c1ccoc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc(/C=C/C(=O)O)c1-c1ccoc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a mixture of ethyl (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]acrylate (800 mg), tetrahydrofuran (10 ml) and ethanol (10 ml) was added 2N aqueous sodium hydroxide solution (6.5 ml) and the mixture was stirred at 60° C. for 1 hr. 1N Hydrochloric acid was poured into the reaction mixture, and the precipitated solids were collected by filtration, washed with water and dried with airflow to give (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (703 mg, 99%) as crystals. Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 218-219° C.
Reaction SMILES: C([C@@H:8]1COC(=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16]C=O)C1C=CC=CC=1.[NH:37]1[C:45]2[CH:44](N)[CH2:43][CH2:42][CH2:41][C:40]=2[CH:39]=[N:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(#N)C>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:8][N:9]([CH:44]3[C:45]4[NH:37][N:38]=[CH:39][C:40]=4[CH2:41][CH2:42][CH2:43]3)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCCc2cn[nH]c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCCc2cn[nH]c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Add a solution of (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde, Preparation 38, (9.95 g, 18.9 mmol) in CH2Cl2 (300 mL) to a solution of 4,5,6,7-tetrahydro-1H-indazol-7-ylamine (2.60 g, 19.00 mmol) in acetonitrile (300 mL) and stir for 30 minutes at room temperature under N2. Add sodium triacetoxyborohydride (12.02 g, 56.9 mmol) to the reaction and stir for 72 hours. Remove the solvent in vacuo and extract solid with ethyl acetate, water and saturated NaHCO3. Dry the organic layer (Na2SO4), filter and concentrate under vacuum. Purify the residue by silica gel chromatography with a gradient of 0 to 10% methanol in CH2Cl2 to afford 2.53 g (28%) of the title compound. MS (m/z): 470 (M+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[CH:26]=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:29]([NH2:32])(=[O:31])=[O:30])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:33][C:34]([Cl:39])([Cl:38])[C:35](Cl)=[O:36].O>O1CCOCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[C:26]([C:35](=[O:36])[C:34]([Cl:39])([Cl:38])[Cl:33])=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:29]([NH2:32])(=[O:30])=[O:31])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: NS(=O)(=O)c1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution containing 0.77 g (0.0017 mol) of 2-morpholin-4-yl-5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzenesulfonamide of Step B and 0.62 g (0.0034 mol) of trichloroacetyl chloride in 50 mL of 1,4-dioxane was heated under reflux for 3 hrours. The solution was allowed to cool to room temperature and then poured into 750 mL of water with stirring. The solid was collected, washed and dries to provide the title compound (0.88 g), m.p. 165-167° C. dec.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]=[CH:7][C:6]2=[O:14].Br[CH:18]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]1Br.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[C:8]3[C:7](=[CH:19][C:20]4[C:21]([CH:18]=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:6](=[O:14])[C:5]=2[CH:4]=1
Reactant: BrC1c2ccccc2C1Br
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
5.65 g (25 mmol) of 6-(trifluoromethyl)-1,4-naphthoquinone, 9.82 g (about 37 mmol) of 1,2-dibromobenzocyclobutene (contaminated with a little 2-bromo-1-iodobenocyclobutene) and 100 ml of xylene are kept under reflux for 16 hours, using a water separator. The mixture is cooled and the precipitate is filtered off and washed with xylene. Yield 5.82 g (71%); melting point 253°-254° C. The procedure in Examples 58 to 61 is analogous.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)[N:8]=1)[NH2:2].[C:19]([O-])([O-])(OCC)[CH3:20]>>[CH3:19][C:20]1[N:4]2[N:5]=[CH:6][C:7]([C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=3)=[N:8][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1nncc(-c2cccc(C(F)(F)F)c2)n1
Product: Cc1nnc2nc(-c3cccc(C(F)(F)F)c3)cnn12

Procedure:
A mixture of 5.1 g. of 3-hydrazino-5-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine and 60 ml. of ethyl orthoacetate is refluxed for 2.5 hours, cooled and the solid is collected by filtration and washed with hexane and ethanol, giving the desired product as yellow plates, m.p. 230°-233° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:9][C:10](OCC)=[O:11])=[O:5])[CH3:2].[O-]CC.[Na+].[Na]>C1C=CC=CC=1.C(O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:8]2[CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10](=[O:11])[CH2:9]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCN(CC(=O)OCC)c1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)C1CN(c2ccc(OC)cc2)CC1=O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of ethyl N-(b-ethoxycarbonylethyl)-N-(4-methoxyphenyl)glycinate (106.7 g, 0.345 mol) in dry benzene (400 mL) is added to a mixture of ethanolic sodium ethoxide in benzene (prepared by dissolving 13.1 g of sodium metal in 300 mL of ethanol and then the ethanolic sodium ethoxide solution is diluted with 500 mL of benzene) at room temperature over a period of 90 minutes. The mixture is heated at reflux for 30 minutes and then is cooled to room temperature. The solid is collected by filtration, and then is suspended in an ice-water mixture (1 L). The mixture, after being neutralized with 1 N hydrochloric acid, is extracted with diethyl ether (3×500 mL). The combined extracts are washed with water, dried over sodium sulfate, concentrated, and the residue is crystallized from n-hexane-diethyl ether to afford 1-(4-methoxyphenyl)-4-ethoxycarbonylpyrrolidine-3-one (87.4 g, 64%), mp 58°-60° C. 1H NMR (CDCl3) d 1.34 (3H, dt, CH2Me), 3.76 (3H, s, OMe), 3.75 (2H, dq, CH2Me), 4.14 (2H, s, 2-CH2), 4.12-4.39 (3H, m, H-4 and 5-CH2), 6.46 and 6.86 (each 2H, m, Ph).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 520.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.21 g, 0.49 mmole) was dissolved in a mixture of dichloromethane (4 ml), pyridine (1 ml) and diisopropylethylamine (0.17 ml) under a nitrogen atmosphere. Methanesulfonyl chloride (0.06 ml, 0.07 mmol) was added to the stirred solution. After stirring 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the expected product were combined and evaporated under vacuum and the residual gum was triturated with diethylether, filtered and dried under vacuum to give the title product as a white solid (0.17 g, 74%); 1H NMR Spectrum: (DMSO d6) 2.18-2.37 (m, 2H); 2.93 (s, 3H); 3.33-3.45 (m, 2H); 3.5 (d, 1H); 3.69 (dd, 1H); 3.92 (s, 3H); 5.17 (m, 1H); 7.15-7.35 (m, 2H); 7.40-7.60 (m, 2H); 7.5 (m, 2H); 7.80 (s, 1H); 8.37 (s, 1H); 9.6 (s, 1H); Mass Spectrum: (M+H)+ 467.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.[F:23][CH:24]([F:40])[O:25][C:26]1[C:31]2[N:32]=[C:33]([CH2:35][CH3:36])[O:34][C:30]=2[C:29]([C:37](O)=[O:38])=[CH:28][CH:27]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:37]([C:29]2[C:30]3[O:34][C:33]([CH2:35][CH3:36])=[N:32][C:31]=3[C:26]([O:25][CH:24]([F:23])[F:40])=[CH:27][CH:28]=2)=[O:38])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
para-Nitrophenol (0.95 g), 4-dimethylaminopyridine (80 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.4 g) were added to a stirred suspension of 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (1.6 g) in dry dichloromethane (60 ml) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 18 hours. Water (20 ml) was added and the aqueous layer extracted with dichloromethane (400 ml). The organic layer was washed with water (80 ml), separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 1:4 ethyl acetate/heptane to 1:1:2 ethyl acetate/dichloromethane/heptane afforded the title compound as a pale yellow solid (1.9 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[N+:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N+:17]#[C-:18])#[C-:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O>Cl(O)(=O)(=O)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:24]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]3[C:10]=2[NH:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N+:17]#[C-:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C=O)cc1OC
Reactant: [C-]#[N+]CCCCCC[N+]#[C-]
Reactant: Cc1ccc(N)nc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: [C-]#[N+]CCCCCCNc1c(-c2ccc(OC)c(OC)c2)nc2ccc(C)cn12

Procedure:
Compound (20) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-5-methylpyridine solution (0.1 M, DCM), 0.575 ml of 1,6-diisocyanhexane solution (0.2 M, DCM), 0.500 ml of 3,4-dimethoxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([Li])(C)(C)C.[CH:11]([C:13]1[CH:22]=[CH:21][C:16](C(OC)=O)=[CH:15][C:14]=1O)=[O:12].[Cl-].[NH4+].O>O1CCCC1>[C:3]1([CH:11]([C:13]2[CH:22]=[CH:21][CH:16]=[CH:15][CH:14]=2)[OH:12])[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: [Li]C(C)(C)C
Reactant: CCCCC
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(bromophenyl)ethylalchol (1.7 g) in tetrahydrofuran (100 mL) was added 1.45 mol/L tert-butyllithium n-pentane solution (12.6 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 10 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.50 g) in tetrahydrofuran (10 mL) was added to the reaction mixture. After the reaction mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give a diphenylmethanol compound (0.28 g). The obtained diphenylmethanol compound (0.28 g) was dissolved in methanol (5 mL) and 10% palladium-carbon powder (0.14 g) was added to the solution. After the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]-benzoate (0.26 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[OH:10])[CH3:2].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][C:22]#N.B(F)(F)F.CC[O:30]CC>>[CH2:1]([C:3]1[C:4]([OH:10])=[CH:5][C:6]([OH:9])=[C:7]([C:22](=[O:30])[CH2:21][C:12]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[CH:8]=1)[CH3:2]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: CCc1ccc(O)cc1O
Reactant: CCOCC
Agent: FB(F)F
Product: CCc1cc(C(=O)Cc2ccc3ccccc3c2)c(O)cc1O
Reaction time: 6 h

Procedure:
To a mixture of 4-ethyl-benzene-1,3-diol (a, 10 mmol) and naphthalen-2-yl-acetonitrile (b, 10 mmol) in boron trifluoride etherate (20 mL) was bubbled gaseous HCl for 12 h. The solids that formed were collected by filtration and heated in 6N HCl (100 mL) and EtOH (20 mL) for 6 h. The mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with water and dried. The oil obtained on concentration of the organic layer was crystallized in EtOAc/hexanes to give 1-(5-ethyl-2,4-dihydroxy-phenyl)-2-naphthalen-2-yl-ethanone (c, 0.74 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH2:12])[N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:11][N:8]1[C:6]2=[N:7][C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:3][C:4]([NH2:12])=[C:5]2[CH:10]=[N:9]1
Reactant: Cn1ncc2c(N)nc(Cl)nc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc2c(N)nc(-c3ccccc3)nc21
Temperature: 170 °C

Procedure:
A suspension of 6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (68 mg, 0.37 mmol), phenyl boronic acid (68 mg, 0.56 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (30 mg, 0.037 mmol), 1,4-dioxane (3 ml), water (0.2 ml), and aqueous sodium carbonate solution (2.0 M, 0.740 ml, 1.5 mmol) in a 5 mL microwave vial was deoxygenated using 10 alternate vacuum/argon flush cycles. The reaction mixture was then heated via microwave irradiation to 170° C. for 10 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (40 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0.5-6.5% methanol/dichloromethane, linear gradient) to afford 1-methyl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. MS ESI calc'd. for C12H12N5 [M+H]+ 226. found 226.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:28])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCNCC2)cc1
Reactant: O=Cc1ccccc1
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105.4 %

Procedure:
In a 4 mL screw cap vial, N4-[4-tert-butyl-2-(piperidin-4-yloxy)benzoyl]-N3-(4-methoxybenzoyl)-3,4-pyridinediamine (38 mg, 76 μmol) was dissolved in 1 mL of freshly prepared dry 95:5 MeOH:AcOH. Benzaldehyde (24.1 mg, 227 μmol, 3 eq) was added and the vial was capped. After 10 minutes, sodium cyanoborohydride solution (0.5 mL of a 19.0 mg/mL freshly prepared stock in dry 95:5 MeOH:AcOH, 9.51 mg NaCNBH3, 151 μmol, 2 eq) was then added to the solution. The vial was re-capped and shaken overnight at room temperature. The mixture was then purified using the method described in Example 34-B to provide the desired compound as a yellow solid (47.5 mg, 106%).
Reaction SMILES: C(C1C=CC=CC=1)C.N([O:11][C:12](C)(C)[CH3:13])=O.ON1C(=O)C2=CC=CC=C2C1=O.C(=NO)(C1C=CC=CC=1)C.[N+](C(C1C=CC=CC=1)C)([O-])=O.[C:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:51])[CH3:50]>C(O)(=O)C>[C:12]([O:51][CH:49]([CH3:50])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:11])[CH3:13]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)(C)ON=O
Agent: CC(=NO)c1ccccc1
Agent: CC(c1ccccc1)[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Solvent: CCc1ccccc1
Product: CC(=O)OC(C)c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
Ethylbenzene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 100° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that acetophenone oxime, (1-nitroethyl)benzene, acetophenone, and α-methylbenzyl acetate were formed in yields of 32%, 5%, 23%, and 15%, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:27])([F:26])/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][CH:19]([C:18]([F:17])([F:27])[F:26])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4]2
Reactant: Nc1ccc(Cl)cc1C=O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Temperature: 100 °C
Yield: 55.7 %

Procedure:
The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol), anhydrous potassium carbonate (27.6 g, 200 mmol), and ethyl 4,4,4-trifluorocrotonate (34 mL, 200 mmol) were mixed in anhydrous dimethyformamide (60 mL) and heated at 100° C. for 7 hours. The contents were allowed to cool and partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (1×100 mL). The ethyl acetate extracts were combined and washed with brine (1×200 mL), dried over MgSO4, and concentrated in vacuo leaving a dark oil which solidified upon standing. The solid was purified by flash chromatography (silica gel; ethyl acetate-hexanes, 1:9). Fractions containing the desired product were combined, concentrated in vacuo and the residue recrystallized from ethyl acetate-hexanes to afford the ethyl 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (16.36 g, 56%): mp 132.6-134.2° C. 1H NMR (CDCl3, 300 MHz) 7.61 (s, 1H), 7.10 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.10 (q, 1H, J=6.0 Hz), 4.55 (brs, 1H), 4.23 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). FABHRMS m/z 306.0468 (M+H+, Calc'd 306.0509). Anal. Calc'd for C13H11NO2F3Cl: C, 51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([O-])([O-])OCC>>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:9])=[CH:7][N:6]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOC([O-])[O-]
Product: CNc1ccc(Cl)nc1
Reaction time: 3 h

Procedure:
To 5.0 g (0.039 mole) of 5-amino-2-chloropyridine was added 40 ml of ethyl orthoformate and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 50 ml of EtOH. After addition of 1.8 g of sodium borohydride, the mixture was stirred at 70°-80° C. for 3 hours. The reaction mixture was concentrated and after addition of 50 ml of iced water and 5 ml of concentrated hydrochloric acid, the mixture was adjusted to pH 7-8 with NaHCO3 and extracted with AcOEt (50 ml×3). The AcOEt layers were pooled, washed with water and dried over MgSO4. The AcOEt was distilled off and hexane was added to the crystalline residue. The crystals are collected by filtration, washed with hexane and dried to give 5.1 g of the title compound as white crystals.