Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12]12[O:17][CH:16]1[CH2:15][CH:14]=[CH:13]2>CS(C)=O.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:13]2[CH2:12][C@H:16]([OH:17])[CH:15]=[CH:14]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=CC2OC2C1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a stirred solution of 2-amino-6-chloro-9H-purine (4.0 g, 23.7 mmol) in dry dimethylsulfoxide (40 mL) at room temperature under N2 is added tetrakis(triphenylphosphine)palladium(O) (0.27 g, 0.23 mmol) and the mixture is stirred for 2 minutes. The solution is cooled to 0° C. and a solution of 6-oxa-bicyclo[3.1.0]hex-2-ene (2.1 g, 25.6 mmol) in dry tetrahydrofuran (20 mL) is added over 15 minutes. The resulting yellow solution is allowed to warm to ambient temperature (about 15°-30° C.) over 3 hours and stirred overnight (about 16 h). The clear, yellow solution is evaporated to a viscous oil which is taken up in dichloromethane (50 mL) and filtered through a small pad of Celite (trademark of Manville Products Corp. for infusorial earth filter aid). The solvent is evaporated and the residue is purified by silica gel chromatography using i) ethyl acetate followed by ii) 10:1 ethyl acetate:methanol as eluent to give cis-(±)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclo-penten-1-ol as a white solid, 5.14 g (86%). M.pt. 160°-162° C. 1H nmr: δ7.83 (s, 1H), 6.34 (dt, J1 =5.5 Hz, J2 =2 Hz, 1H), 5.85 (dd, J1 =5.5 Hz, 1H), 5.34 (d, J=10 Hz, 1H), 5.26 (dq, J1 =9 Hz, J2 =2 Hz, 1H), 5.12 (br s, 2H), 4.85 (br t, J=9 Hz, 1H), 2.97 (ddd, J1 =15 Hz, J2 =9 Hz, J3 =7 Hz, 1H), 2.13 (br d, J=15 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[C:14](=[N:26]\[S@@:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])/[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: C=CCC/C(=N/[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Yield: 42.2 %

Procedure:
A solution of 1-(1-benzylpiperidin-4-yl)pent-4-en-1-one (6.11 g, 21.3 mmol) and (R)-2-methylpropane-2-sulfinamide (3.62 g, 27.6 mmol) in THF (71 mL, 0.3 M) was treated with titanium (IV) ethoxide (12.6 g, 55.3 mmol) and heated to 70° C. overnight. Because the reaction was incomplete, additional portions of (R)-2-methylpropane-2-sulfinamide (1.81 g, 13.8 mmol) and titanium (IV) ethoxide (6.3 g, 27.7 mmol) were added and the mixture was heated to 75° C. for 6 more hours. The reaction was quenched by pouring it slowly into rapidly stirred saturated aqueous sodium chloride (100 mL) and filtering through Celite. The Celite pad was washed with ethyl acetate (3×) and the combined organics were washed with saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (60% ethyl acetate in heptane) to afford the desired product (3.24 g, 42%). Rf 0.44 (EtOAc). 1H NMR (CDCl3, 300 MHz) δ 7.34-7.19 (m, 5H), 5.88-5.75 (m, 1H), 5.09-4.94 (m, 2H), 3.50 (d, J=5.5 Hz, 2H), 2.97-2.83 (m, 2H), 2.74-2.70 (m, 1H), 2.55-2.23 (m, 4H), 2.00 (t, J=8.8 Hz, 2H), 1.77-1.63 (m, 4H), 1.23 (s, 9H). ESI MS found for C21H32N2OS m/z [361.4 (M+1)].
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]([CH3:11])[NH:8][CH:7]([CH3:12])[CH2:6]1)(=[O:4])=[O:3].Br[CH2:14][C:15]1[S:23][C:22]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:20][C:19]([Cl:30])=[N:18][C:17]=2[C:16]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:22]2[S:23][C:15]([CH2:14][N:8]3[C@H:9]([CH3:11])[CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][C@@H:7]3[CH3:12])=[C:16]([CH3:31])[C:17]=2[N:18]=1
Reactant: CC1CN(S(C)(=O)=O)CC(C)N1
Reactant: Cc1c(CBr)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To a mixture of 1-methanesulfonyl-3,5-dimethylpiperazine and 6-bromomethyl-2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine in acetonitrile was added potassium carbonate and the mixture refluxed overnight. After cooling to room temperature, the acetonitrile was removed under reduced pressure. DCM/sat. aq. NaHCO3 extraction and purification on silica gave 2-chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([CH3:31])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:8])[CH3:5].Cl>CO.[OH-].[Na+]>[CH3:31][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=1)=[O:8])([CH3:5])[C:3]([OH:32])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1NCc1ccc(C(F)(F)F)cc1)C(=O)O
Yield: 66.4 %

Procedure:
140 mg 2-methyl-2-{[1-(4-trifluoromethyl-benzylamino)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester in 2 ml methanol and 1 ml 1 M aqueous sodium hydroxide solution was refluxed for 0.5 h. The reaction was acidified with 2 M hydrochloric acid, and the precipitated product was collected by filtration, dissolved in ethyl acetate, dried over sodium sulphate, filtrated, concentrated in vacuo, and the resulting crude product was purified by silica gel chromatography to yield 0.09 g 2-methyl-2-{[1-(4-trifluoromethyl-benzylamino)-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C:9]1[C:10](=[O:20])[O:11][C:12]([OH:19])=[C:13]([C:16](=[O:18])[CH3:17])[C:14]=1[OH:15])(=O)[CH3:7]>>[C:16]([C:13]1[C:12](=[O:19])[O:11][C:10](=[O:20])[C:9](=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:7])[C:14]=1[OH:15])(=[O:18])[CH3:17]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CCCCN
Product: CCCCNC(C)=C1C(=O)OC(=O)C(C(C)=O)=C1O

Procedure:
Similarly, 1.8 g. (0.025 m.) of n-butylamine and 5.3 g. (0.025 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are refluxed overnight in 50 ml. of benzene and the resulting solid filtered to give 5-acetyl-3-[1-(n-butylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 112°-114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[N:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:27]4[CH:28]=[N:29][CH:30]=[C:25]([Cl:24])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cncc(Cl)c4)ncnc32)CC1
Yield: 15.5 %

Procedure:
4-[4-(5-Chloro-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 16%) was prepared using the procedure described for the preparation of Example 96, by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 5-chloro-3-pyridinol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 25 mg, 0.19 mmol) in the presence of potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL). Mass spectrum (ES) MH+=431. HRMS Calcd. for C20H24ClN6O3 (MH+): 431.1593. Found: 431.1593.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>O1CCOCC1.C(OCC)C.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>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27 and 0.6 g (1.7 mmol) of 2-tributylstannyl)-furan in 5 mL of dioxane was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to reflux for 16 hours, cooled to ambient temperature and diluted with 5 mL of ethyl ether. The mixture was washed once with 5 mL of saturated aqueous potassium fluoride, the organic layer was separated and the aqueous portion was extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded a yellow oil which was recrystallized from ethyl ether/hexane to afford 0.2 g (51%) of the title compound.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH2:6]([C:11]1[CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:13][S:14][CH:15]=1)[C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[CH:27]([O:30][C:12]1([C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:15][S:14][S:13]1)([CH3:29])[CH3:28]
Reactant: CC(C)(C)CC1=CSSC1C(C)(C)C
Reactant: CC(C)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCN(CC)CC
Product: CC(C)OC1(C(C)(C)C)SSC=C1CC(C)(C)C
Yield: 98 %

Procedure:
To a sample of 5 grams of Example 2B, i.e., 4-neopentyl-3-t-butyl 1,2 dithiole perchlorate, in 50 grams of isopropanol was added 2.5 grams of triethylamine. The excess of isopropanol was removed by distillation under diminished pressure. The residue was dissolved in ether and the ethereal solution was filtered. The ethereal solution was evaporated under diminished pressure to yield 4.3 grams (98% of theory) of 3-isopropoxy-3-t-butyl-4-neopentyl 1,2 dithiole; n.m.r. (CCl4) in ppm, 3.97, 1H singlet (vinyl); 6.18 1H multiplet (isopropoxy); 7.17, 1H doublet (diastereotopic, J=15 cps, neopentyl; 7.88, 1H doublet (diastereotopic, J=15 cps, neopentyl); 8.62, 9H singlet (t-butyl); 8.83, 6H doublet (isopropoxy); and 8.91, 9H singlet (t-butyl).
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].[CH:7]([N:10]=[N:11][C:12]1(Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])[CH3:8].O>CO>[CH:7]([N:10]=[N:11][C:12]1([S:3][CH2:4][CH2:5][OH:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])[CH3:8]
Reactant: OCCS
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N=NC1(SCCO)CCCCC1
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4.8 grams (.06 moles) of 50% sodium hydroxide in 60 ml of methanol in a 125 ml erlenmeyer flask was added 5.46 grams (.07 moles) of 2-mercaptoethanol while holding the reaction temperature below 25° C. After the addition was complete, the mixture was stirred for 20 minutes at 10° C and 9.5 grams (.05 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise over 25 minutes while holding the temperature below 15° C. After the addition was complete, the reaction was stirred an additional 60 minutes at 5° to 15° C. A .02 mole portion of 50% sodium hydroxide was added, the reaction stirred an additional 10 minutes, poured into 200 ml of water and the product extracted into 100 ml of pentane. The pentane solution was separated and washed successively with 50 ml portions of 5% HCl, water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid weighing 8.5 grams (74% crude yield). The infrared spectrum was in agreement with the structure of 1-isopropylazo-1-(β-hydroxyethylthio)cyclohexane (absence of carbon-chlorine band at 800 - 825 cm-1 and presence of a strong OH band at 3325 cm-1.)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[NH:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNc1ccc(C(=O)OC)cc1N
Yield: 61.1 %

Procedure:
The methyl 4-methylamino-3-nitrobenzoate (6.3 g) obtained above was suspended in 1,4-dioxane (125 ml). 20% Palladium hydroxide (6.3 g) was added thereto, and the mixture was stirred for 91 hours at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; ethyl acetate:n-hexane 1:4→2:3) to give methyl 3-amino-4-methylaminobenzoate (3.3 g, Y.:62%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:34]([C:27]1[N:26]=[C:25]([CH2:24][CH2:23][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12)=[O:35]
Reactant: CNc1ccccc1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1nc(CCN2CCOCC2)n2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of n-methylaniline (0.060 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (105 mg, 64%). 1H NMR (DMSO-d6) δ 8.23 (1H), 8.00 (1H), 7.30 (2H), 7.19 (3H), 7.05 (1H), 6.81 (1H), 3.52 (4H), 3.48 (3H), 2.95 (2H), 2.45 (2H), 2.33 (4H); m/z (M+H)=365.26.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ccc(C(F)(F)F)cn3)cc2)COC1(C)C
Temperature: 110 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
In a pressure tube, (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg), 2-chloro-5-(trifluoromethyl)pyridine (57 mg) and potassium carbonate (431 mg) were combined with toluene (1 ml) to give a yellow solution. The mixture was degassed by bubbling through argon for several minutes. BINAP (12 mg) and palladium(II)acetate (2 mg) were then added and the tube was sealed. The reaction mixture was stirred at 110° C. for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; gradient: 0% to 40% EtOAc in hexane) to afford (S)-2,2-dimethyl-4-{2-[4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl]-ethyl}-oxazolidine-3-carboxylic acid tert-butyl ester (55 mg, 38%) as a yellow amorphous solid. MS (ISP): 466.3 ([M+H]+), 410.2 ([M+H—C4H8]+), 366.2 ([M+H—C4H8—CO2]+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][C:6]1=O.C1COCC1>>[F:15][C:13]1[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=[C:9]2[C:14]=1[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])[CH2:6][CH2:7][CH2:8]2
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Solvent: C1CCOC1
Product: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Temperature: 0 °C

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (600 mg, 2.13 mmol) was added to a round bottom flask equipped with a stir bar. The flask was sealed and purged with argon. Borane.THF (1M solution in THF, 21.3 mL, 21.3 mmol) was added to the starting material and stirred to dissolve. The reaction mixture was heated to reflux overnight. The reaction was cooled to 0° C. and then quenched with methanol (20 mL). The mixture was then concentrated in vacuo, redissolved in methanol and refluxed for 4 h. The mixture was then concentrated onto silica gel and chromatographed using 0-10% (2M NH3 in MeOH) in dichloromethane. Yield: 364 mg, 64%. 1H NMR (CDCl3) δ 1.95 (m, 2H), 2.27 (s, 6H), 2.56 (m, 2H), 2.77 (m, 2H), 3.41 (m, 4H), 7.69 (m, 1H), 7.77 (dd, 1H, J=9 Hz, 2.7 Hz). EI-MS: 58 (100).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3].[OH-].[K+].Cl>C(O)C.O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reaction time: 3 h
Yield: 72 %

Procedure:
Dissolve (+)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl 2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid, ethyl ester (0.49 g, 1.07 mmol) in ethanol (10 mL) and treat with a solution of potassium hydroxide (0.072 g, 1.29 mmol) in water (10 mL). Stir for 3 hours, then dilute with water (200 mL) and acidify with 10% hydrochloric acid. Extract into chloroform (2×400 mL), then ether (400 mL) and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound as a white solid (0.33 g, 72%); [α]d 20 =+81° (C=0.069, DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]([C:21]1(Br)[CH2:24][CH2:23][CH2:22]1)=[O:20].O>CN(C=O)C.COC(C1(Br)CCC1)=O>[CH3:17][O:18][C:19]([C:21]1([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:24][CH2:23][CH2:22]1)=[O:20]
Reactant: COC(=O)C1(Br)CCC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Temperature: 140 °C

Procedure:
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (10 g, 64 mmol) and K2CO3 (13 g, 94 mmol) in DMF (100 mL) was added 1-bromo-cyclobutanecarboxylic acid methyl ester (15 g, 77 mmol, prepared according to Bulletin of the Chemical Society of Japan, 36, 145-7; 1963). The mixture was heated at 140° C. for 1.5 h. Then additional 1-Bromo-cyclobutanecarboxylic acid methyl ester (0.5 g, 2.6 mmol) was added and the mixture was heated at 140° C. for additional 10 min. The mixture was cooled to room temperature and poured into water (200 mL). The mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with water (4×), dried over Na2SO4, concentrated to afford crude product 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester as a dark oil (18 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ccncc3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 4-pyridinecarboxaldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (117 mg, 60.9% yield) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl>[OH-].[K+]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Temperature: 100 °C

Procedure:
Methyl 2-hydroxy-5-[2-[4-[(2-pyridinylamino)sulfonyl]phenyl]ethenyl]benzoate (12 g, 29 mmol) was dissolved in 1M KOH (120 ml) and the solution was refluxed for 7 h. The cooled solution was acidified with an excess of 1M hydrochloric acid. The precipitate was filtered off and washed with water (3×200 ml). The product was redissolved in a small portion of 1M NaOH. Water and dioxane (500+500 ml) was added and the solution was heated to 100° C. The solution was acidified with an excess of 1M HCl, and the product precipitated upon cooling. Yield 9 g (75%).