Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:6]P(=O)(OCC)OCC.[CH3:22][C:23]([CH3:25])=O.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:23]([CH3:25])[CH3:22])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)=O
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)c(OC)c1)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of diethyl (3-methoxy-4-methoxycarbonylbenzyl)phosphonate (1.28 g) and acetone (1.5 ml) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride-oil dispersion (162 mg). The reaction mixture was stirred at room temperature for 14 hours and then poured into ice-cooled 10% citric acid. The mixture was extracted with ether and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (85:15) to give methyl 2-methoxy-4-(2-methyl-1propenyl)benzoate (184 mg) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][CH:35]=1)[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:36][C:19]([F:18])([F:37])[C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][CH:35]=1)[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:27]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
A solution of 1.5 grams (0.011 mole) 3-nitroaniline and 1.0 gram (0.011 mole) triethylamine in 100 milliliters toluene was placed in a flask. There was slowly added, with stirring, a solution of 3.2 grams (0.011 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride in 25 milliliters toluene. The rate of addition was controlled so as to maintain the temperature below 35° C. After the addition was complete the mixture was stirred at 45° C., for one hour, cooled, poured into 100 milliliters toluene, and washed with two 150-milliliter portions of water. The organic phase was separated, dried with magnesium sulfate, filtered and the solvent removed to produce 3.3 grams (73.3% of theoretical yield) of the desired product, m.p. 90°-95° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br>CCOCC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH2:11][Br:17])([O-:3])=[O:2]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
o-Nitroacetophenone (8.3 g, 50 mmol) in ether (100 ml) was treated with aluminium chloride (catalytic amount) followed by bromine (2.55 ml, 50 mmol) over 10 mins and the reaction stirred for 30 mins. The reaction was quenched with aqueous sodium bicarbonate, the ether layer separated, dried (MgSO4) and evaporated under reduced pressure. The residue was taken up in ethyl acetate, the solution was dried (MgSO4), and evaporated under reduced pressure to yield o-nitro phenacyl bromide as a yellow oil (9.45 g, 77%); δH (CDCl3) 7.2-8.35 (4H, m, aryl), 4.30 (2H, S, CH2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: Clc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(Cl)cc4)n3c2)cc1

Procedure:
The title compound, off-white solid (43 mg, 34%), MS (ISP) m/z=389.4 [(M+H)+], mp 171° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-chloro-phenyl)-imidazo[1,2-a]pyridine (intermediate F) (0.1 g, 0.325 mmol) and 1-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][C:23]([OH:25])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH2:26]([O:28][C:29]([CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:30])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:26]([O:28][C:29](=[O:30])[CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:23](=[O:25])[CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:34][CH2:33]1)[CH3:27]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: CCOC(=O)CN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(C(=O)Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (188 mg, 0.98 mmol) and Et3N (137 mL, 0.98 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8 mg, 0.07 mmol) and stir the resulting solution for 10 min. Add 1-(Ethoxycarbonylmethyl)piperazine (63) (112 mg, 0.65 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with DCM (3 times). Wash the combined organic layer with water and brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/MeOH 10+1) to obtain {4-[2-(3,4,5-Trimethoxy-phenyl)-acetyl]-piperazin-1-yl}-acetic acid ethyl ester (64) (99 mg, 40%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 1.25 (t, 3H, J=7.1 Hz); 2.48 (br.m, 2H); 2.58 (br.m, 2H); 3.21 (br.s, 2H); 3.53 (br.m, 2H); 3.65 (s, 2H); 3.71 (br.m, 2H); 3.81 (s, 3H); 3.82 (s, 6 H); 4.16 (q, 2H, J=7.1 Hz); 6.42 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])[C:19]([Cl:36])=[CH:18][N:17]=1>>[Cl:36][C:19]1[C:20]([NH:22][C:23]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])=[N:21][C:16]([NH:14][C:12]2[CH:11]=[CH:10][C:9]3[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]=3[CH:13]=2)=[N:17][CH:18]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3CC)ncc1Cl

Procedure:
2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (50 mg, 20%). LCMS (m/e) 495 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.05 (s, 1H), 7.40-7.23 (m, 3H), 7.09 (s, 1H), 6.93 (s, 1H), 6.87 (d, 1H, J=8.6 Hz), 6.69 (d, 1H, J=8.6 Hz), 6.51-6.42 (m, 1H), 4.16-4.07 (m, 2H), 4.06 (t, 2H, J=5.2 Hz), 3.23-3.11 (m, 4H), 2.24-2.19 (m, 1H), 2.04-1.94 (m, 2H), 1.18 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=[N:26][NH:25][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)C(c1ccc(F)cc1)C(C=O)c1ccc(SC)cc1
Solvent: O
Solvent: CCO
Product: CSc1ccc(C2C=NNC(=O)C2c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 5.3 %

Procedure:
The aldehyde-ester, hydrate, and hydroxy lactone from Example 16 (0.10 g, 3 mmol), were dissolved in 100 mL of ethanol. This solution was treated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resulting solution was stirred at reflux in a Soxhelet apparatus containing molcular sieves. After 18 hours, the reaction mixture was cooled and the volatile materials removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous HCl. The aqueous layer was washed twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (4:1 hexanes/ethyl acetate) to obtain the title compound (yield: 50 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 3.75 (d, J=12 Hz, 1H), 3.87 (d, J=12 Hz, 1H), 6.93-7.08 (m, 6H), 7.16 (d, J=9 Hz, 2H), 8.71 (s(br), 1H). MS (DCI/NH3) m/z 315 (M+H)+ and m/z 332 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[O:8].[Br-:18].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[Br:18][C:5]1[S:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: [Br-]
Reactant: CCCc1ccc(C(=O)c2sccc2C)cc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1ccc(C(=O)c2sc(Br)cc2C)cc1
Temperature: 50 °C
Yield: 64.4 %

Procedure:
To a solution of (3-methylthiophen-2-yl)(4-propylphenyl)methanone (44, 1.12 g, 4.58 mmol) in acetic acid (4.67 mL) was added pyridinium tribromide (3.67 g, 11.5 mmol). The reaction mixture was heated to 50° C. for 3 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (100 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography (Biotage) to provide (5-bromo-3-methylthiophen-2-yl)(4-propylphenyl)methanone (45, 0.95 g, 2.95 mmol, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:14]=1[CH:15]=[O:16]>>[CH3:12][C:13]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:14]=1[CH:15]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=1[C:8]([F:9])([F:10])[F:11])[OH:16]
Reactant: Cc1cc2c(cc1C=O)OCO2
Reactant: FC(F)(F)c1ccnc(Cl)c1
Product: Cc1cc2c(cc1C(O)c1c(C(F)(F)F)ccnc1Cl)OCO2
Yield: 74.1 %

Procedure:
Using 1.5 g (8.3 mmol) of 2-chloro-4-trifluoromethylpyridine and 1.4 g (8.2 mmol) of 2-methyl-4,5-(methylenedioxy)benzaldehyde, 2.1 g (yield 73%) of (2-methyl-4,5-(methylenedioxy)phenyl)(2-chloro-4-trifluoromethyl-3-pyridyl)methanol (m.p. 127-130° C.) was obtained by a process in accordance with step (a) of Synthesis Example 1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][C:7]2[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1.[CH3:19][N:20]([CH3:39])[C:21]1[CH:38]=[CH:37][C:24]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][C@H:29](OS(C)(=O)=O)[CH2:28]2)=[CH:23][CH:22]=1>CCCCCC.CS(C)=O>[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]([C@@H:30]3[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:24]4[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH3:39])=[CH:38][CH:37]=4)[CH2:31]3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1
Reactant: Fc1ccc2c(c1)COc1ccccc1N2
Reactant: CN(C)c1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CN(C)c1ccc(CCN2CC[C@@H](N3c4ccc(F)cc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (100 mg, 2.5 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (8 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 2-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (538 mg, 2.5 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 40 minutes. A solution of (S)-1-(4-dimethylaminophenethyl)-3-methanesulfonyloxypyrrolidine (312 mg, 1.0 mmol, prepared by a method disclosed in International Patent No. 0040570A1) in dimethyl sulfoxide (3 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 13 hours. The reaction mixture was poured into ice/water and then subjected to the extraction with ethyl acetate. The organic layer was dried and then the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) and then with hexane and ethyl acetate (1:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-2-fluoro-5,11-dihydro-5-[1-(4-dimethylaminophenethyl)pyrrolidin-3-yl]dibenzo-[b,e][1,4]oxazepine in the form of a light yellow oily substance (140 mg, 32%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:9][C:8](=[O:10])[O:7][C:5](=[O:6])[CH2:4]1.[Cl:13][C:14]1[C:20]([O:21][CH2:22][C:23]#[CH:24])=[CH:19][C:17]([NH2:18])=[C:16]([F:25])[CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[C:20]([O:21][CH2:22][C:23]#[CH:24])=[CH:19][C:17]([NH:18][C:8](=[O:10])[CH2:9][CH:3]([C:2]([F:1])([F:12])[F:11])[CH2:4][C:5]([OH:7])=[O:6])=[C:16]([F:25])[CH:15]=1
Reactant: O=C1CC(C(F)(F)F)CC(=O)O1
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Solvent: ClCCl
Product: C#CCOc1cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc1Cl

Procedure:
Into a 1 liter three-necked round-bottomed flask equipped with overhead stirrer, dropping funnel, thermometer and nitrogen (N2) inlet were placed 3-(trifluoromethyl)glutaric anhydride (18.2 g, 0.100 mol) and methylene chloride (CH2Cl2) (250 ml). The mixture was stirred to homogeneity and a solution of 4-chloro-2-fluoro-5-propargyloxyaniline (19.9 g, 0.100 mol) in CH2Cl2 (50 ml) was added dropwise over 10 minutes to give a clear solution. The mixture was stirred overnight at ambient temperature, during which time a thick white precipitate was formed.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:3][CH2:4][C:5]([O:7]C(C)(C)C)=[O:6].CO.[OH-].[Na+:22]>O1CCCC1>[OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+:22]
Reactant: Cc1ccccc1C(O)CCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of t-butyl 4-hydroxy-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, (0.5 g) in tetrahydrofuran (3 mL) and methanol (3 mL) is treated with aqueous sodium hydroxide solution (5 N; 0.5 mL) and stirred at ambient temperature for 8 hours. The reaction mixture is concentrated to dryness. The resulting residue is treated with isopropanol (10 mL) and stirred for 30 minutes, and the resulting precipitate is collected and washed with isopropyl ether, to give sodium 4-hydroxy-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, (300 mg) in the form of a white solid, m.p. above 250° C.; 25[α]D=+34° (c=0.01; CH3OH); [NMR(DMSO-d6) (300 MHz):- 1.58-1.75 (m,2H),2.11(m,2H),2.22(s,3H),4.75(m,1H),7.05-7.48 (m.4H).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[C:6](=[O:39])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][S:20]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[N:22]CC4C=CC(OC)=CC=4)=[O:21])=[O:18])=[CH:12][C:11]=3[CH3:38])[C:8](=[O:9])[C:4]=2[CH:3]=1.O.[N+]([O-])([O-])=O.[NH4+]>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[C:6](=[O:39])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][S:20]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[NH:22])=[O:21])=[O:18])=[CH:12][C:11]=3[CH3:38])[C:8](=[O:9])[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN=S(=O)(NC(=O)Nc2ccc(N3C(=O)c4ccc(Cl)cc4C3=O)c(C)c2)c2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(NC(=O)NS(=N)(=O)c2ccccc2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
To 10 mg (0.016 mmol) of {[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]-amino}-N-(N-p-methoxybenzylphenylsulfonimidoyl)carboxamide dissolved in 380 μL of CAN followed by 96 uL of water was added 70 mg (0.13 mmol) of cerric ammonium nitrate. After 20 m, the reaction was complete and purified by RP-HPLC to give 1.8 mg (23%) after lyophilization. ES-MS (M+H)+=469 (Cl).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: CC(C)c1noc(N2CCC(=O)CC2)n1
Reactant: NC1CC1
Product: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. Mass spectrum (ESI+): m/z=251 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.Cl.[CH3:11][O:12][NH2:13].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][NH:13][CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1
Reactant: CON
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONCc1cccnc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 18.1 %

Procedure:
In 200 ml of acetonitrile was suspended 6.6 g (0.04 mole) of 3-pyridylmethyl chloride hydrochloride, followed by addition of 10 g (0.12 mole) of O-methylhydroxylamine hydrochloride and 16.2 g (0.16 mole) of triethylamine. The mixture was stirred at 50° C. for 15 hours. The insoluble matter was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, using EtOH-CHCl3 (1:10) as an eluent. The procedure gave 1.0 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:7]=1[CH:8]=[O:9])(=[O:4])=[O:3].[BH4-].[Na+]>C1COCC1.C(O)C>[CH3:1][S:2]([O:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:7]=1[CH2:8][OH:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(CO)c1
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step A (17.13 g, 58.2 mmol) in 150 mL of 2:1 THF/ethanol at 0° C. was added sodium borohydride (2.27 g, 60.0 mmol). After 30 minutes, the reaction was carefully quenched by the addition oc saturated NH4Cl solution, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a yellow oil which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[C:17][C:18]3[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]=3[CH3:26])[CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[K+]>C(O)C.O>[CH3:26][C:19]1[CH2:20][CH2:21][CH2:22][C:23]([CH3:24])([CH3:25])[C:18]=1[C:17]#[C:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=[CH:14]2
Reactant: CCOC(=O)c1ccc2cc(C#CC3=C(C)CCCC3(C)C)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=C(C#Cc2ccc3cc(C(=O)O)ccc3c2)C(C)(C)CCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.130 g (0.38 mmol) of ethyl-6-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-ethynyl]2-naphthoate (Compound 2) in 0.7 ml of ethanol was added dropwise under nitrogen 0.9 ml of a 1.86M solution of KOH in ethanol and water. After being stirred at 50 degrees C. for 18 hours, solvent was removed in-vacuo and the residue treated with 1 ml of water and extracted with 1×3 ml portions of ether. The aqueous layer was then acidified with dilute HCl and extracted with 3×3 ml portions of ether. Combined ether extracts were dried (MgSO4) and concentrated in-vacuo to give the title product.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: Cc1ccnc(C(=O)c2ccc(F)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccnc(C(O)c2ccc(N)cc2)c1
Reaction time: 8 h
Yield: 113 %

Procedure:
2-(4-fluorobenzoyl)-4-methylpyridine (1.6 g) and sodium azide (2.4 g) were suspended in dimethylsulfoxide (15 ml) under nitrogen atmosphere 90° C., and the mixture was heated with stirring overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was dissolved in tetrahydrofuran (50 ml), and to the solution was added aluminum lithium hydride (0.66 g) under ice-cooling, and the mixture was stirred overnight at room temperature under nitrogen atmosphere. To the solution were added water (0.66 ml), 15% aqueous solution of sodium hydroxide (0.66 ml) and water (1.98 ml) under ice-cooling, the mixture was stirred and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was distilled off, to give (4-aminophenyl)(4-methylpyridin-2-yl)methanol (1.8 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)O)c(OC)c4)C3)nc3scnc23)cc1OC
Temperature: 35 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-methoxybenzoate (126 mg, 0.22 mmol) in dioxane/H2O (8 mL/8 mL) was added NaOH (75 mg, 1.9 mmol), the reaction mixture was heated to 35° C. with stirring for 1 hour, the dioxane was removed in vacuo, and the aqueous layer was adjusted to pH=4-5 with conc. HCl, the precipitate was collected by filtration and washed with methanol (5 mL) to afford 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-methoxybenzoic acid (68 mg, 54.8%) as a off-white solid. 1H NMR (300 MHz, DMSO): δ 10.23 (s, 1H), 9.63 (s, 1H), 8.83 (s, 1H), 7.63 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.46 (s, 1H), 7.33 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 7.14 (dd, 1H, J1=8.4 Hz, J2=1.5 Hz), 6.80-6.78 (m, 1H), 4.79 (d, 1H, J=11.7 Hz), 4.65 (d, 1H, J=12.6 Hz), 3.68-3.61 (m, 9H), 3.10-2.89 (m, 2H), 2.58-2.54 (m, 1H), 2.03-1.99 (m, 1H), 1.78-1.71 (m, 2H), 1.48-1.44 (m, 1H). LC-MS: 585 [M+H]+, tR=1.48 min. HPLC: 96.06% at 214 nm, 97.26% at 254 nm, tR=5.66 min.