Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:21][CH2:22][CH:23](O)[CH2:24][C:25]([F:28])([F:27])[F:26])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]2[C:23]([CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:22][N:21]=[C:9]12)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=NCC(O)CC(F)(F)F)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)OC(C)(C)C)c2ncc(CC(F)(F)F)n21
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 20.8 %

Procedure:
To a solution of tert-butyl{(3S,5S,6R)-6-methyl-5-phenyl-2-[(4,4,4-trifluoro-2-hydroxybutyl)imino]piperidine-3-yl}carbamate (100 mg, 0.23 mmol) in acetonitrile (4.7 mL) was added pyridinium dichromate (440 mg, 1.17 mmol), and the mixture was stirred 45 min at 70° C. Pyridinium dichromate (440 mg, 1.17 mmol) was added, and the mixture was stirred 30 min at 70° C. The mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (19.6 mg). MS 410.3 (M+1)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13](=[O:29])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:27][OH:28].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:29])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH:27]=[O:28]
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
A solution of oxalyl chloride (0.15 mL, 1.76 mmol) in CH2Cl2 (1.0 mL) was added to a solution of DMSO (0.16 mL, 2.25 mmol) in CH2Cl2 (1.0 mL) at −78° C. After 15 min at −78° C., a solution of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid methyl ester (240 mg, 0.88 mmol) in CH2Cl2 (1.5 mL) was added via cannula After 20 min at −78° C., triethylamine (0.37 mL. 2.65 mmol) was added. After 20 min at −78° C., the mixture was allowed to warm to 0° C. After 30 min at 0° C., the reaction was allowed to warm to rt. After 45 min at rt, saturated aqueous NaHCO3 (15 mL) was added and the mixture was extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (40%→70% EtOAc/CH2Cl2, gradient) afforded 96 mg (40%) of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:28]1([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:32][CH2:31][C:30](=[O:33])[O:29]1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][N:14]([C:28]2([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:35])[CH2:32][CH2:31][C:30](=[O:33])[O:29]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Reactant: O=C1CCC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
In 4 ml of dichloromethane was dissolved 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added under ice-cooling 0.08 ml of diisopropyl ethylamine and 90 mg of the Compound (15) obtained in Example 15. The mixture was stirred for 15 minutes under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was washed with water, which was dried (Na2SO4), then the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 71 mg of the subject Compound (8) as colorless foamy product. The IR and NMR spectra of this product were in agreement with those of the Compound (8) obtained in Example 8.
Reaction SMILES: [NH2:1][C@H:2](C(N)=O)[CH2:3][C:4]1C=CC(O)=C[CH:5]=1.Cl.C([N:17]([CH2:20]C)[CH2:18][CH3:19])C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>ClCCl>[N:17]1[C:18]2[CH:19]=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH:20]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Yield: 193.1 %

Procedure:
To a 0° C. crude solution of compound 2 (4.1 g, 15.34 mmol), triethylamine (6.4 mL, 46.02 mmol) in dichloromethane (200 ml) was added pentafluorophenyl trifluoroacetate (6.35 mL, 36.82 mmol) via syringe over 3 mins. After 5 mins the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate=1:0, 50:1) to give compound 3 (3.5 g, 50% yield).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.CN(C=O)C.Cl[CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O>[OH:9][C:4]1[CH:3]=[C:2]([S:1][CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: Oc1cc(O)cc(S)c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(O)cc(O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-sulfanylbenzene-1,3-diol (12.2 g) and DMF (dry) (100 mL) was added methyl 4-chloroacetoacetate (10.0 mL) at room temperature, and the mixture was stirred at 70° C. for 4 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (15.1 g).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:12].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:7]1[C:8]2[C:3](=[C:2]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][N:6]=1
Reactant: OB(O)c1ccncc1
Reactant: CC1=NCCc2c(I)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1=NCCc2c1cccc2-c1ccncc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 5-iodo-1-methyl-3,4-dihydroisoquinoline (3.0 g, 11.1 mmol), pyridin-4-ylboronic acid (2.04 g, 16.6 mmol), Pd(PPh3)2Cl2 (3.88 g, 5.53 mmol) and Cs2CO3 (10.8 g, 33.2 mmol) in 1,4-dioxane (45 mL) was heated to reflux for 24 h. The mixture was allowed to cool to RT, and then filtered. The filter cake was washed with AcOEt, and the filtrate was then concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) to afford the title compound (1.82 g) as a grey solid. UPLC-MS: MS 223.0 (M+H+); UPLC rt 0.38 min.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.Cl>[Pd]>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: c1ccc2c3c([nH]c2c1)CCC3
Agent: [Pd]
Agent: Cl
Product: c1ccc2c(c1)NC1CCCC21
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A mixture of 1,2,3,4-tetrahydrocyclopenta[b]indole (11 mmol, 1.8 g), 5% Pd/C (0.5 g), and concentrated hydrochloric acid (1.2 mL) was hydrogenated at 45 psi on a Parr shaker. After 3 h, the mixture was removed from the shaker and filtered through Celite. The solid bed was washed with methanol. The filtrate was concentrated. The crude oil was dissolved in 1 N HCl and washed with ether. The aqueous phase was treated with 2.5 N NaOH to pH>10 and then extracted with chloroform. The combined chloroform extracts were dried over MgSO4, filtered and concentrated to give the crude indoline. The material was purified by flash column chromatography through silica gel (Biotage, elution with 10% ethyl acetate-hexanes) to give the known indoline (7.6 mmol, 1.2 g, 69%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.Cl.C([O-])(O)=O.[Na+].[C:25]1(=O)[CH2:30]CCC[CH2:26]1.[O-]S([O-])(=O)=O.[Mg+2].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CO>[CH3:16][C:15]1[NH:14][N:13]=[CH:12][C:11]=1[C:9]1[S:10][C:5]2[C:4](=[O:17])[NH:3][C:2]3([CH2:18][CH2:30][CH2:25][CH2:26][CH2:1]3)[NH:7][C:6]=2[CH:8]=1
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCCCC1)N2
Temperature: 50 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
A mixture of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.090 g, 0.343 mmol), 1 M HCl (1.2 mL, 1.2 mmol) and MeOH (4 mL) was stirred at 50° C. for 2 h. Then, the reaction mixture was poured into excess saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was mixed with cyclohexanone (2 mL, 19.3 mmol), MgSO4 (0.041 g, 0.343 mmol), PTSA (3.3 mg, 0.017 mmol) and DMF (2 mL). The mixture was stirred at 80° C. for 3 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained oil was purified again by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to give a yellow solid. This solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (42.8 mg, 41%) as a yellow solid:
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([N:23]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:24](=[O:26])[O-:25])[CH3:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[ClH:37]>CO>[ClH:37].[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([N:23]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:28])=[O:29])[C:24](=[O:25])[OH:26])[CH3:22])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CC(C)N(C(=O)[O-])S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CC(C)N(C(=O)O)S(=O)(=O)c2ccc(C)cc2)cc1
Yield: 90 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate (Example 7, 694 mg, 1.37 mmol) in methanol (4 ml) was added 10% HCl in methanol (2 ml) at room temperature. This mixture was concentrated, and treated with diethylether to afford 624 mg (90%) of the title compound as a slight yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH:5]12[CH2:14]C3C[CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.ON1C(=O)C2=CC=CC=C2C1=O.O=O>>[C:1]12([OH:4])[CH2:2][CH:11]3[CH2:13][CH:7]([CH2:6][CH:5]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: CC(=O)O
Reactant: C1C2CC3CC1CC(C2)C3
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Product: OC12CC3CC(CC(C3)C1)C2
Yield: 37 %

Procedure:
To 25 mmol of acetic acid were added 10 mmol of adamantane, 1 mmol of N-hydroxyphthalimide (NHPI) and a binary co-catalyst [0.03 mmol of acetylacetonatovanadium V(AA)3 and 0.02 mmol of actylacetonatomangan Mn(AA)3], and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 6 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, the adamantane was converted into 1-adamantanol (yield: 37%). 1,3-adamantanediol (yield: 35%). 1,3,5-adamantanetriol (yield: 5%), 1,3,5,7-adamantane-tetranol (yield: 4%) with the adamantane conversion of 100%. The spectrum data of the 1,3,5,7-adamantanetetranol was as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1)[S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)(=[O:33])=[O:32]
Reactant: COC(=O)CCCCCCNCc1ccc(-n2cccn2)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCN(Cc1ccc(-n2cccn2)cc1)S(=O)(=O)c1ccccn1

Procedure:
The title compound of Step B was prepared from 7-(4-pyrazol-1-yl-benzylamino)-heptanoic acid methyl ester, of Step A, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.06 (m, 1H), 8.80 (dd, 1H), 8.10 (m, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.65 (d, 2H), 7.48 (m, 1H), 7.36 (d, 2H), 6.46 (d, 1H), 4.38 (s, 2H), 3.62 (s, 3H), 3.14 (t, 2H), 2.21 (t, 2H), 1.48 (m, 2H), 1.36 (m, 2H), 1.25 (m, 4H); MS 457 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH2:22]([N:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH3:23]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][CH2:28][CH2:27][CH2:26][CH2:25][N:24]([CH2:30][CH3:31])[CH2:22][CH3:23]
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CCN(CC)CCCCN
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)CCCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-diethylbutane-1,4-diamine (36.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 26.0 mg, (26% yield) MS (ES+): 394.2, (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[Na+].[Na+]>>[F:16][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[CH:7]=1)[NH2:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(-c2cc(Oc3ccc(N)cc3F)ccn2)cn1
Yield: 33.4 %

Procedure:
Using a procedure analogous to Example A1, 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3 g, 11.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.4 g, 16.4 mmol), Na2CO3 (2.7 g, 25.2 mmol) and Pd(Ph3)4 (1.5 g, 0.1 eq) were combined to give 3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (1.1 g, 34% yield). 1H NMR (400 MHz, DMSO-d6): δ (8.31 (d, J=5.6 Hz, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.14 (s, 1H), 6.98 (m, 1H), 6.55-6.49 (m, 2H), 6.42 (d, J=7.2 Hz, 1H), 5.44 (s, 2H), 3.86 (s, 3H); MS (ESI) m/z: (M+H+): 285.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: COc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ncn2)cc1
Reaction time: 16 h

Procedure:
4-Chloro-6-(4-nitro-phenoxy)-pyrimidine (1 g, 3.97 mmol), p-anisidine (514 mg, 4.178 mmol), and diisopropylethylamine (0.715 mL, 4.178 mmol) dissolved in 2-propanol (27 mL) are stirred under reflux under Ar. After 16 h, p-anisidine (245 mg, 1.99 mmol) is added and the reaction mixture is stirred for additional 20 h. After cooling the reaction mixture down to rt, compound of Stage 47.2 precipitates as white crystals: M+H=339.1; 1H-NMR (400 MHz, DMSO-d6): 9.49 (s, 1H, NH-pyrimidinyl), 8.25 (s, 1H, pyrimidine), 8.23/7.40/6.90 (d/d/d/, 9.0 Hz, 2H/4H/2H, phenyl-oxolphenyl-OMe), 6.18 (s, 1H, pyrimidinyl), 3.72 (s, 3H, CH3—O); Rf (MeOH/CH2Cl2=1:9): 0.44; HPLC (System 1): 6.15 min.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[N:14]1([C:2]2[N:11]=[C:10]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: C1CCOC1
Product: Clc1ccc2nc(N3CCCCC3)nc(N3CCCCC3)c2c1

Procedure:
Four grams of 2,4,6-trichloroquinazoline was dissolved in 50 ml of tetrahydrofuran. The solution was cooled in an ice bath and 20 ml of piperidine was added with constant stirring. The reaction mixture was heated at reflux overnight and the solid which had precipitated was removed by filtration. The filtrate was evaporated to dryness and diluted with water. The oil which separated crystallized upon scratching. The solid was collected by filtration and recrystallized from ethanol to give 4.2 g of 2,4-bispiperidino-6-chloroquinazoline; m.p. 115°-118°. The following analytical data were obtained:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc(OCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(4-acetamidophenoxy)acetate (237 mg, 1 mmol) in EtOH (10 ml) was added 10% NaOH aqueous solution (10 mL) at 26° C. The mixture was stirred for 30 min and then concentrated. The residue was diluted with water (20 mL) and washed ethyl acetate (2×20 mL). The aqueous layer was then acidified with 2N HCL until pH 3 and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: C([O:8][CH2:9][C:10]([O:12][C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][C:16]([O:22][CH3:23])=[C:15]([O:24][CH3:25])[C:14]=1[O:26][CH3:27])=O)C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]1[O:12][C:13]2[C:14]([O:26][CH3:27])=[C:15]([O:24][CH3:25])[C:16]([O:22][CH3:23])=[CH:17][C:18]=2[N:19]=1
Reactant: COc1cc([N+](=O)[O-])c(OC(=O)COCc2ccccc2)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(CO)oc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(6′-Nitro-2′,3′,4′-trimethoxyphenyl) benzyloxyacetate (1.38 g) was dissolved in methanol (40 mL), 10% palladium on carbon was added to the solution, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in xylene (50 mL), p-toluenesulfonic acid monohydrate (350 mg) was added to the solution, and the mixture was stirred for 1 hour under reflux. After the reaction mixture was concentrated under reduced pressure, water was added to the residue to conduct extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (chloroform:methanol=10:1) to obtain the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([CH2:10][CH2:11][CH3:12])([O-:9])=[O:8].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[N+:7]([CH:10]([CH2:11][CH3:12])[CH:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:20])([O-:9])=[O:8]
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C(O)c1cccnc1)[N+](=O)[O-]
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of LiAlH4 (2M in THF) (0.93 mL, 1.87 mmol) in dry THF (80 mL) at 0° C., was slowly added 1-nitropropane (8.30 mL, 93 mmol) under argon. After 60 min, nicotinaldehyde (2.00 g, 18.7 mmol) was added in one portion. The mixture was stirred for 16 hours, while allowing the temperature to rise from 0° C. to room temperature. The reaction mixture was quenched by addition of 1 mL of 2M aqueous HCl, followed by addition of 4 grams of Na2SO4. The resulting suspension was stirred for 15 minutes and then filtered. The filtrate was concentrated. The residue was purified by column chromatography (40 g SiO2) using EtOAc in hexane from 0% to 100% in order to give the title compound as a white solid (2.6 g, 71%) as a mixture of diastereoisomers A and B. LC-MS: [M+H] 197.1; Rt 0.52 min; (LCMS method 1). A) 1H NMR (400 MHz, CHCl3-d): 8.70-8.60 (m, 2H), 7.80-7.74 (m, 1H), 7.42-7.32 (m, 1H), 5.28 (dd, 1H), 4.70-4.58 (m, 1H), 2.97 (d, 1H), 2.29-2.12 (m, 1H), 1.65-1.42 (m, 1H), 0.99 (t, 3H). B) 1H NMR (400 MHz, CHCl3-d): 8.70-8.60 (m, 2H), 7.80-7.74 (m, 1H), 7.42-7.32 (m, 1H), 5.15 (dd, 1H), 4.70-4.58 (m, 1H), 2.81 (d, 1H), 1.99-1.85 (m, 1H), 1.65-1.42 (m, 1H), 0.94 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23].[K+]>CO.Cl.O>[CH3:20][C:12]1[N:11]=[C:10]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22]([NH2:23])=[O:21])=[CH:3][CH:4]=2)[CH3:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: N#C[O-]
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc(N(C)c2ccc(NC(N)=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of (4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (48 mg, 0.18 mmol) in 250 uL of methanol and 750 uL of 1N HCl was added potassium cyanate (50 mg, 0.62 mmol) in 500 uL of water, and the mixture was stirred overnight at room temperature. The precipitated product was collected by filtration under vacuum, washed with 1 mL of cold water and dried to give the title compound (12.3 mg, 0.04 mmol, 22%). 1H NMR (DMSO): 8.75 (s, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 6.99-7.13 (m, 4H), 5.92 (s, 2H), 3.45 (s, 3H), 2.59 (s, 3H).