Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=1.Cl>CO.O>[CH3:24][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22])[O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2ccc(C(=O)O)cc2)ccc1[N+](=O)[O-]
Temperature: 125 °C
Yield: 22.3 %

Procedure:
4-hydroxybenzoic acid (13.8 g, 0.1 mole) was dissolved in methanol and to this solution was added, sodium methoxide (10.8 g, 0.2 mole). The solution was then evaporated to dryness. To the resulting solid was added DMF (500 mL) followed by 4-fluoro-2-methyl-1-nitrobenzene (available from Aldrich under 5-fluoro-2-nitro-toluene) (10.2 mL 0.1 mole). The mixture was heated at 125° C. for 2 hours, cooled and poured into 3 L of water, acidified to pH2 with 2M HCl and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried and evaporated to dryness. The resulting solid was triturated with ether to give 4-(3-methyl-4-nitro-phenoxy)-benzoic acid (compound 1) as a white solid 6.1 g (22% yield; melting point=187-190° C.).
Reaction SMILES: [O:1]1[CH2:6][C@@:2]1([C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].Cl.[Cl-].[Na+]>ClCCl.CO>[F:8][C:7]([F:10])([F:9])[C@:2]([OH:1])([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@]1(C(F)(F)F)CO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@](O)(C(=O)O)C(F)(F)F
Temperature: -80 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Into a 500 ml three-necked round-bottomed flask equipped with a stirrer, a 1.0 M aluminum diisobutyl hydride/hexane solution (2400 ml, 2.40 mol) was charged in a nitrogen atmosphere. This solution was cooled to −80° C. A dichloromethane (600 g) solution of (S)-2,3-epoxy-2-trifluoromethylpropionic acid (149.82 g, 0.96 mol) was added over a period of two hours from a dropping funnel. After stirring at −70° C. for one hour, stirring was carried out at −50° C. for 6 hours. The reaction solution was cooled to −80° C., and a mixed solution of methanol (100 g) and dichloromethane (100 g) was dropwise added over a period of two hours to terminate the reaction. The reaction solution was dropwise added over a period of two hours to 1800 ml of a 18% HCl aqueous solution cooled to 0° C., and then, 160 g of sodium chloride was added. The mixture was extracted twice with 500 ml of diethyl ether, and the solvent was distilled off to obtain (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (98.6 g) (yield: 65%). This was recrystallized twice from toluene (400 ml) to obtain (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (51.6 g) having an optical purity of 99.9 ee % (yield: 34%). This product shows the same 1H and 13C-NMR and IR spectrum data as the already reported (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid and therefore was determined to be (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3]>Cl.O1CCOCC1>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCC(CC2CCNCC2)CC1
Yield: 84 %

Procedure:
1,1-Dimethylethyl 4-{[1-(1-methylethyl)-4-piperidinyl]methyl}-1-piperidinecarboxylate (may be prepared as described in Description 3) (3.1 g) was stirred in a solution of HCl-Dioxane (100 ml, 4M) for 2.5 h. The solvent was evaporated and the resultant yellow solid was dissolved in saturated potassium carbonate (25 ml). The solution was extracted into dichloromethane (3×50 ml) and the combined organics dried (MgSO4) and evaporated to give the title compound (D4) as a pale yellow oil (1.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22]#[N:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1.[ClH:30].[CH2:31]([OH:33])[CH3:32]>>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22](=[NH:23])[O:33][CH2:31][CH3:32])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCC#N)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)CCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanenitrile (0.041 g, 0.090 mmol, Example 14, Step C) in ethanol (0.5 mL) was added 9.8 M ethanolic HCl (0.5 mL, 4.9 mmol). After stirring at 0° C. for 1 hour and then at ambient temp for 8 hours, the mixture was concentrated under reduced pressure to provide the product.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[F:27])[NH:20][CH:19]=2)=[O:17])[CH:11]([C:29]([O:31]CC)=[O:30])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[F:27])[NH:20][CH:19]=2)=[O:17])[CH:11]([C:29]([OH:31])=[O:30])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2cccc(F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1C(=O)O)c1c[nH]c2cccc(F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a stirred solution of N-(benzoyl)-3-ethoxycarbonyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (100 mg, 0.02 mmol) in methanol (1 ml) and water (1 ml), was added potassium carbonate (9 mg, 0.06 mmol). After stirring for 8 hours at room temperature, the product was concentrated in vacuo to give a residue which was purified by preparative HPLC to yield 2 mg of N-(benzoyl)-3-hydroxycarbonyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 101).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:40]([NH:48][NH2:49])(=[O:47])[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16](=[O:18])[NH:49][NH:48][C:40]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[O:47])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Reactant: NNC(=O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)NNC(=O)c2ccncc2)CC1
Reaction time: 18 h

Procedure:
A solution of 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1, 1.25 g, 4.82 mmol), ethyl-(3-dimethylaminopropyl)carbodiimide (924 mg, 4.82 mmol) and N-hydroxybenzotriazole (651 mg, 4.82 mmol) in anhydrous CH2Cl2 (30 ml) were stirred at rt for 10 min. Isonicotinic acid hydrazide (601 mg, 4.38 mmol) was added in one portion and stirring continued for a further 18 h. The reaction mixture was diluted with CH2Cl2 (150 ml) and washed with water (30 ml), saturated aqueous NaHCO3 (30 ml) and brine (30 ml). After drying (MgSO4) the solvent was removed to afford the title compound: RT=2.89 min; m/z (ES+)=379.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][P:21](=[O:25])([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:20][P:21]([CH3:24])(=[O:25])[CH2:22][CH2:23]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Reaction time: 4 h
Yield: 108.8 %

Procedure:
To a pressure vessel was added 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane 4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The vessel was connected to a Parr apparatus, evacuated, and refilled with nitrogen. The vessel was then evacuated and filled with hydrogen gas to a pressure of 50 psi. The reaction mixture was shaken under 50 psi for 4 h. The mixture was filtered through Celite to a flask containing HCl in ethanol. Concentration of the filtrate afforded the compound as a gray solid (178 mg, 98% yield).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[C:13]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1.I[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu]>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:8]1[C:13]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(-c2ccccc2Nc2cccc3c2oc2ccccc23)cc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Product: COc1ccc(N(c2ccccc2-c2ccccc2)c2cccc3c2oc2ccccc23)cc1
Yield: 83 %

Procedure:
N-([1,1′-biphenyl]-2-yl)dibenzo[b,d]furan-4-amine (9.0 g, 27.0 mmol), 4-iodoanisole (23.4 g, 100.0 mmol), potassium carbonate (13.8 g, 100.0 mmol), copper powder (1.7 g, 27.0 mmol), and 18-crown-6 ether (7.1 g, 27.0 mmol) were mixed. The resultant mixture was bubbled with nitrogen for 30 min. The mixture was then refluxed for 48 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography using 25% DCM/hexane (containing 0.5% triethylamine) to yield N-([1,1′-biphenyl]-2-yl)-N-(4-methoxyphenyl)dibenzo[b,d]furan-4-amine (9.9 g, 83% yield) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].S(=O)(=O)(O)O.[Cl:16][C:17]1C(O)=C[CH:20]=[CH:19][C:18]=1[OH:24]>O>[Cl:16][C:17]1[C:18]([OH:24])=[CH:19][CH:20]=[C:9]2[C:8]=1[O:7][C:5](=[O:6])[CH:4]=[C:3]2[CH2:2][Cl:1]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1cccc(O)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(CCl)c2ccc(O)c(Cl)c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-chloro-3-oxobutanoate (4.91 mL) was added sulfuric acid (12.91 mL) at 0° C., then was added 2-chlorobenzene-1,3-diol (5.0 g) in several portions at 0° C. The mixture was warmed to room temperature and stirred at the same temperature for 2 h. The reaction mixture was poured into water under stirring at 0° C. The precipitate was collected by m filtration and washed with hexane to give the title compound (2.78 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43]Cl)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]2)[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1cc(OCc2ccccc2)c2ccccc2c1
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2O)c1
Product: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OCc3ccccc3)c3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate with 1-benzyloxy-3-chloromethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate as a pale yellow amorphous powder; MS: 582 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.[CH3:26]I>>[CH3:26][N:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=2)=[CH:8][CH:9]=1)[NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)OC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CI
Product: CC(C)OC(=O)NN(C)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
The product (0.4 g) of Step 4 of Example 1 was heated in methyl iodide (5 mL) at reflux for 1 day and then concentrated under reduced pressure to give a red oil (0.5 g).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1.[I-].[Na+].Cl[CH2:45][CH2:46][CH2:47][O:48][C:49]1[CH:58]=[CH:57][CH:56]=[CH:55][C:50]=1[C:51]([O:53][CH3:54])=[O:52]>C(#N)C>[CH3:54][O:53][C:51]([C:50]1[CH:55]=[CH:56][CH:57]=[CH:58][C:49]=1[O:48][CH2:47][CH2:46][CH2:45][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)=[O:11])[CH2:7][CH2:8]1)=[O:52]
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: COC(=O)c1ccccc1OCCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCCN1CCC(NC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Yield: 76.8 %

Procedure:
To a solution of 0.80 g (2.14 mmol.) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride, 1.5 ml (10.76 mmol.) of triethylamine and 0.65 g (4.27 mmol.) of 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) in acetonitrile (20 ml) were added, at room temperature, 0.38 g of sodium iodide and 0.59 g (2.58 mmol.) of methyl 2-(3-chloro-1-propoxy)benzoate. The mixture was heated under reflux for 3 days under nitrogen atmosphere. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by concentration. The concentrate was purified by means of a column chromatography (methanol/ethyl acetate 30-50%), followed by distilling off the solvent under reduced pressure to afford the object compound (0.81 g, 77%) as a reddish amorphous product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][C:41]=1[F:42])[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([OH:38])=[CH:24][C:25]=2[O:27][CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:37])[CH2:35][OH:36])[N:20]=[CH:19][N:18]=1.O>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][C:41]=1[F:42])[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:38][CH2:4][CH2:3][O:2][CH3:1])=[CH:24][C:25]=2[O:27][CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:37])[CH2:35][OH:36])[N:20]=[CH:19][N:18]=1
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 40 °C
Yield: 64 %

Procedure:
2-Bromoethyl methyl ether (22 μl) and potassium carbonate (43 mg) were added to a mixture of 4-[3-chloro-4-fluoroanilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]-methoxy}-quinazolin-7-ol (70 mg) in DMF and the reaction mixture was heated at 40° C. for 16 hours. The reaction mixture was cooled to room temperature and then water (5 ml) was added to leave a white precipitate. The precipitate was filtered, washed with water and then purified by column chromatography using 2-5% methanol in DCM as eluent to give the title compound as a white solid (51 mg, 64%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (t, 2H), 3.50-3.37 (m, 2H), 3.35 (s, 3H), 2.10-1.85 (m, 4H); Mass spectrum MH+ 505.
Reaction SMILES: O=O.[NH3:3].O.[NH3:5].[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13]>>[CH:10]1[CH:11]=[C:12]([C:13]#[N:3])[C:7]([C:6]#[N:5])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1C
Reactant: N
Agent: O=O
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 470 °C

Procedure:
750 ml of a catalyst having a particle size of from 0.05 to 0.3 mm are introduced into a quartz reactor which has a diameter of 60 mm and a length of 1000 mm and is provided with an external heater and a quartz frit for uniformly distributing the reaction gas. The catalyst is composed of 5.0% by weight of V2O5, 5.9% by weight of Sb2O3 0.24% by weight of K2O, 0.56% by weight of BaO and 88.3% by weight of γ-Al2O3. The reactor is heated to 470° C. and a gas mixture consisting of 3.25% by volume of o-xylene, 13% by volume of oxygen and 83.75% by volume of ammonia is passed through. The hot reaction gases are cooled to 70° C. with ammonia water in two wash towers arranged in series. An aqueous suspension of crystals is formed, from which the o-phthalodinitrile is isolated by filtration. 2,687 parts of o-xylene give 2,581 parts of o-phthalodinitrile and 195 parts of o-tolunitrile. By reacting the 195 parts of o-tolunitrile again with ammonia and oxygen, a further 170 parts of o-phthalodinitrile are obtained. The total yield of o-phthalodinitrile is 84.8 mol %, based on converted o-xylene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(F)ccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 35.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,5-difluorophenylboronic acid (Aldrich; 529 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,5-difluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (305 mg, 35%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:9]21[CH2:13]CC[CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(N)(C)CN.CC(C)(O)C#N>>[CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:9]1([CH3:13])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Agent: CC(C)(N)CN
Agent: CC(C)(O)C#N
Product: CC1(C)CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-2,2,5,5-tetramethyl-piperazine was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 2-methyl-propane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13](Cl)(=[O:15])[CH3:14].C(N(CC)CC)C>ClC(Cl)C>[C:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1csc(NC(C)=O)n1

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)acetate was reacted with acetyl chloride in dichloroethane in the presence of triethylamine, and then the reaction mixture was worked up and purified in a usual manner to obtain ethyl 2-(2-acetylaminothiazol-4-yl)acetate as a colorless solid. MS: 229.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[O:11]([CH2:18][CH2:19]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:19][CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6]
Reactant: OCCOc1ccccc1
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: O=C(OCCOc1ccccc1)c1cccc(O)c1
Temperature: 95 °C

Procedure:
Into a 250 mL round bottom flask equipped with magnetic stirrer and heating mantle was added 16.0 parts of 3-hydroxy benzoic acid, 100 parts of 2-phenoxyethanol and 0.5 parts of concentrated sulfuric acid. The reaction mixture was heated at 95° C. for 48 hours. The excess of 2-phenoxyethanol was evaporated under reduced pressure at 90° C. The solid material was dissolved in 250 mL of ethyl acetate. The organic layer was first washed with 200 mL of water, second with 250 mL of 5% solution of sodium bicarbonate in water and finally washed with 3×250 mL of water. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. This material was purified by chromatography on silica gel using 20% ethyl acetate/hexane. The desired fractions were combined and solvent was evaporated to give an oily material which on treatment with hexane gave a solid, yield 5.1 parts. TLC on silica gel plate showed single spot. The structure of the product was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O.O>[O:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CNc2ccccc2O1
Yield: 23.6 %

Procedure:
Ethyl 2,3-dibromopropionate (24 g, 92 mmol) was added dropwise to a refluxing solution of o-aminophenol (10 g, 92 mmol) and potassium carbonate (15 g, 110 mmol) in acetone (100 ml). After 18 h the mixture was cooled and reduced. Ethyl acetate and water were added and the mixture separated. The organic phase was washed with brine, filtered and reduced. Chromatography (30% EtOAc/70% 60-80 petroleum ether) afforded ethyl benzomorpholine-2-carboxylate (4.5 g, 24%) as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:21])[C:19]=2[OH:20])[CH2:16][CH2:15][O:14][C:13]23[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([O:30]C)=O)[CH2:23][CH2:22]2)=[O:9])=[C:4]([N:35]2[C:39]([CH3:40])=[N:38][CH:37]=[N:36]2)[CH:3]=1.[NH:41]([CH3:43])[CH3:42]>>[CH3:42][N:41]([CH3:43])[C:28](=[O:30])[C:27]([N:24]1[CH2:25][CH2:26][C:13]2([C:12]3=[N:11][C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][C:4]=4[N:35]4[C:39]([CH3:40])=[N:38][CH:37]=[N:36]4)=[O:9])=[C:19]([OH:20])[C:18](=[O:21])[N:17]3[CH2:16][CH2:15][O:14]2)[CH2:22][CH2:23]1)=[O:32]
Reactant: CNC
Reactant: COC(=O)C(=O)N1CCC2(CC1)OCCn1c2nc(C(=O)NCc2ccc(F)cc2-n2ncnc2C)c(O)c1=O
Product: Cc1ncnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCOC21CCN(C(=O)C(=O)N(C)C)CC1
Yield: 36 %

Procedure:
A solution of Example 26 and 2M Me2NH/MeoH (2 mL, 4 mmol) was stirred for 18 h. at room temperature. Concentration gave an oil that was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to give the title compound as white solid (0.227 g, 36%). 1H NMR (300 MHz, CDCl3) δ: 8.61 (1H, s), 8.34 (1H, t, J=5.3 Hz), 7.69 (1H, dd, J=8.6, 5.7 Hz), 7.27 (1H, td, J=8.1, 2.3 Hz), 7.01 (1H, dd, J=8.0, 2.2 Hz), 4.48-4.41 (2H, m), (4.18 (1H, dd, J=14.4, 5.3 Hz), 4.02 (4H, s), 3.64-3.59 (1H, m), 3.48-3.40 (1H, m), 3.09-3.04 (1H, m), 3.03 (3H, s), 3.00 (3H, s), 2.54 (3H, s), 2.39-2.29 (1H, m), 2.21-2.10 (1H, m), 1.99-1.88 (1H, m). HRMS (M+H) calcd for C26H30FN8O6: 569.2272; found: 569.2272.