Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.[OH-].[K+]>CN1C(=O)CCC1.O.[Cu]>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:2]1[CH:1]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:11])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccc(O)cc4c3)c2cc1OC
Temperature: 150 °C

Procedure:
To a solution of naphthalene-2,7-diol (8.95 g, 55.88 mmol) in NMP (50 mL) in a sealed tube, was added 4-chloro-6,7-dimethoxyquinoline (5.0 g, 22.35 mmol). KOH (1.40 g, 24.58 mmol) was added, followed by copper powder (0.71 g, 11.18 mmol). The tube was sealed and the solution was stirred and heated to 150° C. for 24 h. The reaction was cooled to RT, diluted with water and extracted with EtOAc 3×. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography with 50% to 100% (95:5:0.5 EtOAc/MeOH/NH4OH) in Hexanes to give the titled compound. MS (ESI, pos. ion) m/z: 348.2 (M+1).
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11]C)=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6].Br>C(O)(=O)C>[OH:2][C:3]1[C:10]([OH:11])=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc([N+](=O)[O-])cc(C=O)c1OC
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1cc([N+](=O)[O-])cc(O)c1O
Reaction time: 7 h

Procedure:
10.0 g of 2,3-dimethoxy-5-nitrobenzaldehyde are treated with 50 ml of glacial acetic acid and 50 ml of constant-boiling hydrobromic acid and held at the reflux temperature for 7 hours. After treatment with ice the separated precipitate is filtered under suction, washed with water and taken up in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is filtered over silica gel with ethyl acetate. After crystallization from ethyl acetate/hexane there is obtained 2,3-dihydroxy-5-nitro- benzaldehyde in the form of brownish crystals of m.p. 226°-228°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][OH:33])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.O>N1C=CC=CC=1>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:33][CH2:32][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(-c2nnc3n2CCCC3(COS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of {8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (178 mg) in pyridine (3 mL) was added 4-methylbenzenesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 4 hr. 4-Methylbenzenesulfonyl chloride (84 mg) was further added, and the mixture was stirred at room temperature for 2 hr, and at 50° C. overnight. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (163 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC1CCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Yield: 66.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.5 g.), 2 N aqueous solution of sodium hydroxide (11.8 ml.), methanol (11.8 ml.) and tetrahydrofuran (11.8 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 2.1 g.), mp. 148° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]=[C:6]2[CH3:16].[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[N:8]([CH3:20])[CH:7]=[C:6]2[CH3:16]
Reactant: CI
Reactant: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C)cn(C)c2cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
A solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (900 mg, 4 mmol) in 7 ml DMF was cooled to zero degrees C., and sodium hydride (104 mg, 4 mmol, 95% powder) was added. The reaction mixture was stirred 15 minutes at zero degrees C., and then iodomethane (270 ul, 4 mmol) was added. The reaction mixture was stirred for 1 hour and allowed to warm to room temperature. The reaction mixture was then cooled to 0° C., quenched by addition of 1 N N4Cl, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-Methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg, 75%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=[CH:5][N:4]=1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:9]([C:8]1[C:3]([CH2:2][N:30]([CH2:29][C:27]2[CH:26]=[CH:25][C:24]3[O:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=2)=[N:4][CH:5]=[N:6][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCOc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Reactant: CCCCc1c(CBr)ncnc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCc1c(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCCO3)ncnc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromomethyl-5-butyl-6-phenyl-pyrimidine (86 mg), (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (93 mg, 0.310 mmol), and K2CO3 (195 mg, 1.4 mmol) in CH3CN (2.0 mL) is stirred at reflux for 1 h and at room temperature for 16 hours. The reaction mixture is then diluted with CH2Cl2 and filtered. The filtrate is concentrated, and the residue purified by preparative TLC, developing with 2:1 hexanes-EtOAc (+0.5% Et3N). The band containing product affords pure (5-butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine. 1H NMR (CDCl3, 300 MHz) δ 8.98 (s, 1H), 7.42 (m, 5H), 7.19 (t, J=8.0 Hz, 1H), 6.92–6.73 (m, 6H), 4.22 (s, 4H), 4.01 (q, J=6.9 Hz, 2H), 3.76 (s, 2H), 3.60 (s, 2H), 3.54 (s, 2H), 2.70–2.64 (m, 2H), 1.41 (t, J=6.9 Hz, 3H), 1.09–0.99 (m, 2H), 0.91 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z 524 [M+1].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[CH:3]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCOc1cc(Cl)ncn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(OCCO)ncn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 28.9 %

Procedure:
To a solution of 2-(6-chloropyrimidin-4-yloxy)ethanol (5.61 g) in dimethylformamide (60 ml) is added sodium azide (4.18 g), and the mixture is stirred at 70° C. for 20 hours. After cooling, the reaction solution is treated with water, and extracted with ethyl acetate. The ethyl acetate layer is dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate=1:1) to give 2-(6-azidopyrimidin-4-yloxy)ethanol (1.68 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:15][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CCCC[C@H](N)c1cccc(C(C)C)c1
Product: CCCC[C@H](NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1)c1cccc(C(C)C)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-isopropylphenyl)pentan-1-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 587 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=1[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:14][C:13]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=1[Cl:11]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C=Nc2ccc(Cl)cc2Cl)c(C)c1

Procedure:
A mixture of 26.8 g. of 2,4-dimethylbenzaldehyde, 32.4 g. of 2,4-dichloroaniline, 0.20 g. of p-toluenesulfonic acid, and 150 ml of toluene is stirred under reflux using a Dean-Stark moisture trap. Evaporation of the mixture affords a solid which is recrystallized from ethanol to yield N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, mp 102°-106°.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[CH:8]12[CH2:14][CH:11]([CH:12]=[CH:13]1)[CH2:10][CH:9]2[CH:15]=[O:16].O1CCCC1.Cl>[Zn].CCCCCC>[OH:16][CH:15]([CH:9]1[CH2:10][CH:11]2[CH2:14][CH:8]1[CH:13]=[CH:12]2)[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4]
Reactant: O=C1OCCC1Br
Reactant: O=CC1CC2C=CC1C2
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OCCC1C(O)C1CC2C=CC1C2
Yield: 71.2 %

Procedure:
Addition reaction was carried out by mixing 98 g of zinc powder, 247 g of α-bromo-γ-butyrolactone, 122 g of 5-norbornene-2-carbaldehyde, and 2 kg of dry tetrahydrofuran and heating the mixture under reflux for 10 hours in a nitrogen atmosphere. The reaction mixture was cooled, to which dilute hydrochloric acid was added for neutralization and hexane was added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by silica gel column chromatography yielded 148 g (yield 71%) of α-[hydroxy(5-norbornen-2-yl)methyl]-γ-butyrolactone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[NH2:21][C@H:22]([CH3:25])[CH2:23][OH:24]>>[NH2:21][C@H:22]([CH3:25])[CH2:23][O:24][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:20])=[C:2]([Cl:1])[CH:7]=1)=[N:10][CH:11]=[N:12]2
Reactant: C[C@@H](N)CO
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Product: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) and (2R)-2-aminopropan-1-ol to give 4-[(5-{[(2R)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol in 100% yield; NMR spectrum (DMSO-d6) 1.16 (d, 3H), 3.29-3.44 (m, 1H), 3.98 (dd, 1H), 4.22 (dd, 1H), 6.96 (d, 1H), 7.09 (d, 1H), 7.30 (d, 1H), 7.58 (dd, 1H), 7.69 (t, 1H), 8.10 (d, 1H), 8.47 (s, 1H) (4 exchangeables); Mass spectrum MH+ 344.9.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:28])[C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[CH:16][C:15]=2[O:22][C@@H:23]([CH3:27])[C:24]#[C:25][CH3:26])[C@H:8]([O:29][CH3:30])[CH2:7]1)=O)C.[OH-].[K+].O>CC(O)C>[CH3:30][O:29][C@H:8]1[C@@H:9]([NH:12][C:13](=[O:28])[C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[CH:16][C:15]=2[O:22][C@@H:23]([CH3:27])[C:24]#[C:25][CH3:26])[CH2:10][CH2:11][NH:6][CH2:7]1
Reactant: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(C(=O)OCC)C[C@H]1OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Yield: 16.3 %

Procedure:
2.50 g of the cis-N-(1-ethoxycarbonyl-3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide prepared in the Example 7 and 4.5 g of potassium hydroxide were dissolved in 2-propanol. The obtained solution was refluxed for 1.5 hours and cooled, followed by the addition thereto of water. The resulting mixture was extracted with 10% 2-propanol/chloroform thrice. The combined organic phases were dried over magnesium sulfate and freed from the solvent. The residue was purified by silica gel column chromatography (5 to 12% methanol/dichloromethane) to give 0.34 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:31]=[CH:30][C:17]([CH2:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.NN>CO.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH2:19])=[CH:30][CH:31]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: NN
Solvent: CO
Solvent: COC(C)(C)C
Product: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 41.1 %

Procedure:
A solution of 2-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-1H-isoindole-1,3(2H)-dione (0.65 g) and aqueous hydrazine solution (0.07 g) in methanol (5 mL) was refluxed for one hour. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}methanamine (0.2 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>C1COCC1>[F:41][C:40]([F:43])([F:42])[CH2:39][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: O=c1[nH]c(-c2ccc(N3CCNCC3)cc2)nc2ccccc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(N3CCN(CC(F)(F)F)CC3)cc2)nc2ccccc12
Yield: 93.5 %

Procedure:
To a mixture of 2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.325 g, 1.06 mmol) in THF (50 mL) was added Hünig's base (0.192 g, 1.48 mmol), followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.295 g, 1.3 mmol). The reaction mixture was heated at reflux for 15 hours, concentrated, and purified by flash chromatography on silica gel, eluting with 100% CH2Cl2 to 100% ethyl acetate, to afford the title compound as an off-white solid (0.385 g, 94%). 1H NMR (300 MHz, DMSO-d6): δ 12.27 (br s, 1H), 8.10-8.14 (m, 3H), 7.76-7.82 (m, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.42-7.47 (m, 1H), 7.05 (d, J=9.1 Hz, 2H), 3.21-3.34 (m, 6H), 2.73-2.78 (m, 4H). APCI MS m/z 389 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].[ClH:15]>CO.[Pd]>[ClH:15].[NH2:11][CH2:10][C:9]1[CH:8]=[C:7]([N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccc(N2CCNC2=O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccc(N2CCNC2=O)c1

Procedure:
40.00 g (210 mmol) 3-(2-oxo-imidazolidin-1-yl)-benzonitrile are suspended in 1500 ml of methanol, 53 ml 37% hydrochloric acid are added. The mixture is hydrogenated for 20 hours at ambient temperature under a pressure of 7 bar with 4.00 g palladium/charcoal. The catalyst is filtered off, the filtrate is concentrated and the precipitate formed is suction filtered, washed with acetone and dried.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)[CH2:3][CH2:2]1.[F:29][C:30]1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:2]=[CH:3][C:1]([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Reactant: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Product: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(Cc3ccc(F)cc3)c2=O)CC1
Yield: 54.8 %

Procedure:
The general procedure of Example 1 (6) was repeated by use of 2-(4-fluorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as a pale yellow powder (yield: 54.8%).
Reaction SMILES: [OH:1]O.[N+:3]1([O-:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:7]=2[N:6]=[C:5]([NH2:16])[N:4]=1)[CH2:13][CH2:12][CH2:11]3.N>CC(O)=O>[N+:3]1([O-:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:7]=2[N+:6]([O-:1])=[C:5]([NH2:16])[N:4]=1)[CH2:13][CH2:12][CH2:11]3
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: OO
Agent: N
Solvent: CC(=O)O
Product: Nc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 50 °C
Reaction time: 96 h
Yield: 14.7 %

Procedure:
H2O2 (70%, 5.0 mL, ca. 99.4 mmol) was added dropwise to a stirred solution of 1-oxide 19 (2.0 g, 9.9 mmol) in HOAc (30 mL) and the solution was stirred at 50° C. for 96 h. The mixture was cooled to 0° C., neutralised with dilute aqueous NH3 solution and the mixture stirred vigorously for 30 min, then extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 20 (317 mg, 15%) as a red solid: mp (MeOH/EtOAc) 190-195° C.; 1H NMR [(CD3)2SO] δ 8.01 (s, 1H, H-9), 7.98 (s, 1H, H-5), 7.87 (br s, 2H, NH2), 3.07 (br t, J=7.4 Hz, 2H, H-6), 3.01 (br t, J=7.4 Hz, 2H, H-8), 2.10 (p, J=7.4 Hz, 2H, H-7); 13C NMR [(CD3)2SO] δ 154.3, 150.8, 144.7, 137.8, 129.6, 115.1, 111.2, 32.6, 31.7, 25.1. Anal. calcd for C10H10N4O2.½CH3OH: C, 53.8; H, 5.2; N, 23.9. Found: C, 53.6; H, 5.2; N, 23.9%.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([CH2:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)([OH:7])[CH2:4][C:5]#[CH:6].[C:26]([C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31](OS(C(F)(F)F)(=O)=O)=[C:30]([CH3:45])[CH:29]=1)#[N:27].C(N(CC)CC)C>C1COCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:45][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]=1[C:6]#[C:5][CH2:4][C:3]([OH:7])([CH2:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)[C:2]([F:1])([F:24])[F:25])[C:26]#[N:27]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
A mixture of 330 mg (0.88 mmol) of 1,1,1-trifluoro-2-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-4-yn-2-ol, 270 mg (0.88 mmol) of trifluoromethanesulfonic acid 4-cyano-2-methyl-6-nitrophenyl ester, 310 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) dichloride, 17 mg (0.09 mmol) of copper (I) iodide, and 0.25 mL of anhydrous triethylamine in 2 mL of THF was warmed at 60° C. in a sealed tube in the microwave. After 20 minutes, the mixture was adsorbed onto CELITE® filter aid and chromatographed on silica gel eluting with ethyl acetate-hexanes (gradient: 0-30% EtOAc) to afford 205 mg (44%) of 3-methyl-5-nitro-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile as a brown oil.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:25]=[CH:24][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].ClC(OCC)=O.O[C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1>ClCCl>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]([O:23][C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=2)=[O:22])=[O:18])=[CH:24][CH:25]=1)([O-:10])=[O:9]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Oc1ccc(C(=O)O)cc1
Reaction time: 0.33 h

Procedure:
Triethylamine (4 ml) was added to a suspension of N-(4-nitrobenzyloxycarbonyl)glycine (7.25 g) in dry dichloromethane at -20° C. Ethyl chloroformate (2.75 ml) was added to the resultant solution and the mixture stirred at -20° to -10° C. for 20 mins. A solution of 4-hydroxybenzoic acid (3.94 g) and triethylamine (4 ml) in dichloromethane (50 ml) was added dropwise, and stirring continued for 2.5 h after addition. The mixture was filtered, the filtrate washed with 10% aqueous citric acid (20 ml), water (20 ml), and brine (20 ml), and dried (MgSO4). Evaporation under reduced pressure afforded the crude product, 4-[N-(4-nitrobenzyloxycarbonyl)glycyloxy]benzoic acid as a pale yellow foam. Without further purification, 4-[N-(4-nitrobenzyloxycarbonyl)glycyloxy]benzoic acid was treated with chloromethylchlorosulphate (5.77 g) under the conditions described in Example 55b. After work-up and chromatography as described therein, the title compound was obtained as a white crystalline solid (1.81 g), m.p. 119°-120° C. (ethylacetate/hexane); νmax (CH2Cl2) 3450, 1780, 1740, 1610, and 1520 cm-1 ; δH (CDCl3) 4.33 (2H, d, J 6 Hz), 5.33 (2H, s), 5.72 (1H, br t, J 6 Hz), 6.03 (2H, s), 7.23-7.70 (4H, m), and 8.18-8.40 (4H, m).