Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]1([OH:38])[C:35]2[CH:34]=[C:33]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([F:31])=[C:18]5[CH2:23][CH2:22][CH:21]([NH:24]C(=O)C(F)(F)F)[C:20]=4[C:19]=35)[C:8](=[O:36])[C:7]=2[CH2:6][O:5][C:4]1=[O:37])[CH3:2].[ClH:39]>>[ClH:39].[NH2:24][CH:21]1[C:20]2=[C:11]3[CH2:10][N:9]4[C:33](=[CH:34][C:35]5[C@:3]([CH2:1][CH3:2])([OH:38])[C:4](=[O:37])[O:5][CH2:6][C:7]=5[C:8]4=[O:36])[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([F:31])=[C:18]([C:19]=32)[CH2:23][CH2:22]1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(F)c3c1c2C(NC(=O)C(F)(F)F)CC3
Agent: Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(F)c3c1c2C(N)CC3

Procedure:
30 ml of 1 N hydrochloric acid was added to 95 mg of the compound prepared in (11) above, and the mixture was heated under reflux for 1 hour. The solvent was evaporated and 30 ml of water was added to remove insoluble substances by filtration. The filtrate was purified with HPLC (CAPCELL PAK C18) using a mixture of acetonitrile-water-1 N hydrochloric acid (20:80:1) to obtain 6.2 mg of Isomer A and 5.9 mg Isomer B of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:16][N:15]=[CH:14][CH:13]=1.CS(O[CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[CH:14][N:15]([CH2:22][CH2:23][NH2:24])[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccn[nH]1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccn(CCN)n1

Procedure:
The title compound was prepared from 5-(2-Methoxy-4-nitrophenyl)-1H-pyrazole (1.00 g) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (1.42 g) using the method of Example 37(c). Yield 0.24 g (as HCl-salt). 1H-NMR (400 MHz; d6-DMSO): δ 3.32 (t, 2H), 4.02 (s, 3H), 4.47 (t, 2H), 6.94 (d, 1H), 7.88-7.93 (m, 3H), 8.12 (br s, 2H), 8.22 (d, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[F-].[K+]>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Temperature: 220 °C
Yield: 53.6 %

Procedure:
A mixture of 2-fluoronitrobenzene (3.5 g, 24.8 mmol), 4-chlorobenzenamine (3.05 g, 24.0 mmol), K2CO3 (3.45 g, 25.0 mmol) and KF (1.5 g, 25.8 mmol) was heated at 220° C. for 28 min under microwave condition. The solid was dissolved in DCM (150 mL), washed with water (50 mL×3), dried over Na2SO4. The solvent was evaporated in vacuo, and then the mixture was purified by Combi-flash (PE:EA=20:1) to give N-(4-chlorophenyl)-2-nitrobenzenamine (3.2 g, 52%) as a scarlet solid. 1H NMR (300 MHz, CD3OD): δ 6.82-6.87 (m, 1H), 7.27-7.31 (m, 2H), 7.41-7.45 (m, 3H), 7.70-7.73 (m, 1H), 8.15-8.18 (m, 1H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f22) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:25]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:31][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-phenyloxyaniline as the starting materials.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:31])[CH:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][CH:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:7]([NH:6][OH:5])=[O:31])(=[O:19])=[O:18])=[CH:25][CH:24]=1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NOC(C)(C)C)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NO)c2ccc(O)cc2)cc1
Yield: 9 %

Procedure:
A 450 mg (1.007 mmol) portion of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide was stirred in neat TFA at room temperature for 72 h. TFA was removed in vacuo. The residue was chromatographed on preparative TLC, eluting with 1% HOAc and 10% MeOH in dichloromethane to provide 33.8 mg (9%) of 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-hydroxyphenyl)acetamide as a white solid. Electrospray Mass Spec 391.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:38][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:31][CH:32]=2)[N:23]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
17 mg (0.42 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 91 mg (0.42 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 127 mg (0.42 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 12 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 102 mg (50%) of the title compound as white powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[F:9][C:10]([F:35])([F:34])[C:11]1[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[N:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:27]([C:24]1[N:25]=[N:26][C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[C:10]([F:35])([F:34])[F:9])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1)=[O:28]
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: NCCc1cccs1
Product: O=C(NCCc1cccs1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 24, making variations only as required to use 2-thiophen-2-yl-ethylamine in place of 2,2-(dimethylcyclopropyl)methylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (40% yield). 1H NMR (300 MHz, CDCl3) δ 8.01, 7.73, 7.58, 7.34, 7.12, 6.98, 6.90, 6.84, 4.03, 3.89-3.55, 3.33, 3.12. 13C NMR (75 MHz, CDCl3) δ 167.6, 163.1, 160.0, 145.2, 141.1, 134.2, 132.4, 129.5, 127.2, 127.0, 126.9, 125.3, 123.9, 121.8, 112.5, 46.4, 44.6, 44.4, 41.3, 40.9, 30.9. MS (ES+) m/z 490.0 (MeI).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:12]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8](=[O:9])(=[O:10])[NH:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=Cc1ccccc1
Product: O=S1(=O)NC(c2ccccc2)Nc2ccccc21

Procedure:
2-Aminobenzenesulfonamide was transformed by Method G (using benzaldehyde). M.p. 125.5-128.5° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[NH:18][C:17]2=[CH:19][CH:20]=[CH:21][C:16]2=[C:15](Cl)[N:14]=1>>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:15]1[N:14]=[C:13]([Cl:12])[NH:18][C:17]2=[CH:19][CH:20]=[CH:21][C:16]=12
Reactant: CC1NCCc2ccccc21
Reactant: Clc1nc(Cl)c2cccc-2[nH]1
Product: CC1c2ccccc2CCN1c1nc(Cl)[nH]c2cccc1-2
Yield: 62.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1-methyl-1,2,3,4-tetrahydroisoquinoline(1.7 g, 11.55 mmol) and 2,4-dichlorocyclopenta[d]pyrimidine(2.0 g, 10.5 mmol) prepared in the above Step 3 were used as starting materials, 1.95 g of the title compound was prepared. (Yield: 62%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH:10]([C:13]#[N:14])[C:11]#[N:12].[CH3:25]I>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:10]([CH3:25])([C:13]#[N:14])[C:11]#[N:12]
Reactant: COc1ccccc1C(c1cccc2ccccc12)C(C#N)C#N
Reactant: CI
Solvent: C1CCOC1
Product: COc1ccccc1C(c1cccc2ccccc12)C(C)(C#N)C#N
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
2-[(2-Methoxyphenyl)(1-naphthyl)methyl]malononitrile of Example 1 (196 mg, 0.63 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled to −35° C. Potassium hexamethyldisilyl amide (1.14 mL, 0.75 mmol, 0.66 M in toluene) was added. The cooling bath was removed, and the reaction allowed to warm to room temperature, after which methyl iodide (0.078 mL, 125 mmol) was added. The reaction mixture was stirred 30 minutes, then quenched with 1 N hydrochloric acid and taken up in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over mgnesium sulfate, filtered, and evaporated to dryness. Following purification on silica (20% ethyl acetate/hexanes) and recrystallization from methanol, 104 mg product was isolated as a crystalline solid, mp 175-177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[N:23]1([CH2:22][CH2:21][N:8]2[C:9]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1cnn2CCN1CCOCC1
Temperature: 60 °C

Procedure:
4-Nitroindazole (1.00 g, 6.13 mmol) and potassium carbonate (2.55 g, 18.4 mmol) in 15 mL of DMF was stirred for 30 min, after which 4-(2-chloro-ethyl)-morpholine hydrochloride (1.71 g, 9.19 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-D6) δ ppm 2.41 (m, 4 H), 2.79 (t, J=6.27 Hz, 2 H), 3.44 (m, 4 H), 4.66 (t, J=6.27 Hz, 2 H), 7.65 (m, 1 H), 8.17 (m, 1 H), 8.29 (m, 1 H), 8.52 (s, 1 H); MS (DCI/NH3) m/z 277 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]2[CH:19]=[N:18][N:17]=[C:4]2[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[N:10]=1.[OH-:20].[Li+].O>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4]3=[N:17][N:18]=[CH:19][N:3]3[C:2](=[O:20])[NH:10][C:9]1=2
Reactant: [OH-]
Reactant: Clc1nc2c(ncn2C2CCCCO2)c2nncn12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2c(ncn2C2CCCCO2)c2nncn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 5-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-[1,2,4]triazolo[3,4-i]purine (0.17 g, 0.50 mmol) in THF (10 mL) was added lithium hydroxide (420 mg, 18 mmol) and water (10 mL). After stirring at room temperature for 10 minutes, the reaction mixture was concentrated under reduced pressure to give the product, which is used for next step without further purification. LCMS calculated for C11H13N6O2 (M+H): 261.1; found: 261.0.
Reaction SMILES: Cl[C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)=[O:5].[CH3:26][CH:27]([OH:34])[CH2:28][NH:29][CH2:30][CH:31]([OH:33])[CH3:32]>>[OH:34][CH:27]([CH3:26])[CH2:28][N:29]([CH2:30][CH:31]([OH:33])[CH3:32])[C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)=[O:5]
Reactant: CC(O)CNCC(C)O
Reactant: O=C(NCCOC1CCCCO1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Product: CC(O)CN(CC(C)O)c1c(C(=O)NCCOC2CCCCO2)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 100.5 %

Procedure:
Reaction of 2-chloro-3,5-dinitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzamide (17) (1.02 g) [For method of preparation see co-pending NZ Application No. 521851] with diisopropanolamine (0.8 g) as above gave 2-[bis(2-hydroxypropanyl)amino]-3,5-dinitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzamide (18) (1.29 g, 100%): as a yellow foam; 1H NMR [(CD3)2SO] δ 9.22 (br, 1 H), 8.66 (d, J=2.8 Hz, 1 H), 8.29 (d, J=2.8 Hz, 1 H), 4.99 (m, 1 H), 4.85 (br, 1 H), 4.62 (br, 1 H), 3.94 (m, 2 H), 3.77 (m, 2 H), 3.53 (m, 4 H), 3.26 (m, 2 H), 1.48 (m, 10 H), 0.98 (m, 6 H); 13C NMR δ 166.5, 147.8, 142.4, 138.2, 132.6, 128.8, 123.8, 98.1, 64.8, 63.5, 61.5, 60.1, 30.1, 25.0, 20.5, 20.2, 19.1. HRMS (FAB) Calcd. For C20H31N4O9 [M+H+] m/z 471.2091. Found; 471.2089.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[N:11][OH:12])=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:12][N:11]=[CH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C=NO)c([N+](=O)[O-])cc1OC
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=NOCc2ccccc2)c([N+](=O)[O-])cc1OC
Reaction time: 4 h

Procedure:
6-Nitroveratraldoxime (113 g, 0.5 mole) was dissolved in 2500 ml of dimethylformamide. To this solution was added sodium methoxide (27 g, 0.5 mole). The suspension was treated with benzyl chloride (63 g, 0.5 mole) and stirring was continued for an additional 4 hr. The orange suspension was diluted with 3 1. of water and the solid was filtered, m.p. 109°-113°, yield: 110 g (78%). A small amount of the material was recrystallized from toluene to give an analytical sample melting at 116°-117°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2Cl.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2cccc(Br)c2n1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2cccc(Br)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
To an ice cold solution of 8-bromo-2,4-dichloro-quinazoline (5.5 g, 0.0197 mol) in DCM (100 mL), morpholine (3.77 mL, 0.0433 mol) was slowly added and the reaction was continued for 15 min. The solvent was evaporated to dryness to get the crude compound. The crude product was purified, using column chromatography (60-120 silica gel, 5-30% ethyl acetate in hexane) to get the title compound [2.5 g, 39%]. 1H NMR (400 MHz, CDCl3): δ 8.05 (dd, J′=7.8 Hz, J″=1.2 Hz, 1H), 7.81 (dd, J′=8.4 Hz, J″=0.9 Hz, 1H), 7.29 (t, J=8.4 Hz, 1H), 3.89 (s, 8H); LC-MS (ESI): Calculated mass: 326.9; Observed mass: 327.9 [M+H]+ (RT: 1.57 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:41]([O:40][C:38]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:17]([CH2:16][O:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH2:18]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(OCC2CNc3ccccc3C2)c(NC(=O)OC(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(NC(=O)OC(C)(C)C)c1
Reaction time: 24 h

Procedure:
To a stirred solution of [5-Methyl-2-(1,2,3,4-tetrahydro-quinolin-3-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester. To a stirred solution of 2-N-Boc-amino-4-methylphenol (129 mg, 0.35 mmol) in CH2Cl2 (1.5 mL) at 0° C. under nitrogen was added DIEA (61 μL, 0.35 mmol) followed by benzyl chloroformate (50 μL, 0.35 mmol) and DMAP (4 mg, 0.035 mmol). After 24 hours, the reaction was diluted to 30 mL with CH2Cl2 and washed (2×30 mL) with 2N HCl and (2×30 mL) with saturated NaHCO3. The organics were dried (MgSO4), filtered and concentrated to a brown oil, which appeared to be a mixture of product and starting material.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>O1CCCC1>[O:3]1[CH2:4][CH2:5][N:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=3[N+:27]([O-:29])=[O:28])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of trans-4-morpholinocyclohexanamine dihydrochloride (5 g, 19.44 mmol), 4-fluoro-3-nitrobenzenesulfonamide (4.32 g, 19.63 mmol) and triethylamine (20 ml, 143 mmol) in tetrahydrofuran (60 ml) was stirred for 16 hours at room temperature. The solid product was filtered off, washed with tetrahydrofuran, ether, dichloromethane (3×) and dried under vacuum.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:15][C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][N:9]1[C:7]1[CH:8]=[C:3]([CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])=[CH:20][CH:21]=2)[N:6]=1
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-phenyl-urea (388 mg) was dissolved in DCM (15 mL) and triethylamine (0.194 mL) and the solution was cooled to 0° C. Methanesulfonyl chloride (0.108 mL) was added and the reaction stirred for 90 mins at 0° C. The reaction mixture was concentrated in vacuo and partitioned between DCM (20 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to give the desired compound (273 mg) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=2[CH3:19])=[N:6][CH:7]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:15]([CH3:17])=[CH:14][C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=3[O:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(C(=O)COc2cc(C)cc(C)c2C)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(-c2coc3c(C)c(C)cc(C)c23)nc1
Yield: 87 %

Procedure:
Using 1-(5-methylpyridin-2-yl)-2-(2,3,5-trimethylphenoxy)ethanone obtained in Reference Example 168, the title compound was synthesized in the same manner as in Reference Example 191. Yield 87%. Melting point: 134-135° C. (ethyl acetate-hexane).
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6](O)=[O:7].ClC(OCC(C)C)=O.C([N:31](CC)CC)C.N>C1COCC1>[CH3:20][N:17]1[C:18](=[O:19])[N:13]2[CH:12]=[N:11][C:10]([C:2]3[S:3][CH:4]=[C:5]([C:6]([NH2:31])=[O:7])[N:1]=3)=[C:14]2[N:15]=[N:16]1
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cn1nnc2c(-c3nc(C(N)=O)cs3)ncn2c1=O
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.700 g; 2.5 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.50 mL; 3.8 mmol), followed by triethylamine (0.53 mL; 3.8 mmol). The mixture was stirred for 1 hour, and then ammonia solution (0.5 M in dioxane; 20 mL) was added, and stirring continued for a further 3 hours. The precipitate was filtered, washed with water (5×20 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.223 g; 40%). δH (DMSO-d6) 8.94 (1H, s), 8.42 (1H, s), 7.74 (1H, bs), 7.59 (1H, bs), 3.89 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:37][C:36]1[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:3][C:2]=1[F:1]
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN(C)C)c(F)c2)c1
Yield: 11.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-dimethylacetamide (9.6 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.