Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH2:16][C:17]([OH:19])=O)[C:13]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:12]=2[N:11]3[CH3:25])=[CH:4][CH:3]=1.[CH3:26][NH2:27]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH2:16][C:17]([NH:27][CH3:26])=[O:19])[C:13]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:12]=2[N:11]3[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)n1c(CC(=O)O)c(-c3ccc(Cl)cc3)nc1n2C
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccc(Cl)cc2)nc2n(C)c3ccc(C)cc3n12
Reaction time: 6 h

Procedure:
Under a nitrogen stream, a suspension of 1.0 g (0.0028 mol) of 2-(4-chlorophenyl)-6,9-dimethyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran. 1.0 g (0.0063 mol) of N,N'-carbonyldiimidazole in solution in 50 ml of dry tetrahydrofuran is added and the mixture is stirred for 6 h. The solution is then treated with an excess of dry gaseous methylamine and again stirred for 4 h. The solvent is evaporated under reduced pressure. The residue is taken up in water, drained, washed with water and dried. 0.65 g of product is obtained which is purified by silica gel column chromatography, eluting with a chloroform/acetone 93/7 mixture. 0.26 g of compound is finally isolated. Melting point: 258°-260° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:5])[CH3:2]
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Temperature: -50 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a -50° C. solution of 12.1 g (25.1 mmol) of N-ethoxycarbonyl-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinone in 90 ml methanol and 90 ml of tetrahydrofuran is added 1.04 g (27.5 mmole) of sodium borohydride. The reaction is stirred 2 hours at -50° C. and then allowed to warm to 25° C. The reaction is quenched by addition to 300 ml saturated sodium chloride and the mixture extracted with ethyl ether (2 liters). The organic extract is washed with 300 ml saturated sodium chloride, dried over magnesium sulfate and the ether evaporated in vacuo. The crude product is purified via column chromatography on 2 kg silica gel eluting in 500 ml fractions with 2% methanol-5% ether-93% dichloromethane to yield (fractions 20-26) 6.04 g (50%) of the title compound as an oil and 3.75 g (31% of a mixture of the title compound and its trans-isomer. Further chromatography yields pure trans-isomer.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[Li+].O>CN(C=O)C.C1COCC1>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCNC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and pyrrolidine (Fluka 83240; 500.48 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 60° C. for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4Cl. The organic layer was washed three times with aq. NH4Cl then brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The latter was taken up in THF (5 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) then water (5 mL) were added. The reaction mixture was stirred at room temperature for 16 hours then the THF was evaporated and the residue was diluted with water. After acidification with AcOH, the formed precipitate was filtered and dried under high vacuum to afford the title compound (497 mg, 90%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34]>>[OH:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][OH:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: OCCNCCO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(CCO)CCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and diethanolamine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h then 60° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.83 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 4.30 (br, 2H), 3.95 (t, 2H), 3.90 (s, 3H), 3.39 (m, 4H), 2.56-2.36 (m, 6H), 1.74 (m, 2H), 1.38 (m, 4H), 1.28 (m, 2H); MS (ESI): 539.3.
Reaction SMILES: Br[C:2]1[C:3]([S:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([C:35]#[N:36])=[CH:27][CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:35]([C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([C:2]2[C:3]([S:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:27]=1)#[N:36]
Reactant: CCOC(=O)C(C)(C)Sc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(C#N)c3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Sc1ncccc1-c1ccc(C#N)c2ccccc12
Temperature: 80 °C
Yield: 36.1 %

Procedure:
A mixture of ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate (271 mg, 0.89 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (248 mg, 0.89 mmol), palladium tetrakis triphenylphoshine (51 mg, 0.044 mmol) and aqueous sodium carbonate solution (2M, 1.5 mL, 3 mmol) in dioxane (3 mL) was degassed and heated to 80° C. for 5 hours. The mixture was washed with water and extracted with ethyl acetate. The organic layer was dried with Mg2SO4, concentrated and purified by chromatography to yield ethyl 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoate (0.121 g, 36%).
Reaction SMILES: CO[CH:3]([O:22]C)[C:4](=O)[CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].[C:24]([OH:27])(=[O:26])[CH3:25]>O1CCCC1>[O:26]1[CH2:5][CH2:4][CH2:3][CH2:25][CH:24]1[O:27][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:4]([CH:3]=[O:22])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18]
Reactant: CC(=O)O
Reactant: COC(OC)C(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C=O)=CCCC(C)=CCOC1CCCCO1

Procedure:
Following the procedure stated in Example 2-(1), 5.8 g of (E)-4-methyl-6-(2'-tetrahydropyranyloxy)-4-hexan-1-yltriphenylphosphonium iodide was treated with n-buthyllithium in 30 ml of anhydrous tetrahydrofuran. Then, the resultant was treated with 3.2 g of 1,1-dimethoxy-6,10,14-trimethyl-5,9,13-pentadecatrien-2-one prepared by the process stated in Referential example 7. The resulting oil was treated with 40 ml of 50% acetic acid to yield 4.2 g of 7-formyl-3,11,15,19-tetramethyl-2,6,10,14,18-eicosapentaen-1-ol tetrahydropyranyl ether. The product was reduced with 150 mg of sodium borohydride and treated with p-toluenesulfonic acid in methanol in the same manner as stated earlier, and purified by the silica gel column chromatography to yield 1.6 g of the desired product. This was a mixture of the (E,E,E,E), (E,Z,Z,E), (E,Z,E,E) and (E,E,Z,E) isomers.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC)(=[O:21])C>CN(C1C=CN=CC=1)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol produced in Example XV in dry CH2C12 at 0 degree C. there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H2O, saturated aqueous NaHCO3 and brine solution, dried over Na2SO4, and concentrated in vacuo to a yellow oil. Purification by SiO2 column chromatography yielded the p-toluenesulfonate.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH3:3].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:14][S:15]([O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH3:3])(=[O:17])=[O:16]
Reactant: COC(=O)c1ccc(C(C)O)nc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)OS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a 0° C. solution of methyl 6-(1-hydroxyethyl)nicotinate (0.100 g, 0.552 mmol) and 4-dimethylaminopyridine (152 mg, 1.32 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (75.9 mg, 0.662 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 hour. Additional methanesulfonyl chloride (75.9 mg, 0.662 mmol) was added and the mixture stirred at room temperature for an additional 2 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude methyl 6-(1-(methylsulfonyloxy)ethyl)nicotinate (134 mg) as an oil which was used in the next step directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])=[CH:4][CH:3]=1.C([NH:29][C@H:30]([C:32](O)=[O:33])[CH3:31])(OCC1C=CC=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[NH2:29][C@@H:30]([CH3:31])[C:32]([NH:18][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:33]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(N)(Cc1ccc(F)cc1)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: C[C@H](N)C(=O)NC(C)(Cc1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a stirred solution of 1,2-bis(4-fluorophenyl)-2-propylamine (11.07 g, 0.045 mol) in 200 ml of chloroform under nitrogen, were added N-CBZ-L-alanine (10.0 g, 0.045 mol) and then a solution of dicyclohexylcarbodiimide (9.90 g, 0.05 mol) in 100 ml of chloroform, and the mixture was stirred for 16 hours. The precipitated solid was removed by filtration and the solvent evaporated. The residue was treated with ethyl acetate (100 ml), filtered, an additional 300 ml of ethyl acetate added, and then washed with 1% cold HCl (100 ml), brine (2×100 ml), dried over MgSO4, and the solvent evaporated. The residue was dissolved in 450 ml of methanol and 35 ml of 10% HCl and hydrogenated at 40 psi in a Parr apparatus over 3.0 g of 5% Pd/C catalyst for 3 hours. The catalyst was removed by filtration, the solvent evaporated and the residue dissolved in water (200 ml) and chloroform (300 ml), basified to pH 11 with 50% NaOH, shaken and separated. The aqueous phase was extracted with chloroform (2×200 ml), and the combined organic phases were washed with water (2×200 ml), and dried over MgSO4. Removal of solvent gave a white solid. This solid was recrystallized from cyclohexane/hexane and then from hexane/ethanol, and vacuum dried to give 1.5 g of (2S)-2-amino-N-[1,2-bis(4-fluorophenyl)-1-methylethyl]propanamide, mp. 134°-135° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)[NH2:4].[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[C:24]([C:28](O)=[O:29])[NH:25]2)=[CH:21][C:20]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[C:24]([C:28](=[O:29])[NH:4][CH:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:6]=3)[C:2]([F:1])([F:16])[F:17])[NH:25]2)=[CH:21][C:20]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Reactant: NC(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3ccc(F)c(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
2,2,2-Trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine (0.82 g, 3.05 mmol) was dissolved in N,N-dimethylformamide (6 ml), and 6-chloro-5-(ethoxycarbonyl)-1H-indole-2-carboxylic acid (0.82 g, 3.05 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (1.16 g, 3.05 mmol) and 4-methylmorpholine (0.92 g, 9.10 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulphate, adsorbed on silica gel and chromatographed with cyclohexane/ethyl acetate (4/1). 1.29 g (65% of theory) of ethyl 6-chloro-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate were obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Sodium hydride (0.20 g, 60% dispersion in mineral oil) was added to a solution of-4-hydroxypiperidine-1-car-boxylic-acid-tert-butyl ester (0.92 g) in anhydrous 1-methyl-2-pyrrolidinone (5 μl), precooled in ice. After stirring for 30 minutes under nitrogen, 2,5-dibromopyridine (1.0 g) was added. The reaction mixture was then stirred for two hours at room temperature before heating to 70° C. for four hours. The resultant dark mixture was poured onto ice (200 ml) containing 2% citric acid (20 ml), and was extracted with diethyl ether (3×15 ml). The aqueous phase was then basified to pH 13 with solid sodium hydroxide, and extracted with diethyl ether (2×15 ml). The combined organics were washed with water (3×20 ml), saturated brine (20 ml) and dried over anhydrous sodium sulfate and evaporated to give the title compound as a light brown oil (0.87 g, 58%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:25][C:26]1[C:31]([NH2:32])=[C:30]2[O:33][CH2:34][O:35][C:29]2=[CH:28][CH:27]=1>>[Br:25][C:26]1[C:31]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:30]2[O:33][CH2:34][O:35][C:29]2=[CH:28][CH:27]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Nc1c(Br)ccc2c1OCO2
Product: COc1cc2c(Nc3c(Br)ccc4c3OCO4)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 15, 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline was reacted with 6-bromo-2,3-Methylenedioxyaniline to give the title compound as a solid; NMR Spectrum: DMSOd6 and CF3CO2D) 2.3 (m, 2H), 2.95 (s, 3H), 3.2–3.9 (br s, 8H), 3.4 (m, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 530 and 532; Elemental Analysis: Found C, 54.25; H, 5.54; N, 12.8. C24H28BrN5O4 requires C, 54.35; H, 5.32; N, 13.2%.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[P:10](Cl)([Cl:13])([Cl:12])=[O:11].C(N(CC)CC)C.O>C(Cl)(Cl)(Cl)Cl>[P:10]([Cl:13])([Cl:12])(=[O:11])[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][Br:1])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc(CBr)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc(CBr)c1
Reaction time: 0.67 h
Yield: 84.3 %

Procedure:
To mixture of 17 g of m-bromomethylphenol in 150 ml of carbon tetrachloride under argon was added a solution of 25.5 g of phosphorous oxychloride in 25 ml of carbon tetrachloride. The solution was cooled in a water bath and a solution of 9.18 g of triethylamine in 35 ml of carbon tetrachloride was added dropwise with stirring over 40 minutes. This mixture was stirred in the water bath for 1 hour then overnight at room temperature, filtered through diatomaceous earth and washed with carbon tetrachloride. The mother liquor was taken to dryness giving 23.29 g of the desired compound as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=1)[C:27](O)=[O:28]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:27]([C:26]3[CH:30]=[CH:31][N:32]=[C:24]([CH3:23])[CH:25]=3)=[O:28])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: Cc1cc(C(=O)O)ccn1
Agent: Cl
Product: Cc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)ccn1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-methylisonicotinic acid. 1H NMR (400 MHz, CD3OD) δ1.51-2.00 (m, 6H), 2.57 (s, 3H), 3.27 (m, 1H), 3.45 (m, 1H), 4.28 (m, 1H), 4.73 (t, 1H, J=10.5 Hz), 5.42 (m, 1H), 6.66 (d, 1H, J=8.1 Hz), 6.87 (d, 1H, J=8.1 Hz,), 7.22 (m, 1H), 7.26 (s, 1H), 7.48 (t, 1H, J=8.6 Hz), 8.50 (d, 1H, J=4.8 Hz). MS 430 (MH+).
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=3[Cl:19])[C:4]=2[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][N:33]=2)[CH2:25][CH2:24]1>>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:20]=[CH:21][C:2]([C:35]3[CH:36]=[CH:37][C:32]([NH:31][CH2:30][CH2:29][N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)=[N:33][CH:34]=3)=[C:3]([CH3:22])[C:4]1=2
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Reactant: Cc1c(Br)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2
Product: Cc1c(-c2ccc(NCCN3CCOCC3)nc2)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2

Procedure:
The entitled compound can be prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine and 2-(2-morpholinoethylamino)pyridine-5-boronic acid pinacol ester as described in example 25.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH3:17][O:16][NH:18][C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CONC(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 35.8 %

Procedure:
1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (2.00 g, 9.94 mmol), methoxylamine hydrochloride (1.09 g, 13.02 mmol), EDC.HCl (2.50 g, 13.02 mmol), HOBT (1.99 g, 13.02 mmol) and N-methylmorpholine (2.61 g, 25.8 mmol) were dissolved in anhydrous DMF (20.0 mL) and the resulting reaction mixture was stirred at RT for 5 days. The reaction mixture was evaporated to dryness and the residue was taken up in DCM and washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column eluting with 70% EtOAc/hexanes to afford the title compound (0.82 g, 36%): 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.23 (s, 1H), 3.53 (s, 3H), 1.38 (s, 9H), 1.20 (q, J=4.3 Hz, 2H), 0.85 (q, J=4.3 Hz, 2H). This material is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(CO)ccc1Oc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To the solution of 2-((6-chloropyridin-3-yl)oxy)-5-formylbenzonitrile (340 mg, 1.314 mmol) in methanol (5 ml), was added NaBH4 (74.6 mg, 1.972 mmol). The reaction mixture was stirred at rt for 30 min, and then quenched by water and extracted with EA twice. The organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo to give crude product 2-((6-chloropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile (240 mg, 0.921 mmol, 70.0% yield) as brown oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][S:9][C:8]1=[O:13].C1(C)C=CC=CC=1.[Cl:30][C:31]1[CH:38]=[C:35]([CH:36]=O)[C:34]([OH:39])=[CH:33][CH:32]=1>N1CCCCC1.C(O)(=O)C.O>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([OH:39])=[C:35]([CH:38]=1)[CH:36]=[C:10]1[S:9][C:8](=[O:13])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=2)[C:11]1=[O:12]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C1CSC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1SC(=Cc2cc(Cl)ccc2O)C(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of 3-[3,5-bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione (0.20 g, 0.58 mmol), piperidine (3 drops), acetic acid (3 drops) and toluene (5 mL) was stirred at room temperature for 10 minutes, then 5-chlorosalicylaldehyde (92.3 mg, 0.59 mmol) was added and the mixture was refluxed for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to give the title compound (173.2 mg, 62.0%) as a light yellow powder.