Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:22][CH:21]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(SCCCCCCCc2ccccc2C(=O)O)cc1

Procedure:
The compound of Example 14(a), 2-(7-bromoheptyl)benzoic acid (1 g., 3.34 mm) was reacted with 4-methoxybenzenethiol (0.618 ml, 5.03 mm), and triethylamine (1.87 ml, 13.42 mm) in DMF (40 ml) as in Example 14(b) to afford the desired product.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(OCC)(=O)C.C(O)C>[CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)Oc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCC(C)Oc1ccc(OC(=O)c2ccc(O)cc2)cc1
Yield: 90.9 %

Procedure:
Optically active p-benzyloxybenzoic acid p-(1-methylheptyloxy)phenyl ester (69.0 g, 0.16 mol) prepared above in (iv) was dissolved in a mixed solvent (2:1) (1,000 ml) of ethyl acetate-ethanol, followed by reducing it in the presence of 5% PdC (5.0 g) to obtain optically active p-hydroxybenzoic acid p-(1-methyl-heptyloxy)phenyl ester (49.8 g).
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:13][C:12]2[N:11]3[C:14]([CH3:17])=[N:15][N:16]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[C:6]=2[CH:5]=1)[CH3:3].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:1][CH:2]([C:4]2[S:13][C:12]3[N:11]4[C:14]([CH3:17])=[N:15][N:16]=[C:10]4[CH2:9][N:8]=[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[C:6]=3[CH:5]=2)[CH3:3])=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1ccccc1C1=NCc2nnc(C)n2-c2sc(C(C)O)cc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccccc1C1=NCc2nnc(C)n2-c2sc(C(C)OC(=O)c3ccc(Cl)cc3)cc21
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
To a solution of 1.1 g of 2-(1-hydroxyethyl)-4-(2-methyl-phenyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine dissolved in 14 ml of pyridine is added 0.63 g of 4-chlorobenzoyl chloride under ice-cooling and then stirred for 2.5 hours. After completion of the reaction, the mixture is concentrated under reduced pressure and the residue is dissolved in 50 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off, the filtrate is concentrated under reduced pressure and the residue is subjected to chromatography on silica gel and eluted with chloroform-methanol (100:1-100:3). The objective fraction is concentrated under reduced pressure to give 0.5 g of 2-(1-(4-chlorobenzoyl)oxyethyl)-4-(2-methylphenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine as an amorphous powder.
Reaction SMILES: [P:1]([O:40]C(C)(C)C)([O:35]C(C)(C)C)([O:3][CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH2:23])[N:17]=[C:16]2[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])=[O:2]>FC(F)(F)C(O)=O>[P:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH2:23])[N:17]=[C:16]2[C:24]([N:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34]1)=[O:25])([OH:40])([OH:35])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3COP(=O)(O)O)ccc2n1

Procedure:
1.3 g of [2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4,5-difluorophenyl]methyl di-tert-butyl phosphate are stirred at 25° C. for 1 h in 20 ml of trifluoroacetic acid. The mixture is evaporated at 25° C. in vacuo, and the residue is taken up in 100 ml of water. The pH is adjusted to 6 using bicarbonate solution, and the precipitate formed is filtered off. Drying at 40° C. in vacuo gives product.
Reaction SMILES: C([O:5][C:6](=[O:14])[C@H:7]([CH3:13])[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])(C)(C)C>Cl.O1CCOCC1>[CH3:13][C@H:7]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([OH:14])=[O:5]
Reactant: C[C@H](CS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](CS(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.9 %

Procedure:
To 2.68 g of 2(S)-methyl-3-(methylsulfonyl)propionic acid t-butyl ester was added 20 mL of 4N hydrochloric acid/dioxane and the mixture stirred at room temperature for 19 hours. The solvent was removed under reduced pressure to afford 2.18 g of crude product, which was recrystallized from ethyl acetate/hexane to yield 1.44 g of 2(S)-methyl-3-(methylsulfonyl)propionic acid as white crystals.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>O.CC(C)=O>[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC

Procedure:
A solution of 823 g. potassium permanganate in about 8.5 liters of H2O was gradually added to a refluxing solution of 3,4-dimethoxy-2-nitrobenzaldehyde (550 g., 2.60 moles) in 5.6 liters of acetone. The reaction mixture was refluxed for four more hours, then filtered through diatomaceous earth while hot and the filter cake washed with hot water. The acetone was removed in vacuo and a small amount of unreacted solid was filtered off. The aqueous solution was acidified with 2 N hydrochloric acid (1.8 liters) to yield 505 g. (85%) of the essentially pure title compound. Recrystallization from water afforded colorless crystals, M.P. 200°-202° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH2:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH:13]=[CH2:14]>C(O)C.O>[CH2:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:22][CH:23]=1)[CH:13]=[CH2:14]
Reactant: CCOC(=O)C1CCNCC1
Reactant: C=CCOc1ccc(C=O)cc1
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc(CN2CCC(C(=O)OCC)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
The reaction conditions taught by A. E. Moormann, Syn. Comm., 23(6), 789-795 (1993) were used in the following preparation. To a stirred solution of 4.8 grams (0.030 mole) of ethyl piperidin-4-ylcarboxylate and 4.9 grams (0.030 mole) of 4-(2-propen-1-yloxy)benzaldehyde in 50 mL of ethanol was added 3.8 mL (0.030 mole) of borane-pyridine complex. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was then taken up in water and extracted with methylene chloride. The organic layer was washed with water and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure, yielding 9.0 grams of ethyl N-[4-(2-propen-1-yloxy)phenylmethyl]piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][C:24]3=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([C:4]([OH:5])=[O:9])=[CH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)OC
Reactant: O=C1CCCc2ccc(-c3ccc(F)cc3)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1=Cc2cc(-c3ccc(F)cc3)ccc2CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (15.5 g), dimethyl carbonate (91 ml) and 7—(4-fluorophenyl)-1-tetralone (13.8 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C., and to the mixture was gradually added 3N hydrochloric acid (200 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (90 ml), and to the mixture was added sodium boron hydride (1.36 g) at 0° C. and then was dropwise added methanol (9 ml) for 30 minutes. The reaction mixture was stirred at 0° C. for 4 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in methanol (80 ml), and to the mixture was added 1N sodium hydroxide (100 ml). The mixture was refluxed for 4 hours and cooled to room temperature. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (50 ml), and to the mixture was added concentrated hydrochloric acid (10 ml). The mixture was stirred at 100° C. for 2 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethylether. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7—(4-fluorophenyl)-3,4-dihydronaphthalene-2-carboxylic acid (6.01 g) as pale brown crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C([N:28](CC1SC(C2ON=C(C3C=CC(COS(C)(=O)=O)=CC=3)N=2)=CC=1C)CC)C>N.CO>[NH2:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCl)cc3)no2)cc1C
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(COS(C)(=O)=O)cc3)no2)cc1C
Agent: N
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CN)cc3)no2)cc1C

Procedure:
To a solution of {4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol (971 mg, 2.72 mmol) in DCM (40 mL), DIPEA (526 mg, 4.07 mmol) and methanesulfonyl chloride (373 mg, 3.26 mmol) is added. The reaction mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM. The combined organic extracts are dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (1.48 g) as an orange solid containing {5-[3-(4-chloromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine; LC-MS: tR=0.58 min; [M+1]+=436.11. b) A solution of the above crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (248 mg, 0.569 mmol) in 7 N NH3 in methanol (10 mL) is stirred in a sealed vial at 80° C. for 16 h. The solvent is removed in vacuo and the residue is dissolved in EA and washed with brine and water. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 5% of 7N NH3 in methanol to give the title compound (137 mg) as a pale yellow oil; LC-MS: tR=0.38 min; [M+1]+=357.30; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 3.98 (s, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.67 (s, 1H), 8.13 (d, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([CH2:11]/[C:12](/[CH3:21])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18]Br)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH2:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1.O>C1COCC1>[CH2:1]([CH2:11]/[C:12](/[CH3:21])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][NH:32][CH2:22][C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Reactant: NCc1ccc2c(c1)OCO2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 200 ml of THF was dissolved 20.5 g of geranylgeranyl bromide, 14.4 ml of piperonylamine was added and stirred at room temperature for one hour. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (using as a developing solvent hexane-ethyl acetate (4:1)→ethyl acetate) to give 17.6 g of N-geranylgeranylpiperonylamine as a yellow liquid.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(N(CC)C(C)C)(C)C.[N:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[C:20]=[O:21]>ClCCl.CN(C=O)C>[OH:6][C:5]1[NH:4][C:2](=[O:3])[NH:1][C:8](=[O:9])[C:7]=1[C:20]([NH:19][CH2:22][C:23]([OH:25])=[O:24])=[O:21]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)[nH]c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 22 %

Procedure:
Barbituric acid (512 mg, 4 mmol) was dissolved in a mixture of dichloromethane (3 mL) and DMF (5 mL). N,N-Diisopropylethylamine (2 mL) was added followed by ethyl isocyanatoacetate (645 mg, 5 mmol) and the solution was stirred overnight. After evaporation of all volatiles, the residue was re-dissolved in a mixture of ethanol (5 mL) and 1M aqueous NaOH (5 mL). After stirring at room temperature for one hour, this solution was neutralized by addition of 1M aqueous HCl. The resulting solid was collected, washed with water, and dried under vacuum overnight to give the title compound (202 mg, 22%). LC/MS m/z 230 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[ClH:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[NH:36][CH2:35][CH2:34][CH2:33]2.C([BH3-])#N.[Na+]>C(O)(C)C>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][CH:14]([N:36]3[C:37]4[C:32](=[CH:31][C:30]([O:29][CH3:28])=[C:39]([O:40][CH3:41])[CH:38]=4)[CH2:33][CH2:34][CH2:35]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc2c(cc1OC)NCCC2
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#N)CCC(N3CCCc4cc(OC)c(OC)cc43)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexanone (3.5 mmol), triethylamine (3.5 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroquinoline hydrochloride (3.5 mmol) and sodium cyanoborohydride (5 mmol) in 50 ml iso-propanol was stirred at 25° C. for several days, poured onto ice water and extracted with ethyl acetate. The salt was prepared from anhydrous HCl in ethyl acetate. ##STR15##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH3:27][C:28]1[C:32]([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])=[CH:31][NH:30][N:29]=1>>[CH3:27][C:28]1[C:32]([NH:33][C:34](=[O:35])[C:36]2[CH:43]=[CH:42][C:39]([C:40]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:38][CH:37]=2)=[CH:31][NH:30][N:29]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: Cc1n[nH]cc1NC(=O)c1ccc(C=O)cc1
Product: Cc1n[nH]cc1NC(=O)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 232 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(3-methyl-4-pyrazolyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C29H27N7O2: 506.23; found: 506.25.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][CH2:46]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:46][CH2:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: OCCc1ccccn1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCc3ccccn3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 40 h
Yield: 12.1 %

Procedure:
To a solution of N-[1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (300 mg, 0.58 mmol), 2-pyridinethanol (71 mg, 0.58 mmol) in THF (5 ml) were added triphenylphosphine (152 mg, 0.58 mmol), and diethyl azodicarboxylate (101 mg, 0.58 mmol), and the mixture was stirred at room temperature for 40 hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:5) and thin layer chromatography to give the title compound (43 mg, 0.07 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]([CH3:34])[C:32](=[O:35])[O:31][CH2:30][CH2:29][C:28]=2[CH:36]=1>>[Cl:22][C:5]1[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])=[N:7][C:2]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[N:33]([CH3:34])[C:32](=[O:35])[O:31][CH2:30][CH2:29][C:28]=3[CH:36]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: Fc1cccc(OC2CCOC2)c1Oc1nc(Cl)ncc1Cl
Product: CN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Oc4c(F)cccc4OC4CCOC4)n3)ccc21

Procedure:
2-{5-Chloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenoxy]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one was prepared from 2,5-Dichloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenoxy]-pyrimidine and 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one in an analogous manner to Example 1221d. Title compound was isolated as a white solid HPLC purity=99%, LCMS 503.21 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.88 (s, 1H), 8.52 (s, 1H), 7.30-7.18 (m, 5H), 7.02 (d, J=8.7 Hz, 1H), 4.87 (s, 1H), 4.26-4.23 (m, 2H), 3.69-3.65 (m, 4H), 3.19 (s, 3H), 2.65 (m, 2H), 1.94-1.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:40][C:38]1[CH:39]=[C:34]([CH3:33])[N:35]=[C:36]([C:41]2([NH:44][C:26]([C:25]3[C:24]([O:30][CH3:31])=[CH:23][C:22]([CH3:32])=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=3)=[O:27])[CH2:42][CH2:43]2)[N:37]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.17 g, 0.1 mmol, 3 eq) (60% purity), HOBT (0.046 g, 0.34 mmol, 1.0 eq), EDC.HCl (0.072 g, 0.37 mmol, 1.1 g) in DCM at ambient temperature under a nitrogen atmosphere was added diisopropylethylamine (0.132 g, 1.0 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.44 (d, J=3.36 Hz, 2H), 1.51-1.54 (d, J=3.48 Hz, 2H), 2.32-2.34 (d, J=5.8 Hz, 9H), 2.81-2.82 (d, J=4.6 Hz, 3H), 4.0 (s, 3H) 7.0 (s, 1H), 7.15 (s, 1H), 7.34-7.42 (m, 3H), 7.52 (s, 1H), 7.72-7.74 (d, J=8.8 Hz, 2H), 7.97-8.02 (m, 2H), 8.46-8.48 (d, J=4.56 Hz, 1H), 8.91 (s, 1H). LCMS: (ES+) m/z=579.2 (M+H)+