Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCC(=O)CCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCC(=O)CCCCCNc1ccc(C(=O)OCC)cc1

Procedure:
A solution of 15 g. of 6-oxohexadecyl bromide and 15.6 g. of ethyl 4-aminobenzoate in 60 ml. of hexamethylphosphoramide is stirred at 120° C. for 18 hours, allowed to cool, and diluted with water. The mixture is filtered and the resulting solid is dissolved in methylene chloride. The solution is washed with diluted hydrochloric acid, dried, and evaporated to yield a brown solid. Crystallization from ethanol yields ethyl 4-(6-oxohexadecylamino)benzoate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31]C(OC)=O)=[CH:26][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1.[OH-].[Na+].O.[ClH:39]>CO>[ClH:39].[F:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCc4ccncc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline (300 mg, 0.63 mmol) and 2M aqueous sodium hydroxide (0.38 ml, 0.76 mmol) in methanol (6 ml) was stirred at ambient temperature for 2 hours. Water was added and the mixture adjusted to pH7 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum. The solid was dissolved in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was diluted with isopropanol, and the methylene chloride and methanol solvents were removed by evaporation. The resulting precipitate was collected by filtration, washed with methylene chloride and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline hydrochloride (270 mg, 94%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([NH2:23])[CH:22]=1>CCOCC>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:21]([NH:23][C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:22]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Solvent: CCOCC
Product: Cc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C(F)(F)F)ccc23)c1

Procedure:
The product from Example 7d (65 mg, 0.28 mmol) and the product from Example 1f (61.5 mg, 0.28 mmol) was reacted 28 h following the procedure from Example 1g giving the title compound as a hydrochloride salt after trituration with ether giving (131 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.43 (d, J=6.99 Hz, 1H) 7.23 (m, 4H) 7.35 (m, 4H) 8.39 (d, J=8.82 Hz, 1H) 8.55 (d, J=6.99 Hz, 1H) 9.48 (d, J=8.46 Hz, 1H) 11.55 (brs, 1H); MS (ESI+) m/z 412 (M−Cl)+; (ESI−) m/z 410 (M−HCl)−.
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:17]=2)=[CH:13][CH:12]=1.Br[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=[CH:37][CH:36]=1>O>[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=[CH:37][CH:36]=3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:32])[CH3:33])[N:17]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccnc2ccccc12
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)Cn1cc(-c2ccnc3ccccc23)c(-c2ccc(Cl)s2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
To a degassed solution of acetonitrile (4 mL) and water (1 mL) were added potassium carbonate (4 eq, 2.8 mmol), 3-(5-chloro-2-thienyl)-1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq, 0.7 mmol), 4-bromoquinoline (1 eq, 0.7 mmol) and 1,1′-bis(diphenylphosphinoferrocene)palladium(II)dichloride (0.1 eq, 0.07 mmol). The mixture was stirred at 130° C. in the microwave for 60 min. The solvent was evaporated and water and dichloromethane were added. The aqueous layer was extracted two times with dichloromethane. The combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol 1:0 to 9:1) to afford 45 mg of 4-[3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazol-4-yl]quino line (15% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[C:11]1([CH3:17])[CH2:15][CH2:14][CH:13](C)[CH2:12]1.[I-].[Na+]>>[CH:11]1([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1CCC(C)(I)C1
Reactant: O=Cc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Product: O=Cc1ccc(OCC2CCCC2)cc1
Yield: 51 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and 1-iodo-3-methylmethylcyclopentane (344 mg, 0.98 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-(cyclopentylmethoxy)benzaldehyde (102 mg, 50% crude) as a yellow oil that was used without further purification or characterization.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9]Cl.[I-].[K+].[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>CN(C)C(=O)C>[C:15]([C:14]1([C:13]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8]1)(=[O:16])[CH3:17]
Reactant: COC(=O)CC(C)=O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
A total of 662.4 g of potassium carbonate, 1161.2 g of 1,2-dichloroethane, 696.7 g of N,N-dimethylacetamide, 33.2 g of potassium iodide, and 464.5 g of methyl acetoacetate were mixed, followed by a reaction at 100° C. for 13 hours. The reaction mixture was cooled to room temperature and was filtrated, the resulting filtrate was washed with two portions of 5% by weight hydrochloric acid, and the organic layer was washed with water. The washing with the aqueous layer was extracted with 999.7 g of 1,2-dichloroethane. The extract with the organic layer was concentrated under a reduced pressure to distill off 1,2-dichloroethane, was subjected to distillation under a reduced pressure and thereby yielded 160.1 g of methyl 1-acetyl-1-cyclopropanecarboxylate as a colorless liquid as a fraction at 75° C./20 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[N:11][N:10]([CH3:26])[N:9]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:24])([F:25])[F:23])=[CH:16][N:15]=1
Reactant: CNc1nc(Nc2ccc(-c3nn[nH]n3)cc2Cl)ncc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CNc1nc(Nc2ccc(-c3nnn(C)n3)cc2Cl)ncc1C(F)(F)F
Temperature: 40 °C
Yield: 68.5 %

Procedure:
A mixture of N2-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (80 mg, 0.22 mmol), K2CO3 (45 mg, 0.32 mmol) and methyl iodide (15 uL, 0.24 mmol) in acetone (2 mL) was heated at 40° C. for 1 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and the crude residue purified via silica gel column chromatography (0-100% ethyl acetate/isohexane) to give N2-(2-chloro-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (58 mg, 70%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=385 at 4.31 min. 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J=8.7, 1H); 8.23-8.19 (m, 2H); 8.05 (dd, J=8.7, 2.0, 1H); 7.72 (s, 1H); 5.29 (s, 1H); 4.40 (s, 3H); 3.12 (d, J=4.7, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:7]
Reactant: C1COCCN1
Reactant: Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
In N,N-dimethylformamide (DMF) (108 ml), 3-amino-4-nitrobenzoic acid [the compound of the formula (1a)] (10.8 g) which was prepared in accordance with a known method (HECHENG HUASUE, page 91, 1995) was dissolved. Further, morpholine (10.3 ml), 1-Hydroxybenzotriazole (HOBt) (9.60 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI.HCl) (13.6 g) were successively added to the solution, and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into a 1N HCl aqueous solution to precipitate crystals, and the whole was filtrated to obtain the crystals and a filtrate. The filtrate was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The above crystals and the concentrate were combined to obtain 3-amino-4-nitrobenzoic acid morpholide (12.1 g; yield=81.2%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][C:17](Br)=[CH:16][CH:15]=2.[H][H].ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Nc1ncnc2c1ncn2Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ncn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Yield: 36.9 %

Procedure:
To a solution of Example 1 (0.1 g, 0.22 mmoles) in methanol (10 ml), palladium on carbon (10 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 3 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as pale yellow solid (0.030 g, 37% yield). MP: 173-175° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.10 (d, J=12.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.48-7.41 (m, 6H), 7.22 (s, 2H), 5.34 (s, 2H). Mass: 370.05 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:13]1[N:17]=[CH:16][NH:15][N:14]=1)(=[O:12])=[O:11].[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:13]1[N:17]=[CH:16][N:15]([C:20](=[O:21])[N:19]([CH3:18])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]=1)(=[O:11])=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)c2nc[nH]n2)c(C)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: Cc1cc(C)c(S(=O)(=O)c2ncn(C(=O)N(C)c3ccccc3)n2)c(C)c1

Procedure:
3-(2,4,6-Trimethylphenyl)sulfonyl-1H-1,2,4-triazole and N-methyl-N-phenylcarbamoyl chloride were employed to synthesize the title compound as in Example 22.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:24])C>>[C:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCc2c(Cc3ccccc3)cccc21
Reactant: CC(=O)O
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21
Reaction time: 8 h

Procedure:
In 100 ml. of acetic acid is dissolved 7.3 g. of ethyl 4-benzylindan-1-carboxylate and, under cooling with ice, 3.4 g. of chromic anhydride is added. After the mixture is stirred overnight, the reaction mixture is poured over 500 g. of ice and extracted with chloroform. The extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography (700 g. silica gel; eluted with a 40:1 mixture of benzene and ethyl acetate). The procedure gives ethyl 4-benzoylindan-1-carboxylate as an oily product.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][CH:7]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CC(C)n1nccc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A dry flask was charged with 2-Isopropyl-2H-pyrazole-3-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (101 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.328 g, 0.84 mmol, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])cnc1O
Product: Cc1cc([N+](=O)[O-])cnc1Cl
Yield: 92 %

Procedure:
3-Methyl-5-nitropyridin-2-ol (134 g, 0.872 mol) (J. Org. Chem. 1949, 14, 328-332) was divided into 3 portions and placed in three 1-L round bottom flasks. POCl3 (200 mL) was added to each flask and the mixtures were heated to reflux for 2 h. The solutions were cooled and the excess POCl3 was removed in vacuo. The residues were poured into ice water (1 L) with stirring and the precipitates were collected by filtration and air dried for 20 min. The combined products were recrystallized from 10% ethyl acetate in hexanes (300 mL) and air dried to give 2-chloro-3-methyl-5-nitropyridine (139 g, 92% yield) as a white solid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J=2.5 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][C@@H:15]([C:17]2[CH:28]=[CH:27][C:20]3[O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24][C:19]=3[CH:18]=2)[O:14][C:13]1=[O:29])[CH2:2][C:3]#[CH:4].I[C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:26][C:22]1([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][C:17]([C@H:15]3[O:14][C:13](=[O:29])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][C:3]#[C:4][C:31]4[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=4)[CH2:16]3)=[CH:18][C:19]=2[CH2:24][O:23]1
Reactant: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reactant: NS(=O)(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCC#Cc4cccc(S(N)(=O)=O)c4)C(=O)O3)ccc2O1
Reaction time: 17 h
Yield: 94.7 %

Procedure:
(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.79 g) was stirred with 3-iodobenzene sulphonamide (1.4 g) in acetonitrile:triethylamine (1:1, 42 ml) under nitrogen for 10 min. Cuprous iodide (0.083 g) and dichlorobis(triphenylphosphine)palladium (0.192 g) were added and the mixture was stirred for 17 h under nitrogen at 21°. The mixture was evaporated to dryness and the residue was chromatographed on silica gel (250 g) in 30% ethyl acetate:petroleum ether (bp 40–60°), then 50%, then 75% and finally ethyl acetate to give the title compound (2.35 g), LCMS RT=3.44 min.
Reaction SMILES: C[Li].Br[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[NH:7][CH3:8].C([Li])(C)(C)C.[B:17](OC)([O:20]C)[O:18]C.Cl>C(OCC)C.O1CCCC1>[CH3:8][NH:7][C:6]1[CH:5]=[C:4]([B:17]([OH:20])[OH:18])[CH:11]=[CH:10][CH:9]=1
Reactant: CNc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
166 mL (0.242 mol, 1.2 eq) of 1.6 M methyllithium in diethyl ether are added to a solution cooled to −70° C. of 37.6 g (0.202 mol, 1 eq) of 3-bromo-N-methylaniline (prepared in Example 7c) in 300 ml of tetrahydrofuran. The reaction medium is stirred at −70° C. for one hour and 306 mL (0.444 mol, 2.2 eq) of 1.5 M tert-butyllithium in diethyl ether are then added. The reaction medium is stirred at −70° C. for 45 minutes and 103.5 mL (0.808 mol, 4 eq) of trimethyl borate are then added. The reaction medium is stirred at room temperature for one hour and then hydrolyzed by addition of ice, acidified with 1 L of 2N hydrochloric acid and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 4.2 g (14%) of 3-(methylamino)phenylboronic acid are obtained. The aqueous phase is basified and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 3.4 g (11%) of 3-(methylamino)phenylboronic acid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(C(=C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1
Reactant: [H][H]
Solvent: CO
Product: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 1.6 parts of 4-[bis(4-fluorophenyl)-methylene]-1-(phenylmethyl)piperidine and 80 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of rhodium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 1.2 parts of 4-[bis(4-fluorophenyl)methylene]piperidine as a residue (intermediate 14).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18](O)=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46].O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18]([NH:45][OH:46])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid (1.1 g, 2.6 mmol) in tetrahydrofurane was added carbonyldiimidazole (0.73 g, 4.5 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine HCl salt (0.4 g, 2.3 mmol). The resulted mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-hydroxy-propionamide as a white solid (700 mg, 61%): mp 129-131° C.; 1HNMR (DMSO-d6): δ 0.33-0.35 (m, 2H), 0.54-0.57 (m, 2H), 1.15-1.30 (m, 1H), 3.11 (d, J=5 Hz, 2H), 3.87 (d, J=7.5 Hz, 2H), 5.71 (t, J=7.5 Hz, 1H), 6.95-6.98 (m, 1H), 7.03 (t, JH-F=75 Hz, 1H), 7.11-7.17 (m, 2H), 7.85 (s, 4H), 8.80 (s, 1H), 10.60 (s, 1H). 13C NMR (CDCl3): δ 0.7, 3.9, 3.9, 10.8, 35.7, 52.0, 74.6, 112.6, 114.9, 116.7, 120.8, 120.9, 123.6, 124.2, 132.3, 135.00, 137.7, 140.9, 151.3, 169.0; Anal. Calcd. for C22H20F2N2O6: C, 59.19; H, 4.52; N, 6.28. Found: C, 58.98; H, 4.41; N, 6.16.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[N:8][CH:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[N:8]([C:30](=[O:33])[CH2:31][CH3:32])[C:9]([CH3:13])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(C)N=C(C)N(C(=O)CC)C1c1ccccc1[N+](=O)[O-]
Yield: 58.2 %

Procedure:
1.00 g (3.30 millimole) of 5-Ethoxycarbonyl-2.6-dimethyl-4-(2-nitrophenyl)-dihydropyrimidine was dissolved in 15 ml of chloroform. To the solution, 2 ml of triethylamine (14.3 millimole) was added with stirring and then 0.4 g (4.32 millimole) of propionyl chloride was added dropwise. The mixture was stirred at room temperature for 40 minutes and concentrated under reduced pressure. The residue was purified on silica gel by column chromatography and recrystallized from benzene/hexane to obtain 0.69 g (58% yield) of title compound.