Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[N:26](CC=C)[C:25]2[C:24](=[O:30])[NH:23][C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=2[N:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[NH:26][C:25]2[C:24](=[O:30])[N:23]([CH2:15][CH2:14][CH2:13][C:11]3[O:10][N:9]=[C:8]([CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]=3)[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=2[N:19]=1
Reactant: OCCCc1nc(Cc2ccccc2)no1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 3 h

Procedure:
A solution of 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (88 mg, 0.4 mmol) in THF (4 ml) was treated with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.34 mmol) and PPh3 (115 mg, 0.44 mmol) under nitrogen. DBAD (101 mg, 0.44 mmol) was added in one portion and the reaction left to react for 5 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (39 mg, 0.034 mmol) was added and the mixture degassed once more. Morpholine (294 μl, 3.4 mmol) was added and the mixture was stirred under nitrogen for 3 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The title compound was obtained as a white solid after purification by MDAP (64 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[N:8]=[C:7]([S:16]([CH3:18])=O)[C:6]2=[O:19].[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:18][S:16][C:7]1[C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([CH3:15])[N:8]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(=O)c(S(C)=O)nn(C)c2cc1OC
Product: COc1cc2c(=O)c(SCOC(C)=O)nn(C)c2cc1OC

Procedure:
A mixture of 11 g of 6,7-dimethoxy-1-methyl-3-(methylsulfinyl)-4(1H)-cinnolinone and 100 ml of acetic anhydride was refluxed for 2 hours. The solution was chilled, and the crystalline precipitate was filtered off, washed with Skelly B, and recrystallized from CH3CN, mp. 229°-33°, yield 11 g (87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl>[CH3:32][S:33]([O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1)(=[O:35])=[O:34]
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol), triethylamine (293 mg, 2.90 mmol) and methansulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water, and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compound as white solids.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1.ClCCl>C(#N)C>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH2:13][CH2:12]1
Reactant: NCCCN1CCOCC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 30 g (0.17 mol) of 1-methylimidazole-4-sulfonyl chloride from Example C-1 in 150 ml of acetonitrile is added dropwise to a solution of 24 ml (0.17 mol) of 3-morpholinopropylamine in 50 ml of acetonitrile (or dichloromethane). The temperature of the reaction mixture is kept at room temperature or below by external cooling with ice-water. Stirring is continued for 6 h at room temperature. The precipitate deposited is filtered off with suction and recrystallized from acetonitrile in order to give 46 g (85% of theory) of the title compound (hydrochloride) of melting point 207°-208° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][OH:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].ClN1C(=O)CCC1=O.[CH2:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:28]=[CH2:29].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:11]([C:12]2[CH2:29][CH:28]([CH2:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:14][N:13]=2)=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Reactant: C=CCc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(Cc3ccccc3)C2)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.80 g (2.7 mmol) of methyl 2-chloro-3-hydroximinomethyl-4-methylsulfonylbenzoate are dissolved in 20 ml of dimethylformamide with 0.38 g (2.9 mmol) of N-chlorosuccinimide. After stirring at room temperature for 4 hours, 0.49 g (2.9 mmol) of allylbenzene and then 0.29 g (2.9 mmol) of triethylamine are added dropwise at 0° C. After stirring at room temperature for 16 hours, the reaction mixture is concentrated in a rotary evaporator, the residue is dissolved in dichloromethane and the solution is washed with sodium bicarbonate solution and with water. After drying over magnesium sulfate and evaporating the solvent, 1.1 g (100% of theory) of methyl 2-chloro-3-(5-benzylisoxazolin-3-yl)-4-methylsulfonylbenzoate are obtained as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][SH:7])=[O:5].[H-].[Na+].Cl[C:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[N:14]=[C:13]([CH3:20])[CH:12]=1>C(O)C.ClCCl.O>[CH2:2]([O:3][C:4]([CH2:6][S:7][C:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[N:14]=[C:13]([CH3:20])[CH:12]=1)=[O:5])[CH3:1]
Reactant: Cc1cc(Cl)n2ncnc2n1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CSc1cc(C)nc2ncnn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl thioglycollate, 1.2 g, is dissolved in 30 ml of dry ethanol, to which 400 mg of sodium hydride (60% in an oil) is added under cooling with ice water and stirred for 10 minutes. Then 1.7 g of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine and 10 ml of dry dichloromethane are added and stirred for 16 hours. To the reaction mixture, water and dichloromethane are added and the organic layer is separated. The separated organic layer is washed with saline and dried over anhydrous potassium carbonate. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography [on 40 g of silica gel, developed and eluted with ethyl acetate] to give 2.2 g of the desired compound as a colorless powder.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[OH:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH:10]([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][C:8]1([CH3:20])[CH3:19]>C(O)(C)C>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[OH:6][NH+:7]1[C:12]([CH3:13])([CH3:14])[CH2:11][CH:10]([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][C:8]1([CH3:20])[CH3:19]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Solvent: CC(C)O
Product: CC(=O)NC1CC(C)(C)[NH+](O)C(C)(C)C1
Product: O=S(=O)([O-])O

Procedure:
2.6 ml of concentrated sulfuric acid is added dropwise to a solution of 10.0 g (46.9 mmol) 1-oxyl-2,2,6,6-tetramethyl-4-acetamidopiperidine in 50 ml isopropanol. After 48 hrs the resulting white solid is collected by filtration, washed with isopropanol and dried under vacuum, mp 198° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])#[N:35].O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[C:34]#[N:35])(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccccc3C#N)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.12 mmol) and triethylamine (0.36 mmol) in DCM (6 ml) was added 2-cyanobenzene-1-sulfonyl chloride (0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17].C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1O
Temperature: 25 °C
Yield: 78 %

Procedure:
Piperidine (0.50 mL, 5.1 mmol) was added to a suspension of 4-hydroxy-3-methoxybenzaldehyde (0.77 g, 5.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.0 g, 4.5 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 3 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (12.0 mL) and water (12.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.1 g, 78%) as a yellow crystalline solid; mp 207.5-208.5° C., lit.5 230-233° C.; δH (500 MHz, DMSO-d6) 3.83 (s, 3H, OCH3), 6.71 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6=8.5 Hz, 1H, H5′), 7.13 (dd, J5,6=8.5, J2′,6′=1.5 Hz, 1H, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.34 (d, J2′,6′=1.5 Hz, 1H, H2′), 7.52 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=2.0 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=2.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 9.57 (s, 1H, OH), 11.27 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([OH:18])=O)[N:14]=1)=[O:8].[NH2:22][CH:23]1[C:38](=[O:39])[N:25]2[C:26]([C:35]([OH:37])=[O:36])=[C:27]([CH2:30][S:31][C:32](=[O:34])[CH3:33])[CH2:28][S:29][C@H:24]12>C(Cl)Cl.C(N(CC)CC)C>[C:32]([S:31][CH2:30][C:27]1[CH2:28][S:29][C@@H:24]2[CH:23]([NH:22][C:16](=[O:18])[C:15]([C:13]3[N:14]=[C:10]([NH:9][C:7](=[O:8])[CH2:6][Cl:5])[S:11][CH:12]=3)=[N:19][O:20][CH3:21])[C:38](=[O:39])[N:25]2[C:26]=1[C:35]([OH:37])=[O:36])(=[O:34])[CH3:33]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1
Reaction time: 0.25 h

Procedure:
3.8 ml of thionyl chloride and 26 ml of methylene chloride were added at 0° C. under nitrogen to a mixture of 15.3 g of the syn isomer of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid in 80 ml of methylene chloride and after standing at 0° C. for 15 minutes, 7 ml of triethylamine were added thereto. A mixture of 14.4 g of 7-amino-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid in 100 ml of methylene chloride and 14 ml of triethylamine were added to the mixture at 0° C. under nitrogen and the temperature was allowed to return to 20° C. The mixture was stirred for an hour and was then evaporated to dryness at 30°-35° C. under reduced pressure. The residue was taken up in 250 ml of water and the solution was raised through carbon black. 50 ml of 2 N hydrochloric acid were added thereto and the mixture was vacuum filtered. The product was washed with water and the raw product was suspended in 80 ml of ethanol. 7 ml of triethylamine were added thereto at 5° C. and 15 ml of 4 N sulfuric acid were added thereto all at once with stirring at 5° C. After standing for 15 minutes, the mixture was vacuum filtered and the product was empasted with ethanol, then with ether and was dried under reduced pressure to obtain the syn isomer of 3-acetylthiomethyl-7-[{2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[Cl:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:14])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(Cl)C(=O)c3ccccc3C2=O)CC1
Yield: 45.9 %

Procedure:
A mixture of 11.35 g of 2,3-dichloro-1,4-naphthoquinone, 15.8 g of 1-piperazinecarboxylic acid, ethyl ester and 400 ml of absolute ethanol was heated at reflux for 3 hours and then evaporated to dryness. The residue was taken up in 300 ml of dichloromethane and filtered through silica gel. The filtrate was evaporated and the residue triturated with ether, giving 8.0 g of the desired product as red crystals, mp 120°-122° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([F:28])[CH:24]=[CH:25][C:26]([F:27])=[C:19]3[C:18]2=[O:29])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:43][OH:44]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([F:28])[CH:24]=[CH:25][C:26]([F:27])=[C:19]3[C:18]2=[O:29])[CH2:13][C:14]([NH:43][OH:44])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3c(F)ccc(F)c3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3c(F)ccc(F)c3C2=O)ccc1OC
Yield: 56.6 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)propanoic acid (580 mg, 1.43 mmol), carbonyldiimidazole (255 mg, 1.57 mmol) and hydroxylamine hydrochloride (120 mg, 1.73 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N-hydroxypropionamide as a white solid (340 mg, 57% yield): mp, 171.0-172.0° C.; 1H NMR (DMSO-d6) δ1.32 (t, J=6.9 Hz, 3H, CH3), 3.03 (dd, J=7.9, 14.8 Hz, 1H, CHH), 3.16 (dd, J=8.1, 14.9 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 3.91 (q, J=6.9 Hz, 2H, CH2), 5.62 (t, J=7.8 Hz, 1H, NCH), 6.878-6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.74 (t, JH-F=5.8 Hz, 2H, Ar), 8.81 (br s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.64, 33.88, 50.29, 55.44, 63.71, 111.64, 112.44, 118.02 (t, JC-F=9.2 Hz), 119.77, 125.47 (t, JC-F=15 Hz), 130.42, 147.65, 148.59, 152.93 (dd, JC-F=4.2, 261 Hz), 163.49, 165.84; Anal Calcd for C20H18N2O6F2: C, 57.14; H, 4.32; N, 6.66. Found: C, 56.93; H, 4.37; N, 6.31.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[NH:8][CH:9]=[CH:10][C:11]=1[NH2:12])=[O:6])C.C(O)(=O)C.[CH:17](N)=[NH:18]>CCO>[N:12]1[C:11]2[CH:10]=[CH:9][NH:8][C:7]=2[C:5](=[O:6])[NH:18][CH:17]=1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: N=CN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc[nH]c12
Temperature: 110 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
To a solution of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (3.4 g, 17.7 mmol, 1 equiv.) in 40 mL of EtOH was added formamidine acetic acid salt (2.8 g, 26.6 mmol) and the mixture warmed at 110° C. After 18 hours, the reaction was cool to room temperature and the solids were filtered, rinsed with EtOH, and dried to provide 1.92 g (80%) of 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one as a beige solid.
Reaction SMILES: [OH:1][CH:2]([CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[S:6][N:5]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.[CH2:26]([NH:29][CH3:30])[CH:27]=[CH2:28]>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:13][C:11]1[CH:10]=[CH:9][C:8]2[C:4]([CH2:3][CH:2]([OH:1])[CH:14]=[C:15]([CH3:17])[CH3:16])=[N:5][S:6][C:7]=2[CH:12]=1.[CH2:26]([N:29]([CH3:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:13][C:11]1[CH:10]=[CH:9][C:8]2[C:4]([CH2:3][CH:2]([OH:1])[CH:14]=[C:15]([CH3:17])[CH3:16])=[N:5][S:6][C:7]=2[CH:12]=1)[CH:27]=[CH2:28]
Reactant: C=CCNC
Reactant: CC(C)=CC(O)Cc1nsc2cc(O)ccc12
Reactant: BrCCCCCCBr
Product: C=CCN(C)CCCCCCOc1ccc2c(CC(O)C=C(C)C)nsc2c1
Product: CC(C)=CC(O)Cc1nsc2cc(OCCCCCCBr)ccc12

Procedure:
From (RS)-3-(2-hydroxy-4-methyl-pent-3-enyl)-benzo[d]isothiazol-6-ol (Ex. 7b) with 1,6-dibromohexane and N-allyl-methyl-amine and salt formation (analogously to Ex. 1d) via (RS)-1-[6-(6-bromo-hexyloxy)-benzo[d]isothiazol-3-yl]-4-methyl-pent-3-en-2-ol there is obtained (RS)-1-[6-[6-(allyl-methyl-amino)-hexyloxy]-benzo[d]isothiazol-3-yl]-4-methyl-pent-3-en-2-ol.fumarate (1:1), MS: m/e 403 (M+H+),
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:20]3)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[NH:42][C:43](=[O:45])[CH3:44].CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1.CCOC(C)=O>[C:43]([NH:42][C:41]1[CH:40]=[C:39]([NH:38][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:20]3)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=2)[CH:48]=[CH:47][CH:46]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(=O)OCc4ccccc4)C3)n2)c1
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A mixture of benzyl 3-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (582 mg, 1.16 mmol), 3′-amino-acetanilide (210 mg, 1.40 mmol) and pTsOH (220 mg, 1.16 mmol) in dioxane (10 mL) was stirred at 100 C for 4 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl. During the washing white solids precipitated out, which were collected to give the titled compound (412 mg). MS 518.5 (M+H); UV 201.6, 249.8 nm.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][O:41][C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:40][O:41][C:42]([NH:44][C@H:45]([C:49]([N:2]1[CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:1]1)=[O:50])[CH:46]([CH3:47])[CH3:48])=[O:43]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (101) (200 mg, 0.94 mmol), HATU (392 mg, 1.03 mmol) and N-[(methyloxy)carbonyl]-L-valine (181 mg, 1.03 mmol) in anhydrous CH2Cl2 (6 mL) was added Hunig's base (0.33 mL, 1.88 mmol) and the solution stirred at rt under nitrogen. After 2 h, the reaction was concentrated in vacuo, purified by C18 RP chromatography, eluting with 10-90% ACN/water/0.2% NH4OH, to afford the product as a yellow oil (313 mg, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:10]([Cl:23])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(F)c(F)c2)cc1
Solvent: ClCCl
Product: CSc1ccc(C=C(C(=O)Cl)c2ccc(F)c(F)c2)cc1
Reaction time: 1 h
Yield: 102.2 %

Procedure:
A mixture of 2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]acrylic acid (12 g) and phosphorus pentachloride (9.0 g) in dichloromethane (120 ml) was stirred for 1 hour. The solvent was evaporated to give a solid of 2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]acryloyl chloride (13 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:41][CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: O=C(NC1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and tetrahydro-2H-pyran-4-amine using methods similar to Example 563 to provide a white solid: ES+ MS: 523 (M+H+).