Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH:33]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCCC1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCCC4)ncnc32)[C@]1(C)F
Yield: 67.4 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.55 g, 1.10 mmol) in ethanol (about 5 ml) was added cycloheptylamine (about 1.80 ml, 14.2 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.4 g) as a colorless solid. Yield: 62%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 8.04 (d, 2H), 7.97 (s, 1H), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 2H), 6.52 (d, 1H, J=22.2 Hz), 5.81 (bs, 1H), 4.83-4.77 (m, 2H), 4.48-4.41 (m, 1H), 2.15 (s, 3H), 1.89-1.88 (s, 3H), 1.62-1.11 (m, 16H); ES Mass: [M+1]+ 540 (60%), [M+Na] 562 (100%); IR cm−: 3430, 2924, 2853, 2348, 1753, 1725, 1617, 1451, 1274, 1060, 950, 711. HPLC: 92%.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[CH2:20]([O:22][C:23](=[O:47])[C@H:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42](Br)[CH:41]=2)[CH:34]=1)[NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH3:21].C(OCC)(=O)C>O1CCOCC1>[CH2:20]([O:22][C:23](=[O:47])[C@H:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[CH:45]=2)[CH:34]=1)[NH:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CCOC(=O)[C@H](Cc1cccc(Oc2cccc(Br)c2)c1)NC(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1cccc(Oc2cccc(-c3ccncc3)c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A solution of 4-(tributylstannyl)pyridine (288 mg, 0.782 mmol) in degassed 1,4-dioxane (1 ml) and tetrakis(triphenyl-phosphine)palladium (46 mg, 0.04 mmol) were added in turn to a solution of 3-(3-bromophenoxy)-N-trifluoroacetyl-L-phenylalanine ethyl ester (360 mg, 0.782 mmol) in degassed 1,4-dioxane (6 ml) at room temperature and the mixture was stirred under heating for 8 hrs. After the mixture was cooled to room temperature, ethyl acetate was added thereto and the mixture was washed with saturated sodium fluoride solution, water and brine in turn and then dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1) to give N-trifluoroacetyl-3-[3-(4-pyridyl)phenoxy]-L-phenylalanine ethyl ester (235 mg, 66%) as colorless resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35])(OCC)=O>O.C(#N)C>[C:26]1(=[O:35])[N:13]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:12])[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(C)N)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(C)N2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27.3 %

Procedure:
To a stirred solution of 1-(3′,4′dimethoxyphenyl)ethylamine (1.81 grams, 10.0 mmol) and sodium carbonate (1.14 grams, 10.8 mmol) in a mixture of water (80 milliliters) and acetonitrile (50 milliliters) was added N-carbethoxyphthalimide (2.19 grams, 10 mmol). The resulting suspension was stirred for 3.5 hours at room temperature and then filtered to afford 1.24 grams (40%) of crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 0.85 grams (27%) of the product as white crystals: mp 124-125° C.; 1H NMR (DMSO-d6) δ7.96-7.78 (m, 4H), 7.09-6.81 (m, 3H), 5.40 (q, J=7.2 Hz, 1H), 3.73 (s, 3H), 3.72(s, 3H), 1.81 (d, J=7.2 Hz, 3H); 13C NMR (DMSO-d6) δ167.6, 148.4, 148.0, 134.4, 132.9, 131.3, 122.9, 118.8, 111.5, 110.8, 55.4, 48.6, 17.7. Anal. Calculated for C18H17NO4. Theoretical: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.63; H, 5.45; N, 4.42. HPLC 100%.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27]>ClCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([F:27])=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (I-5D, 197 mg, 0.766 mmol) and pyridine (0.074 mL, 0.919 mmol) in dichloromethane (5 mL) at room temperature was added cyanuric fluoride (0.078 mL, 0.919 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (40 mL) and washed with an ice-cold 0.5N aqueous solution of hydrochloric acid (20 mL). The aqueous layer was extracted with dichloromethane (20 mL), and the combined organic layers were washed with ice-cold water (20 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (199 mg, 0.768 mmol, 100% yield) as a pale yellow oil. The compound had an HPLC retention time=2.53 min. (methyl ester)-Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][O:12][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (3,4-dihydroxybutyl)carbamic acid tert-butyl ester (2.60 g, 12.7 mmol), triethylamine (2.03 mL, 14.50 mmol) and 4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) in anhydrous dichloromethane (40 mL) at room temperature was added tert-butyldimethylchlorosilane (2.0 g, 13.17 mmol) in one portion. The resulting mixture was stirred at room temperature for 18 hours, washed with water, brine and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave an oil which was purified by column chromatography on silica using ethyl acetate-petroleum ether mixture as eluent to afford a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](I)[S:12][C:3]=12.[CH3:14][N:15]([CH3:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.O>COCCOC.C(=O)(O)[O-].[Na+].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:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:16]([N:15]([CH3:25])[CH3:14])=[CH:17][CH:18]=3)[S:12][C:3]=12
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(C)c1ccc(-c2cc3ncc(C#N)c(Cl)c3s2)cc1
Yield: 59.6 %

Procedure:
A mixture of 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (321 mg, 1.0 mmol), 4-(dimethylamino)phenylboronic acid (248 mg, 1.5 mmol) and 58 mgs of tetrakis(triphenylphosphine)palladium(0) in 13 mL of ethylene glycol dimethyl ether and 11 mL of aqueous saturated sodium bicarbonate is heated at reflux for 6 hours. 4-(dimethylamino)phenylboronic acid (105 mg) and tetrakis(triphenylphosphine)palladium(0) (29 mg) are added and the reaction mixture is heated at reflux for 6 hours. The mixture is treated with water and extracted into dichloromethane and the organic phase is washed with brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to provide 187 mg (60%) of 7-chloro-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as an orange solid, mp 270-272° C.; 1H NMR (CDCl3) δ 3.07 (s, 6H), 6.73 (d, J=5 Hz, 2H), 7.58 (s, 1H), 7.63 (d, J=5 Hz, 2H), 8.74 (s, 1H); HRMS found: 314.05127.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:19](Cl)=[O:20].[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH2:44])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH:44][C:19]([C:4]3[CH:5]=[C:6]([C:9]4[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:20])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 90.2 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (55 mg) was prepared from 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl chloride (31 mg, 0.1 mmol) and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (40 mg, 0.12 mmol) following the general procedure M.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccccn2)cc1
Temperature: 77 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of 4-formyl-phenylboronic acid (5.0 g, 33.0 mmol) and 2-bromopyridine (5.53 g, 35.0 mmol, 1.05 equiv.) in 265 mL of 4:3 toluene/95% ethanol was degassed with nitrogen for 30 minutes and then heated under a nitrogen atmosphere, resulting in a clear solution. A slurry of Pd(PPh3)4 (0.77 g) in 50 mL of a 4:4 mixture of toluene and 95% ethanol was added, followed by 50 mL of 3M aqueous Na2CO3. The resulting mixture was gently refluxed at 77° C. After 16 hours, the reaction mixture was cooled to room temperature, and the solid removed by filtration. The filtrate was transferred to a separatory funnel, and the layers separated. The aqueous layer was extracted with toluene (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and dried over sodium sulfate. The solution was filtered, and the filtrate concentrated under reduced pressure to give a yellow oil. Purification by Biotage chromatography (40+M cartridge; gradient, 0 to 5% methanol/dichloromethane) gave 4.13 g (68%) of (3) as a light-yellow solid. TLC Rf (hexane/ethyl acetate, 2:1)=0.25; 1H NMR (CDCl3) δ 10.1 (s, HCO), 8.77 (d, 1H), 8.20 (d, 2H), 8.00 (d, 2H), 7.81 (m, 2H), 7.31 (q, 1H); MS (M)+=184; HPLC tR 1.2 minutes.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC[C@H](CCCCOCc1ccccc1)CCOc1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COC(=O)CC[C@H](CCCCO)CCOc1cccnc1

Procedure:
To a solution of methyl (S)-8-(benzyloxy)-4-[2-(3-pyridyloxy)ethyl]octanoate (1.1 g, 2.7 mmol) in ethanol (20 ml) is added cyclohexene (10.5 ml) followed by 20% palladium hydroxide on carbon (0.28 g). The mixture is heated at reflux for 18 hours. The catalyst is filtered off and washed with ethanol (3×10 ml). The solvent is evaporated and the residue purified by chromatography on silica gel using ethyl acetate as eluent to obtain methyl (S)-8-hydroxy-4-[2-(3-pyridyloxy)ethyl]octanoate; IR (CH2Cl2): 3600, 1732, 1282, 1230 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.O[NH:29][C:30](=[NH:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[O:12][N:37]=[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)c1ccncc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1nc(-c2ccncc2)no1

Procedure:
A solution of tert-butoxycarbonylaminoacetic acid (11.0 g, 5.71 mmol) and triethylamine (802 μl, 5.71 mmol) in toluene (30 ml) was cooled to 0° C. and isobutylchloroformate (740 μl, 5.71 mmol) introduced dropwise. The reaction mixture was stirred at 0° C. for 10 min and at rt for 30 min, whereupon N-hydroxyisonicotinamidine (652 mg, 4.76 mmol) and powdered 3 Å molecular sieves (4 g) were added. After heating under reflux for 12 h the reaction was cooled, filtered through celite and the solvent removed in vacuo. The residue was dissolved in EtOAc (200 ml) and washed with water (30 ml) and saturated aqueous NaHCO3 (30 ml), then dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (IH-EtOAc, 2:3) to afford the title compound: RT=2.97 min; m/z (ES+)=277.1 [M+H]+.
Reaction SMILES: Cl(O)(=O)(=O)=O.C(OC(NN=[C:13]([CH3:33])[C:14](=[N:30][O:31][CH3:32])[C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16])=O)C.[OH-:34].[Na+]>>[CH3:32][O:31][N:30]=[C:14]([C:13](=[O:34])[CH3:33])[C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16]
Reactant: CCOC(=O)NN=C(C)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: [OH-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 2 h

Procedure:
70% Perchloric acid (4.1 ml.) was added to a solution of 7-(3-ethoxycarbonylhydrazono-2-methoxyiminobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 4.1 g.) at room temperature and stirred at the same temperature for 2 hours. After adjusting to pH 2.0 with 1N sodium hydroxide aq. acetone was evaporated in vacuo from the resultant solution. Ethyl acetate (100 ml.) and a sodium chloride saturated aqueous solution (50 ml.) to the residue and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (100 ml.) and combined with the ethyl acetate layer. The solution was washed with a sodium chloride saturated aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether and the precipitates were collected by filtration to give 7-(2-methoxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 3.25 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.Cl[CH2:13][CH:14]=O.C(=O)(O)[O-].[Na+]>O>[CH3:11][O:10][C:4]1[N:3]2[CH:13]=[CH:14][N:1]=[C:2]2[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: O=CCCl
Reactant: COc1cc(N)nc(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc2nccn2c(OC)n1
Temperature: 80 °C

Procedure:
A mixture of 1.5 g (0.01 mole) of 4-amino-2,6-dimethoxypyrimidine and 3.0 g (0.015 mole) of 50% aqueous chloroacetaldehyde in 20 ml of water was heated at 80° C. for one hour, and was then cooled with an ice bath with concomitant neutralization with sodium bicarbonate. The solid which formed was separated by filtration and recrystallized from cyclohexane with treatment with decolorizing charcoal. White crystals of 5,7-dimethoxyimidazo[1,2-c]pyrimidine, m.p. 120°-121° C., were obtained. Analysis: Calculated for C8H9N3O2 : %C, 53.6; %H, 5.1; %N, 23.5; Found: %C, 53.5; %H, 5.0; %N, 23.6. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18](Cl)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:18](=[O:19])[C@H:16]([CH3:17])[NH:15][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:22]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)Cl
Reactant: CCO
Product: CCOC(=O)[C@H](C)N[C@@H](CCc1ccccc1)C(=O)OCC

Procedure:
In the Examples, the purity of the obtained inorganic acid salt of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanylchloride was measured by reacting the obtained acid chloride with ethanol in the presence of a base to produce N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine ethylester, which was then subjected to a high performance liquid chromatography (hereinafter referred to as "HPLC"). More particularly, about 100 mg of the sample of the acid chloride was put in a 10 ml messflask, to which absolute ethanol containing 0.3% (w/v) of triethylamine was added to give 10 ml of the solution and the esterification was carried out by stirring the solution with a magnetic stirrer at room temperature for 30 minutes. To 1.0 ml of the sample of the thus obtained solution, 4 ml of ethanol solution containing 10 mg of n-propylbenzoic acid (internal standard reagent) was added, the mixture was subjected to the analysis by the column chromatography under the following conditions.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:26]=1[N:32]1[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:34](=[O:45])[CH2:33]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:17]([O:24][C:25]1[CH:30]=[C:29](/[CH:16]=[CH:15]/[C:14]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:11]=[CH:12][CH:13]=2)[CH:28]=[CH:27][C:26]=1[N:32]1[S:36](=[O:37])(=[O:38])[N:35]([CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[C:34](=[O:45])[CH2:33]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=Cc1ccnn1COCc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/c3ccnn3COCc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 110 °C

Procedure:
A mixture of 1-benzyloxymethyl-5-vinyl-1H-pyrazole (385 mg, 1.80 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (500 mg, 0.90 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), P(o-tolyl)3 (43 mg, 0.14 mmol) and triethylamine (0.21 mL, 1.5 mmol) in MeCN is heated at 110° C. for 30 min in a microwave apparatus. The reaction mixture is concentrated and chromatographed using a gradient of 15-30% EtOAc/hexanes to afford the title compound as a yellow oil: (M+1)+=631.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13](=O)[CH3:14]>>[Br:1][C:2]1[C:3]2[O:10][CH:12]=[C:13]([CH3:14])[C:4]=2[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)c(F)cc1Br
Reactant: CC(=O)CBr
Product: Cc1coc2c(Br)cc(F)c(F)c12
Yield: 12 %

Procedure:
An operation similar to that in Step 1 of Example 12 was performed using 2-bromo-4,5-difluorophenol (1.05 g, 5.00 mmol) in place of 2-bromo-4-fluorophenol, and bromoacetone (0.504 mL, 6.00 mmol) in place of bromoacetaldehyde dimethyl acetal to thus obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:37][CH2:36]1
Reactant: OC1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCC(O)CC1
Yield: 42 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.3 equivalents of 4-hydroxy-piperidine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:16])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1sc(C(=O)O)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCc1sc(C(=O)OC)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The suspension of 4-bromo-5-ethylthiophene-2-carboxylic acid (800 mg) in MeOH (4 mL) was added dropwise SOCl2 (0.50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, warmed to 60° C., and then stirred for 15 hours. The reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=98:2 to 70:30) to obtain methyl 4-bromo-5-ethylthiophene-2-carboxylate (765.0 mg) as a colorless liquid.