Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:25](O)=[O:26]>>[F:19][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[N:30]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1ncccc1-c1ccncc1NCC(F)F
Product: COc1ncccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-(2-methoxy-[3,4]bipyridinyl-3′-yl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 67 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (64%). MS (ESI): m/z=507.11 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH3:22][CH:23]1OS(=O)(=O)[N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]1>CN(C=O)C>[C:34]([O:33][C:31]([NH:26][CH2:25][CH2:24][CH:23]([N:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:22])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Reactant: CC1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCNC(=O)OC(C)(C)C)c2n1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 1.00 g, 3.81 mmol) in DMF (15 mL) cooled to 0° C. is added 60% sodium hydride in mineral oil (168 mg, 4.19 mmol). The mixture is stirred at 0° C. for 20 min after which a solution of tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (1.05 g, 4.19 mmol) in DMF (2 mL) is added. After being stirred overnight, the mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The layers are separated and the aqueous layer is further extracted with ethyl acetate. The combined organic phases are washed with brine, and are dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-30% ethyl acetate/heptanes to afford the title compound as a yellow oil (1.20 g, 73%). LCMS: 434.89 (M+H+).
Reaction SMILES: [F:1][C:2]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]1.FC(F)(F)C([O-])=O.[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH3+:37].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH:37][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:2]2([F:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(CC2(F)C#CCCCCC2)cc1
Reactant: [NH3+]CCCN1C(=O)C=CC1=O
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C=CC1=O)c1ccc(CC2(F)C#CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
TEA (0.508 mL, 3.65 mmol) was added to a solution of cyclooctyne 3b (0.200 g, 0.768 mmol), amine 13 (0.235 g, 0.875 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (HATU, 0.305 g, 0.802 mmol), and 1-hydroxybenzotriazole (HOBT, 0.123 g, 0.802 mmol) in CH2Cl2 (3 mL) at rt. The reaction was stirred for 15 min at rt, quenched with H2O (10 mL), and diluted with CH2Cl2 (50 mL). The organic layer was washed with 1 N HC, (3×50 mL), saturated NaHCO3 (3×50 mL), and brine (2×25 mL) and dried over MgSO4. Chromatography of the crude product (2:1 to 1:1 hexanes/EtOAc) yielded the desired product as a white solid (0.198 g, 65%, Rf=0.30 in 1:1 hexanes/EtOAc), mp 122.0-124.0° C. (dec). IR: 3413, 2931, 2854, 2222, 1705, 1640 cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.39 (m, 1H), 1.74 (m, 2H), 1.81-2.06 (m, 6H), 2.14-2.32 (m, 3H), 3.05 (d, 1H, J=2.8 Hz), 3.09 (s, 1H), 3.40 (q, 2H, J=6.4 Hz), 3.67 (t, 2H, J=6.0 Hz), 6.75 (s, 2H), 6.93 (m, 1H), 7.41 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 20.5, 26.0, 28.1, 29.4, 34.0, 34.8, 36.2, 44.6 (d, J=25.0 Hz), 47.8 (d, J=24.0 Hz), 90.7 (d, J=32.0 Hz), 95.3 (d, J=174.0 Hz), 104.5 (d, J=10.0 Hz), 126.7, 130.5, 132.9, 134.2, 139.6, 167.1, 171.1. 19F NMR (CDCl3, 376 MHz): δ −139.0 (m). FAB—HRMS: Calcd. for C23H26N2O3F+ [M+H]+: 397.1927, found: 397.1920.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>ClCCl>[CH3:18][O:17][CH:12]([O:15][CH3:16])[C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: COc1ncc(Br)cc1C=O
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: COc1ncc(Br)cc1C(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.58 g of 5-bromo-2-methoxy-3-pyridinecarboxaldehyde was dissolved in 30 ml of dichloromethane, a mixture of 9 ml of trimethyl orthoformate and montmorillonite K-10 (3 g) was added thereto, and the mixture was stirred at room temperature for 2 hours. After filtering the reaction solution, the filtrate was evaporated. To the residue was added ethyl acetate, followed by filtering through alumina. The filtrate was evaporated, to give 3.09 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:26])[CH:16]=2)[N:11]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
Intermediate 5 ( 0.0528 mol) was added in phosphoryl chloride (200 ml) at room temperature. The mixture was stirred at 100° C. for 3 hours and cooled to room temperature. The solvent was evaporated. The residue was taken up in DCM. The solvent was evaporated till dryness. The residue was taken up in DCM, poured out into ice water, neutralised with K2CO3 solid and extracted with DCM. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 8.5 g (40%) of intermediate 6. The mother layer was evaporated. The residue was purified by column chromatography over silica gel (eluent:toluene/EtOAc 95/5; 15-35 μm). The pure fractions were collected and the solvent was evaporated. A part (0.5 g) of the residue (8.9 g, 42%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.3 g of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-fluorophenyl)-methanone (intermediate 6), mp. 138° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(OP(N)([NH2:24])=O)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([NH2:24])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1[nH]c(=O)ccc1-c1ccccc1
Reactant: NP(N)(=O)Oc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(N)ccc1-c1ccccc1

Procedure:
A mixture of 6-methyl-5-phenyl-2-pyridone (12.0 grams) and phenylphosphorodiamidate (14.4 grams) in 300 ml diphenyl ether was heated for 19-20 hours at approximately 220°-225° [250]° C. After cooling, the reaction mixture was chromatographed over silica gel with ethyl acetate. A total of 0.8 gram, of desired product was collected and recrystallized from dichloromethane/petroleum ether, m.p. 110°-113° C.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8](OC(C)(C)C)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1CBr)[C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[CH2:8][N:2]1[CH2:3][C@@H:4]2[CH2:7][C@H:1]1[CH2:6][NH:5]2)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)c(OC)c1

Procedure:
Following the above procedure, 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and methyl 3-methoxy-4-(bromomethyl)benzoate are reacted together to give methyl 3-methoxy-4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[C:8]2[N:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:7]1=2)=[O:5].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:22][N:18]1[C:8]2[C:9](=[O:17])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([C:4](=[O:5])[CH2:3][CH2:2][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:7]=2[C:20]([CH3:21])=[CH:19]1
Reactant: Cc1cn(C)c2c1N(C(=O)CCBr)c1ccccc1NC2=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCN1CCCC1)c1ccccc1NC2=O

Procedure:
1.9 g of 4-(3-bromopropionyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 0.75 g of pyrrolidine are warmed at 80° C. for 4 hours in 50 ml of dioxane. After the solvent has been stripped off in vacuo, the residue is taken up in a little saturated sodium carbonate solution. The mixture is extracted three times with 30 ml of ethyl acetate each time, the combined extracts are dried over sodium sulfate, and the solvent is stripped off in vacuo. The remaining crystalline residue is recrystallized from a little acetonitrile. Yield: 1.5 g of the title compound of m.p. 185° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])([CH3:6])[CH2:3][CH2:4][OH:5].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:6][C:2]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])([CH3:1])[CH2:3][CH:4]=[O:5]
Reactant: COc1ccc(F)cc1C(C)(C)CCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC=O
Reaction time: 3 h

Procedure:
To a solution of 3-methyl-3-(2-methoxy-5-fluorophenyl)butan-1-ol (3.30 g) in methylene chloride (40 mL) stirred at room temperature was added pyridinium chlorochromate (4.2 g) portionwise over 5 minutes. The mixture was stirred for 3 hours and then filtered through CELITE® filter aid. The solvent was evaporated in vacuo and the residue was fractionated by chromatography over silica gel (methylene chloride-hexane (1:3 to 1:1 gradient)) to give 3-methyl-3-(2-methoxy-5-fluorophenyl)butyraldehyde an oil (2.5 g, 76%).
Reaction SMILES: C([Li:5])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]>CCOCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Li:5])[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li]c1cc(OC)c(OC)c(OC)c1
Reaction time: 1 h

Procedure:
To a stirred solution of n-butyllithium (15.0 mL, 1.6 M in hexane solution, 24.0 mol) in dry ether (160 mL), a solution of 3,4,5-trimethoxyphenylbromide (2.97 g, 12.0 mol) in ether (40 mL) was added under dry nitrogen at −78° C. The solution was stirred for 1 h in order to form 3,4,5-trimethoxyphenyllithum.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.S(=O)(=O)(O)[OH:27]>CCOC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=3[C:15]([NH2:16])=[O:27])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1ccc(C#N)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(N)=O)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL round-bottomed flask charged with 2-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-methylbenzonitrile (PREPARATION x83, 52 mg, 0.146 mmol) was added sulfuric acid (1.6 mL, 29.2 mmol). The resulting yellow solution was stirred overnight at room temperature and was subsequently diluted with EtOAc and washed with saturated NaHCO3 to adjust the pH to −8. The combined organic layers were dried over MgSO4, filtered, and concentrated to give an orange solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.88-3.02 (m, 5H), 3.09-3.18 (m, 3H), 3.19-3.28 (m, 2H), 3.41-3.51 (m, 3H), 3.59-3.71 (m, 2H), 3.80-3.91 (m, 3H), 3.91-4.00 (m, 2H), 4.19-4.29 (m, 3H), 4.30-4.58 (m, 2H), 7.16-7.29 (m, 10H), 7.37-7.45 (m, 2H), 7.73-7.82 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C18H20ClN5O2, 374.1. found 374.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1I.[CH3:12][O:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][N:19]([C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[S:20]([C:23]2[CH:24]=[CH:25][C:26]3[NH:31][CH2:30][CH2:29][O:28][C:27]=3[CH:32]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:31]1[CH2:30][CH2:29][O:28][C:27]2[CH:32]=[C:23]([S:20]([N:19]([CH2:18][C:17]3[CH:38]=[CH:39][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:21])=[O:22])[CH:24]=[CH:25][C:26]1=2
Reactant: CC(C)c1ccc(I)c(Br)c1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(C)C)cc2Br)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
A microwave vial was charged with 2-bromo-1-iodo-4-isopropylbenzene (Oakwood, 0.117 g, 0.359 mmol), N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M, 0.150 g, 0.359 mmol), Xantphos (0.042 g, 0.072 mmol), Pd2(dba)3 (0.033 g, 0.036 mmol) and sodium tert-butoxide (0.069 g, 0.719 mmol). The mixture was diluted with toluene (3.59 ml), and purged with nitrogen, and stirred at 130° C. in the microwave for 30 minutes, until clean conversion to the desired product. After completion, the reaction was filtered over a plug of Celite, washing well with DCM. The filtrate was concentrated in vacuo. The crude material was purified using a 5-g SCX column (product eluted with methanol wash to yield 4-(2-bromo-4-isopropylphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.175 g, 0.285 mmol, 79% yield) as an orange oil. m/z (ESI) 614.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:29](=[O:30])[N:5]2[C:6]([C:13]([O:15]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:14])=[C:7](/[CH:10]=[CH:11]\[CH3:12])[CH2:8][S:9][C@H:4]12.C(=O)(O)[O-].[Na+].[NH2:36][C:37]1[S:38][CH:39]=[C:40](/[C:42](=[N:55]/[O:56][CH3:57])/[C:43](ON2C3C=CC=CC=3N=N2)=[O:44])[N:41]=1>CN(C=O)C>[NH2:36][C:37]1[S:38][CH:39]=[C:40](/[C:42](=[N:55]/[O:56][CH3:57])/[C:43]([NH:2][CH:3]2[C:29](=[O:30])[N:5]3[C:6]([C:13]([OH:15])=[O:14])=[C:7](/[CH:10]=[CH:11]/[CH3:12])[CH2:8][S:9][C@H:4]23)=[O:44])[N:41]=1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(N)n1
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 117 %

Procedure:
To a stirred solution of 7-amino-3-trans-propenyl derivatives XIII (E, R3 =R4a =H) (720 mg, 3 m moles) and sodium bicarbonate (504 mg, 6 m moles) in 50% DMF (60 ml) was added 1-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzotriazole (954 mg, 3 m moles) and the mixture was stirred for 30 min. An additional amount of the active ester (1.81 g, 6 m moles) was added in four portions at 30-min intervals. The mixture was stirred for additional 2 hr at room temperature and passed through a column packed with the packing of prepPAK-C18 cartridge (300 ml, Waters). The column was washed with water and then eluted successively with 10% methanol and 20% methanol. Fractions of 20% methanol eluate showing a peak at retention time 5.57 min by HPLC* were collected and evaporated to dryness. The residue was dissolved in methanol and filtered. The filtrate was concentrated to 5 ml and the residue was triturated with a mixture of ether-isopropyl ether to give 805 mg (63%) of the title compound, melting at 180° C. (grad. dec.), 80% pure by HPLC*.
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:42][O:43][CH3:44])[C:11]([NH:13][CH:14]2[C:40](=[O:41])[N:16]3[C:17]([C:37]([OH:39])=[O:38])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH2:28][NH:29]C(OC(C)(C)C)=O)=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[ClH:1].[ClH:1].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:42][O:43][CH3:44])[C:11]([NH:13][CH:14]2[C:40](=[O:41])[N:16]3[C:17]([C:37]([OH:39])=[O:38])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH2:28][NH2:29])=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Conc.hydrochloric acid (1.82 g) was added to a suspension of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 3.9 g) in methanol (60 ml), and the mixture was stirred at room temperature for 2 hrs. After evaporation of the solvent under reduced pressure, methanol was added to the residue and evaporated again. The residue was washed with diethyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 3.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.ClC1C=CN=CC=1.[Li+].CC([N-]C(C)C)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=C(Br)[S:35][CH:36]=2)=[CH:28][CH:27]=1>[Cl-].[Cl-].[Zn+2].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:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:8]([C:7]3[CH:6]=[N:5][CH:4]=[CH:3][C:2]=3[Cl:1])[S:35][CH:36]=2)=[CH:30][CH:31]=1
Reactant: O=Cc1cnccc1Cl
Reactant: Clc1ccc(-c2csc(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Clc1ccncc1
Product: Clc1ccc(-c2csc(-c3cnccc3Cl)n2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
According to the synthetic example of compound (19), 4-chloropyridine (1.14 g, 10.0 mmol) and LDA (12 mmol) were reacted and ZnCl2 (1.63 g, 12.0 mmol) was added to the obtained the reaction mixture. The mixture was stirred at −78° C. for 10 min. and compound (41) (548 mg, 2.0 mmol) and tetrakistriphenylphosphinepalladium (580 mg, 0.5 mmol) were added. The mixture was stirred at room temperature for 30 hrs. The reaction mixture was partitioned between ethyl acetate and NH4Cl aq., and the ethyl acetate layer was washed once with NH4Cl aq. The extract was dried (MgSO4) and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (250 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)([OH:16])[CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)([OH:16])[CH3:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(O)(c1cccc(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(O)(c1cccc(-c2ccc(F)cc2)c1)c1c[nH]cn1
Yield: 68.8 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-ethanol (1.51 g) and pyridine hydrochloride (599 mg), the title compound (559 mg) was obtained as colorless plate crystals.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:35][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ncccn4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ncccn3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield the desired product. 1H NMR (400 MHz, CDCl3) δ8.76 (d, 1 H), 8.45 (d, 2 H), 8.06 (d, 2 H), 7.15 (t, 2 H), 6.76 (d, 2 H), 6.71 (d, 2 H), 4.14 (t, 2 H), 2.93 (t, 2 H), 2.33 (s, 3 H), 1.45 (s, 6 H); MS (EI) 460.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]=[CH2:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:12]([O:11][C:10]1[CH:15]=[CH:16][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C=CCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Methanesulfonyl chloride (5.06 mL, 65.32 mmol) was added to a stirred solution of 3-[(4-amino)phenoxy]-1-propene (8.11 g, 54.43 mmol) in pyridine (80 mL) at 0° C. The mixture was stirred for 72 hours and was then poured slowly into ice-water and extracted with ether. The organic phase was washed with cold 1N HCl and was then extracted with 1N NaOH solution. The aqueous phase was acidified and the product (9.05 g, 73%) precipitated out as a white solid.