Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]
Reactant: Cc1ccc(Nc2ncccn2)cc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ncccn2)ccc1C
Yield: 57 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-methyl-5-(pyrimidin-2-ylamino)phenol (65 mg, 0.32 mmol) and Cs2CO3 (111 mg, 0.34 mmol) in acetone (3.2 mL) was treated with 4-bromo-2-methyl-2-butene (37 μL, 0.34 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 57% yield (50 mg).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15](CC2CCCC2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.[CH:34]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:38][CH2:37][CH2:36][CH2:35]1.[CH:63]1(CNC2C=C(C=CC=2)C(N(C)C)=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:34]1([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[N:23]([CH3:24])[CH3:25])[CH:17]=2)[C:13](=[O:14])[N:12]([CH3:63])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:33])=[CH:8][N:9]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N(C)C)c2)s1
Reactant: CN(C)C(=O)c1cccc(NCC2CCCC2)c1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CN(C)C(=O)c1cccc(N(C(=O)N(C)c2ncc(SCC(=O)O)s2)C2CCCC2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoylphenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.Cl[C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45]>C1(C)C=CC=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OC(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.087 g, 0.23 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) at 0° C. was added N,N-Diisopropylethylamine (0.1190 mL, 0.6832 mmol) followed by 1.0 M of Isopropyl Chloroformate in Toluene (0.340 mL). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.84 (dt, J=12.5, 6.2, 1H), 4.49 (s, 2H), 3.79-3.68 (m, 4H), 3.55 (s, 2H), 3.47 (d, J=4.4, 4H), 3.18-3.05 (m, 2H), 2.68 (t, J=5.0, 2H), 1.24 (d, J=6.2, 6H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+469.3 (M+H)+
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[C:22](/[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](/[C:36](/[CH3:48])=[CH:37]/[CH2:38][O:39][CH2:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)\[CH3:23])C.Cl>C1COCC1.C(O)C>[Si:41]([CH2:40][O:39][CH2:38]/[CH:37]=[C:36](/[C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24](/[C:22](/[CH3:23])=[CH:21]/[CH2:20][OH:19])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1)\[CH3:48])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc(-c2ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc2)cc1
Reaction time: 0.5 h

Procedure:
A 1M solution of DIBAL-H in toluene (7.3 mL, 7.3 mmol) was, under a atmosphere of nitrogen, added dropwise at −70° C. over 20 min. to a stirred solution of (E)(E) 3-(4′-{3-[(tert-butyldimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-enoic acid ethyl ester (1.13 g, 2.43 mmol) in dry THF (25 mL). The mixture was stirred for 30 min. followed by 2 h at room temperature. Ethanol (1 mL) was carefully added, followed by 1N HCl (50 mL) and the resulting mixture extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give 1.02 g (99%) of (E)(E) 3-(4′-{3-[(tert-butyldimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-en-1-ol.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:20]=[CH:19][C:17](N)=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[BrH:21].N([O-])=O.[Na+].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28]>CC(C)=O.O.[Cu]I>[Br:21][CH:27]([CH2:28][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:15][CH:16]=1)[C:26]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: C=CC(=O)OCC
Reactant: Br
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(N)cc1
Agent: [Cu]I
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Br)Cc1ccc(OCCn2c(CC)nc(C)cc2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]aniline (2.80 g, 10.26 mmol) (obtained from preparation 22) in acetone (10 ml) was added aqueous HBr (47%, 1 ml) and stirred for 10 min. at 0° C. To the above reaction mixture a solution of NaNO2 (850 mg, 12.30 mmol) in water (1.7 ml) was added slowly dropwise at 0° C. and stirring was continued further for 30 min at the same temperature. To this reaction mixture, ethyl acrylate (6.77 ml, 62.0 mmol) was added and allowed to warm to 30° C. Catalytic amount of copper (I) iodide (20 mg) was added in one portion and the reaction mixture was stirred further for 1 h at 30° C. Acetone was removed under reduced pressure and the resultant residue was extracted with EtOAc (3×10 ml). The combined EtOAc layers were washed with dilute NH3 solution, water, followed by brine; dried over anhydrous Na2SO4 and concentrated to afford the crude compound which was purified by flash chromatography using 40% EtOAc/petroleum ether as eluent to yield the title compound (2.47 g, 55%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2>N1C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)=[O:6]
Reactant: CCCCOC(=O)c1ccc2ccc(C)nc2c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCCCOC(=O)c1ccc2ccc(C)nc2c1OC(=O)C(C)(C)C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
10.4 ml (84 mmol) of pivaloyl chloride are added, at 0° C., to a solution of the preceding ester 2 (step 1) (11.0 g, 42 mmol) in pyridine (45 ml). After 1 hour at 20° C., the pyridine is distilled under reduced pressure, and then 20 ml of water and 50 ml of dichloromethane are added. The phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting with a 2/1 cyclohexane/ethyl acetate mixture so as to give 11.7 g (82%) of n-butyl 8-(2,2-dimethylpropionyloxy)-2-methylquinoline-7-carboxylate 3 in the form of a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][C@H:15]1[CH2:20][N:19]([CH3:21])[CH2:18][CH2:17][N:16]1[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.O1CCOCC1>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:16]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C@@H:15]3[CH3:14])=[CH:28][CH:27]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: C[C@H]1CN(C)CCN1c1ccc(N)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)C[C@@H]3C)cc2)nc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (420 mg), 4-[(2S)-2,4-dimethylpiperazin-1-yl]aniline (392 mg), diisopropylethylamine (665 μL), and dioxane (8.4 mL) was stirred at 110° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=95:5) to obtain 5-chloro-3-({4-[(2S)-2,4-dimethylpiperazin-1-yl]phenyl}amino)-6-ethylpyrazine-2-carboxamide (560 mg) as a brown solid.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:13]N1C(=O)C2=CC=CC=C2C1=O.[C:25]([OH:28])(=O)[CH3:26]>>[C:5]12([OH:13])[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][C:3]([OH:11])([CH2:2]3)[CH2:4]1)[CH2:6]2.[C:25]12([OH:28])[CH2:26][C:7]3([OH:13])[CH2:8][C:1]([OH:12])([CH2:2][C:3]([OH:11])([CH2:9]3)[CH2:4]1)[CH2:10]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Product: OC12CC3(O)CC(O)(C1)CC(O)(C2)C3
Product: OC12CC3CC(O)(C1)CC(O)(C3)C2
Temperature: 95 °C
Reaction time: 6 h
Yield: 37 %
Yield: 62 %

Procedure:
A mixture of 1.68 grams (10 millimoles) of 1,3-adamantanediol, 0.13 gram (0.8 millimole) of N-hydroxyphthalimide, 0.015 gram (0.06 millimole) of Co(AA)2 and 25 milliliters of acetic acid was stirred under an oxygen atmosphere at a temperature of 95° C. for 6 hours. Thus, 1,3-adamantanediol was transformed, with a transformation rate of 99%, into 1,3,5-adamantanetriol (selectivity for 1,3-adamantanediol 37%, yield 37%) and 1,3,5,7-adamantanetetraol (selectivity for 1,3-adamantanediol 62%, yield 62%). The selectivity for the alcohols was 99%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[C:10]([Br:33])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1

Procedure:
Prepared in analogy to that of Example 133(a) from 2,3-Dibromo-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NBS in MeCN. The title compound, ESI MS (m/z): 547 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:27]=2[O:28][C:29]=1[CH3:30])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:31][C:27]=2[O:28][C:29]=1[CH3:30])=[O:24]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@H]5COC)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-2-methoxymethylpyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 2a with 6-Hydroxy-2-methyl-benzofuran-3-carboxylic acid methyl amide 12c and Cs2CO3 in a manner as previously described for example 1. 1H NMR (DMSO-d6). δ8.57 (1H, d, J=5.3 Hz), 8.02 (1H, s), 7.98 (1H, m), 7.83 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.0 Hz), 7.25 (1H, dd, J=8.6, 2.0 Hz), 6.72 (1H, d, J=5.3 Hz), 4.31 (1H, m), 3.94-3.80 (2H, m), 3.60-3.39 (2H, m), 3.28 (3H, s), 2.82 (3H, d, J=4.6 Hz), 2.63 (3H, s), 2.06-1.85 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1

Procedure:
Following the general procedure of Example 39, Step 2, and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.2982 g) and 1-[3-(trifluoromethyl)phenyl]piperazine (Aldrich; 0.34 mL) are converted to product, followed by chromatography on silica gel using methanol/dichlormethane (2/98). Crystallization from ethyl acetate and then from ethyl acetate/dichloromethane gives 0.053 g of the title compound; mp 145-145.5° C.; MS m/z 394; IR (mineral oil) 1117, 1163, 1451, 1073, 1339 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.28, 3.78, 7.12, 7.34, 7.52, 7.54, 8.14.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([O:58][C:59]([NH:61][C:62]1[S:63][CH:64]=[C:65]([C:67](=[O:71])[C:68](O)=[O:69])[N:66]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:68](=[O:69])[C:67]([C:65]4[N:66]=[C:62]([NH:61][C:59]([O:58][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:60])[S:63][CH:64]=4)=[O:71])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and 2-(2-t-butoxycarbonylaminothiazol-4-yl) glyoxylic acid (303 mg : 1.11 mMol.) in dichloromethane (8 ml) cooling at -30° C., are added N- methylmorpholine (0.27 ml) (2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 1 hour. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=2:1) to give 7β-[2-(2-t-butoxycarbonylaminothiazol-4-yl)- glyoxylylamino]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4- carboxylic acid diphenylmethyl ester (679 mg) as yellow foam. Yield : 64%.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[Li+].O>CN(C=O)C.C1COCC1>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCNC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and pyrrolidine (Fluka 83240; 500.48 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 60° C. for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4Cl. The organic layer was washed three times with aq. NH4Cl then brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The latter was taken up in THF (5 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) then water (5 mL) were added. The reaction mixture was stirred at room temperature for 16 hours then the THF was evaporated and the residue was diluted with water. After acidification with AcOH, the formed precipitate was filtered and dried under high vacuum to afford the title compound (497 mg, 90%) as a yellow solid.
Reaction SMILES: [Na].C(O)C.[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]([C:19]#[N:20])[CH:14]=[CH:15][CH2:16][CH2:17]C>CCCCCC>[NH2:20][C:19]1[CH2:13][CH:14]([CH2:15][CH2:16][CH3:17])[N:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]=1
Reactant: CCCC=CCC#N
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCCCCC
Solvent: CCO
Product: CCCC1CC(N)=NN1c1ccccc1

Procedure:
A 0.2 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 3.1 g. of phenylhydrazine is added followed by 2.7 g. of 2-hexenecarbonitrile. The reaction mixture is refluxed for 18 hours then is evaporated to dryness in vacuo. The residue is dissolved in dichloromethane. The solution is washed with water, dried over anhydrous magnesium sulfate, filtered through a short column of a hydrous magnesium silicate and evaporated to dryness in vacuo to give a tan gum. Hexane is added and the gum solidifies. The tacky solid is collected and dried. The solid is dissolved in ether and concentrated while adding hexane to give 3.3 g. of the product of the Example as light tan crystals, m.p. 118°-120° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([C:19]2[CH:23]=[C:22]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])[S:21][C:20]=2[C:30]([OH:32])=[O:31])[C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][O:34][P:35]1(=[O:42])[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:29][C:26]([CH3:27])([CH3:28])[C:25]#[C:24][C:22]1[S:21][C:20]([C:30]([OH:32])=[O:31])=[C:19]([N:9]([CH:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH:38]3[CH2:39][CH2:40][P:35]([O:34][CH3:33])(=[O:42])[CH2:36][CH2:37]3)[CH2:8][CH2:7]2)[C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH3:18])[CH2:16][CH2:17]2)=[O:11])[CH:23]=1
Reactant: COP1(=O)CCC(=O)CC1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(N)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COP1(=O)CCC(NC2CCC(N(c3cc(C#CC(C)(C)C)sc3C(=O)O)C(=O)[C@H]3CC[C@H](C)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(N-(4-aminocyclohexyl)-4-methylcyclohexanecarboxamido)-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylic acid hydrochloride (40 mg, 0.083 mmol) and 1-methoxy-1-oxo-1λ5-phosphinan-4-one (27 mg, 0.166 mmol) were dissolved in 2 mL of DMF. Sodium triacetoxyborohydride (35 mg, 0.166 mmol) was added. The reaction mixture was allowed to stir at room temperature over 18 hours, and then diluted with EtOAc, washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid) to give title compound (38.6 mg): MS (m/z): 591.3 [M+H]−; HPLC retention time: 3.28 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[F:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 4-fluoro-3-hydroxybenzoate (2.814 g, 15.3 mmol), K2CO3 (1.95 g, 14.1 mmol) in DMF (15 ml) was added 2,6-Dimethylbenzyl chloride (2.21 g, 14.3 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours at the room temperature, diluted with ethyl acetate and washed with water (2×), and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 4:1) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.COC(OC)[N:39]([CH3:41])C.C[N:45](C=O)C.C(OCC)(=O)C>O>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2[NH:45][N:39]=[CH:41][C:33]=2[CH2:34]1
Reactant: COC(OC)N(C)C
Reactant: CN(C)C=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3[nH]ncc3C2)c2ncnn12
Temperature: 85 °C
Reaction time: 11 h
Yield: 71 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.0 g), 1,1-dimethoxy-N,N-dimethylmethanamine (2.5 mL) and N,N-dimethylformaldehyde (2.5 mL) was stirred at 85° C. for 11 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethanol (10 mL). Hydrazine monohydrate (1 mL) was added, and the mixture was heated under reflux for 1.5 hr. Ethyl acetate and water were added to the reaction mixture. After evaporation of the solvent under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.74 g, 71%).