Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=1.C(Cl)CCl.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=4)=[O:26])[CH2:22][CH2:23]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)O)CC3)nc3scnc23)cc1OC
Reactant: NCCc1cc[nH]c(=O)c1
Agent: Br
Agent: Cn1ccnc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(C(=O)NCCc4cc[nH]c(=O)c4)CC3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
The mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylic acid (70 mg, 0.22 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (70 mg, 0.32 mmol), EDC (170 mg, 0.89 mmol) and 1-methyl-1H-imidazole (108 mg, 1.32 mmol) in 20 mL of DCM was stirred at room temperature overnight. Excess of DCM was removed under reduced pressure and the residue was triturated with H2O (30 mL) and EtOAc (20 mL) then dried under reduce pressure to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)piperidine-4-carboxamide (25 mg, 40%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.62 (s, 1H), 7.61 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=7.2 Hz), 7.20 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.95 (d, 1H, J=8.7 Hz), 6.36-6.32 (m, 2H), 4.83-4.79 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.44 (t, 2H, J=6.8 Hz), 3.00-2.92 (m, 2H), 2.70 (t, 2H, J=6.8 Hz), 2.45 (brs, 1H), 1.80-1.64 (m, 4H). LC-MS: 536 [M+H]+, 534 [M−H]−, tR=1.38 min. HPLC: 95.70% at 214 nm, 96.10% at 254 nm, tR=3.65 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1.O1CCOC[CH2:34]1.C[Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23]([OH:25])([CH3:34])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1
Reactant: C1COCCO1
Reactant: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)=O)n3)cc2OC)cn1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)(C)O)n3)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(2-(3-Methoxy-4-(4-methoxy-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-4-yl)ethanone (145 mg, 0.32 mmol) was coevaporated with dioxane and dissolved in THF (10 mL). The mixture was added slowly to a well stirred solution of methylmagnesium bromide (0.857 mL, 3 M solution, 2.57 mmol) in THF (5 mL). The mixture was stirred at rt for 5 min. The mixture was cooled on ice bath and ammonium chloride (aq, 5 mL) was added. The mixture was extracted with ethyl acetate (2×10 mL), the organic phase was filtered and concentrated in vacuum. The residue was separated purified by preparative HPLC to give the title compound as a dry film, 68 mg (46%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]1[C:36]([CH2:37][O:38][CH3:39])=[C:35]([CH:40]=[O:41])[N:34]=[CH:33][C:14]=1[N:15]2[CH2:20][C:21]([N:23]([CH3:32])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]1[C:36]([CH2:37][O:38][CH3:39])=[C:35]([CH2:40][OH:41])[N:34]=[CH:33][C:14]=1[N:15]2[CH2:20][C:21]([N:23]([CH3:32])[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCc1c(C=O)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(CO)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
25 mg of sodium borohydride is added to a solution of 35 mg of 5-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carbaldehyde in 1 ml of tetrahydrofuran at 0° C., and it is then stirred for 3 hours at 0° C. Then, the reaction mixture is poured into ice water and extracted three times with ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation in a vacuum. 34 mg of 5-benzyloxy-3-hydroxymethyl-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole is obtained.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[N:20]1[N:21]([C:29]2[N:50]=[CH:49][CH:48]=[CH:47][C:30]=2[C:31]([NH:33][CH:34]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]([OH:39])[C:36](O)=[O:37])=[O:32])[CH:22]=[C:23]2[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]2.Cl.[CH3:52][O:53][NH2:54]>CN(C=O)C>[OH:39][CH:35]([C:36]([NH:54][O:53][CH3:52])=[O:37])[CH:34]([NH:33][C:31](=[O:32])[C:30]1[CH:47]=[CH:48][CH:49]=[N:50][C:29]=1[N:21]1[CH:22]=[C:23]2[C:28]([CH:27]=[CH:26][CH:25]=[CH:24]2)=[N:20]1)[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (663 mg, 3.46 mmol) and Et3N (0.900 ml, 6.46 mmol) were successively added to a solution of 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid (1200 mg, 2.88 mmol) and O-methylhydroxylamine hydrochloride (0.350 ml, 4.61 mmol) in DMF (35 ml) at 5° C., and the mixture was stirred for 5 minutes. A pH of 10 was adjusted by adding Et3N (0.643 ml, 4.61 mmol), stirring was continued for 1 hour at 5° C. and then overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. To the obtained residue were added water (150 ml) and a saturated aqueous solution of NaHCO3 (20 ml) with stirring. Following stirring for about 20 minutes the precipitate formed was filtered off with suction and treated with methyl-tert.-butylether (40 ml) to give, after filtration and drying in vacuo, 1.07 g of the title compound as an off-white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:19][CH2:18][C:13]4(OCC[O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cc2c(cc1C1CCC3(CC1)OCCO3)OCO2
Solvent: CC(C)=O
Product: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Yield: 87 %

Procedure:
A solution of 8-(1,3-benzodioxol-5-yl)-1,4dioxaspiro[4,5]decane in acetone was reacted as described in example 4 to give the product (87%, mp: 92°-93.5° C.). Calc'd for C13H14O3 : C, 71.55%; H, 6.47%. Found: C, 71.37%; H, 6.43%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([S:41]([F:46])([F:45])([F:44])([F:43])[F:42])[CH:40]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:23]3[N:19]([N:20]=[C:21]([C:24]4[CH:25]=[N:26][N:27](CC5C=CC(OC)=CC=5)[CH:28]=4)[CH:22]=3)[CH:18]=[CH:17]2)[CH:10]=1)=[O:7])#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([S:41]([F:46])([F:43])([F:42])([F:44])[F:45])[CH:40]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:23]3[N:19]([N:20]=[C:21]([C:24]4[CH:25]=[N:26][NH:27][CH:28]=4)[CH:22]=3)[CH:18]=[CH:17]2)[CH:10]=1)=[O:7])#[N:2]
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(C#N)cc(S(F)(F)(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12

Procedure:
80 mg (0.10 mmol) of the compound of Example 75A were stirred in 0.8 ml of trifluoroacetic acid at 90° C. for 60 min. The reaction was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 34). This gave 49 mg (90% of theory) of the title compound.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20]C(NC)=O>C(OCC)(=O)C>[CH3:19][NH:20]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: CNC(=O)NC
Solvent: CCOC(C)=O
Product: CN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 66 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-benzo[b]thiophen-3-ol, but using N,N'-dimethylurea in place of ammonium acetate, with a yield of 66% of theory, m.p. 156°-157° C. (ethyl acetate). On the basis of its thin-layer chromatogram, mixed melting point, elemental analysis and IR spectrum, the product was identical to that of Example 2.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:23])=[C:6]([Cl:22])[C:7]([N:14]2[CH2:19][C@H:18]([CH3:20])[O:17][C@H:16]([CH3:21])[CH2:15]2)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].Cl.[NH2:25][OH:26]>CO.N1C=CC=CC=1>[Cl:22][C:6]1[C:7]([N:14]2[CH2:19][C@H:18]([CH3:20])[O:17][C@H:16]([CH3:21])[CH2:15]2)=[C:8]([CH:13]=[C:4]([C:1](=[N:25][OH:26])[CH3:2])[C:5]=1[F:23])[C:9]([O:11][CH3:12])=[O:10]
Reactant: NO
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)c1cc(C(C)=NO)c(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 5-acetyl-3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluorobenzoate (Intermediate 107, 800 mg, 2.32 mmol) in methanol:Pyridine (1:1, 6 mL) was added hydroxylamine hydrochloride (223 mg, 3.48 mmol) and the mixture was stirred at room temperature for 12 hours. Solvents were removed under vacuum and the residue was subjected to silica gel column chromatography using a gradient of ethyl acetate in pet. ether to give title compound. Yield: 700 mg (87%).
Reaction SMILES: C([C:5]1[C:6]([CH3:14])=[N:7][CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])C(C)C.C(O[C:18](=O)[C:19]1C=CC(Cl)=N[CH:20]=1)C.C([Mg]Cl)C(C)C>>[CH2:14]([C:6]1[CH:5]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)[CH:19]([CH3:20])[CH3:18]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Cc1ncc(C(=O)O)cc1CC(C)C
Agent: CC(C)C[Mg]Cl
Product: CC(C)Cc1ccc(C(=O)O)cn1

Procedure:
6-Isobutyl-nicotinic acid is prepared in analogy to 5-isobutyl-6-methyl-nicotinic acid from commercially available 6-chloronicotinic acid ethyl ester and isobutylmagnesium chloride; LC-MS: tR=0.52 min, [M+1]+=180.30.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([O:22]S(C(F)(F)F)(=O)=O)[CH:11]=[C:12]([O:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])[CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH:11]=[C:10]([OH:22])[CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C(c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1)C1CCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
Trifluoro-methanesulfonic acid 3-cyclopentanecarbonyl-5-trifluoromethanesulfonyloxy-phenyl ester (1.5 g) was dissolved in 1,2-dimethoxyethane (30 mL), followed by addition of cesium carbonate (1.5 g). The resulting suspension was stirred at 80° C. for 3 h and then quenched with saturated solution of ammonium chloride. The solution was then extracted with diethyl ether and combined etherate extracts were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to yield 300 mg of the title compound (28% yield). HRMS calcd for C13H13O5S1F3 [M+H]+ 339.0509, observed 339.0509.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15](O)[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3)[CH3:2].P(Cl)(Cl)([Cl:21])=O.C(N(CCC)CCC)CC>>[Cl:21][C:15]1[C:6]2[N:7]([C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=2
Reactant: CCc1nnc2c(O)nc3cc(OC)ccc3n12
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Product: CCc1nnc2c(Cl)nc3cc(OC)ccc3n12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there were placed 1.87 g. (0.0076 mole) of 1-ethyl-4-hydroxy-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline and 25 ml. of phosphorus oxychloride together with 1.8 ml. of tri-n-propylamine. The reaction mixture was then refluxed overnight for approximately 16 hours and finally cooled to room temperature prior to being slowly poured over ice/water. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the solid product so obtained was subsequently washed with cold water and then dissolved in chloroform. The latter organic solution was thereafter washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was finally obtained a yellow solid product which was triturated with diethyl ether and filtered to ultimately afford 1.6 g. (80%) of pure 4-chloro-1-ethyl-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 173°-175° C. Mass Spectrum: m/e, 262 (P); m/e 264 (P+2); m/e, 261 (P-1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21](O)=[O:22])[C:16]=1[CH3:24].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:55][O:56][C:57](=[O:64])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][NH2:63]>[Cl-].[Na+].O.CN(C=O)C>[CH3:55][O:56][C:57](=[O:64])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][NH:63][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:14]=[N:13][N:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:19][C:18]=1[CH3:20])=[O:22]
Reactant: COC(=O)CCCCCN
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (328 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (287 mg, 63% yield) as a red solid. LC-MS (m/z) 456 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(OC)cc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-5-methoxy-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-5-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.65 (br, —CO2H); 7.11 (m, 1 arom.H); 7.00 (m, 2 arom.H); 5.95 (m, —CH═CH2); 5.39, 5.17 (2 d-like, CH═CH2); 4.49 (d-like, CH2—CH═CH2); 3.68 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 167.06 (C═O); 152.69; 150.99; 133.70; 122.54; 118.27; 116.84; 115.76; 115.08; 69.50; 55.49.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13](=[O:33])[NH:14][C:15]3[N:20]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)[CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:3][CH:2]=1.[Li+].[OH-]>CO.O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13](=[O:33])[NH:14][C:15]3[N:20]=[C:19]([CH2:21][N:22]4[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)[CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1cccc(CN2CCC(C(=O)O)CC2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 45 °C

Procedure:
Ethyl 1-{6-[3-(2-(pyridin-4-yl)thiazol-4-yl)ureido]-pyridin-2-ylmethyl}-piperidine-4-carboxylate (55 mg, 0.12 mmol, Example 61) was suspended in MeOH (10 ml) followed by adding LiOH (50 mg, 1.18 mmol) in H2O (1 ml). The resulting mixture was heated at 45° C. for 15 h. After cooling to RT, the solvent was removed. The residue was suspended in H2O (20 mL). The ph was adjusted to 7 using HCl (1N). The resulting mixture was extracted with CHCl3:IpOH (3:1). The organic layer was washed with H2O and brine. After being dried over anhydrous MgSO4, the solvent was removed in vacuo to yield the final compound as light yellow solid. MS m/z: 438.7 (M+H). Calc'd. for C21H22N6O3S-438.51.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (1.55 g, 3.54 mmoles) and K2CO3 (636 mg, 4.6 mmoles) in DMF (4 ml) was added at 5° C. 1-bromoethyl acetate (769 mg, 4.6 mmoles). The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate (300 ml), washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (50 g) with 1% methanol in CHCl3. The desired fractions were combined and concentrated to a small volume. The resdiue was triturated with isopropyl ether to give 1.29 g (70%) of the title compound as the isopropyl ether solvate. Estimated purity 90% (by HPLC). Mp. 103°-110° C. (dec.).
Reaction SMILES: C([NH:4][C:5]1[N:10]([O:11]C(=O)C)[C:9](=[NH:15])[N:8]=[C:7](Cl)[CH:6]=1)(=O)C.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[NH2:4][C:5]1[N:10]([OH:11])[C:9](=[NH:15])[N:8]=[C:7]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1
Reactant: C1CCNCC1
Reactant: CC(=O)Nc1cc(Cl)nc(=N)n1OC(C)=O
Solvent: ClC(Cl)Cl
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Reaction time: 1 h
Yield: 80 %

Procedure:
After adding 0.49 g (2 mmoles) of 6-acetamido-1-acetoxy-4-chloro-1,2-dihydro-2-iminopyrimidine to a solution containing 10 ml of chloroform and 2 ml of piperidine, the mixture is refluxed for 30 minutes, then evaporated under reduced pressure. The residue is dissolved in the mixture of 10 ml of ethanol and 3 ml of 1N aqueous sodium hydroxide solution. The reaction mixture is left to stand at room temperature for one hour and then again evaporated under reduced pressure. After taking up the residue in 10 ml of water, the crystals are filtered, washed with water and dried to give 0.34 g (80% yield) of the aimed compound which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([O:29][CH3:30])[C:20]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:16]2[CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[O:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38]Cl.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([O:29][CH3:30])[C:20]([N:21]([CH2:38][CH:34]3[CH2:35][CH2:36][CH2:37][O:33]3)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: ClCC1CCCO1
Reactant: COc1cc(C)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(-c2cccc3c(N(CC4CCCO4)C(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
After dissolving tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate (50 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) was added while cooling on ice, and then 2-tetrahydrofuranylmethyl chloride (16 μL) was added and the mixture was stirred for 3 hours at 60° C. under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylcarbamate. The crude product was dissolved in ethyl acetate (2 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer washed with water and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure to obtain N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine as a crude product. This was dissolved in tetrahydrofuran (2 mL) without purification, and after adding cyclopropanecarboxyaldehyde (27 μL) and 3 M aqueous sulfuric acid (0.121 mL), sodium borohydride (9 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, the solvent was concentrated, the residue was purified by silica gel column chromatography, and the title compound (31 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.