Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:8][C:7]=12)#[CH:2].Br[C:26]1[CH:27]=[CH:28][C:29]([C:32]([NH2:34])=[O:33])=[N:30][CH:31]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH2:34])=[O:33])=[N:30][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NC(=O)c1ccc(Br)cn1
Product: NC(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 g, 1.0 mmol) and 5-bromo-pyridine-2-carboxylic acid amide (example B.47) (181 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 65%). MS (ISP) 458.1 [(M+H)+]; mp 276-277° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:15]([O:17]C)=[O:16])[C:11]([O:13]C)=[O:12].CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:15]([OH:17])=[O:16])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C(=O)OC)c1c(C)cc(C)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(C(C(=O)O)C(=O)O)c(Cl)c1
Temperature: -10 °C
Yield: 84.8 %

Procedure:
10 g of dimethyl 2-chloro-4,6-dimethylphenylmalonate according to Example (VI-1) were initially introduced and treated successively with 20 ml of methanol and 6.8 g of KOH dissolved in 9.1 ml of water. After an hour, the mixture was diluted with a further 20 ml of solvent (MeOH/water 1:1). The mixture was heated at reflux for 10 h, then cooled and concentrated. The residue which remained was taken up in a little water and washed once with toluene. The aqueous phase was then diluted further with water, added to the same amount of ether and cooled to about −10° C. It was acidified with concentrated HCl (pH 1), and the organic phase was separated off and reextracted a further 1 or 2 times. The combined organic phases were dried and concentrated. The residue was crystallized from toluene and afforded 7.6 g of 2-chloro-4,6-dimethylphenylmalonic acid having a melting point of 174 to 176° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.O.[B-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCc2ccc(C(=O)O)cc21
Agent: [B-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2ccc(CO)cc21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of 1-methylindoline-6-carboxylic acid (321 mg, 1.80 mmol) in tetrahydrofuran (6 mL) was added N,N′-carbodiimidazole (309 mg, 1.89 mmol) at room temperature. The mixture was stirred at 50° C. for 15 minutes, and then cooled to 0° C. Then, thereto were added water (1 mL) and sodium hydroborate (204 mg, 5.40 mmol), and the mixture was stirred at the same temperature for 1 hour. The reaction solution was cooled to room temperature, and then thereto was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→1:1) to give (1-methyl-2,3-dihydro-1H-indol-6-yl)methanol (245 mg, 83%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@@H:3]([OH:5])[CH3:4].N1C=CC=CC=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[C:13]([O:6][CH2:1][CH2:2][C@@H:3]([O:5][S:23]([CH3:22])(=[O:25])=[O:24])[CH3:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](O)CCO
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C[C@@H](CCOC(=O)c1ccccc1)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 48.7 %

Procedure:
To a mixture of (S)-butane-1,3-diol (0.2450 g, 2.718 mmol), pyridine (1.50 mL, 18.5 mmol), and methylene chloride (10.0 mL, 156 mmol) at −15° C. was dropwise added benzoyl chloride (0.32 mL, 2.8 mmol). After 3.5 hours, methanesulfonyl chloride (0.300 mL, 3.88 mmol) was added to the reaction mixture, and the temperature was maintained at 0° C. After 1.5 hours, the reaction was warmed to room temperature. After 2 additional hours, triethylamine (1.0 mL, 7.2 mmol) was added. After one additional hour, the reaction mixture was poured into 50 mL dichloromethane and washed once with 50 mL water. The aqueous layer was extracted with an additional 50 mL of dichloromethane. The combined organic portions were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl acetate in heptanes) to yield 0.3603 g (49%) of (S)-3-(methylsulfonyloxy)butyl benzoate. LCMS (ESI): M+H=273.2; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J=7.6 Hz, 2H), 7.66 (t, J=7.4 Hz, 1H), 7.53 (t, J=7.7 Hz, 2H), 4.94 (h, J=6.3 Hz, 1H), 4.45-4.26 (m, 2H), 3.17 (s, 3H), 2.09 (q, J=6.2 Hz, 2H), 1.42 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[O:13]([C:20]1[C:25]([CH:26]=O)=[C:24](OC2C=CC=CC=2)[N:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C1COCC1>[O:13]([C:20]1[N:21]=[CH:22][N:23]=[C:24]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:11])([F:12])[F:1])[N:10]=[CH:26][C:25]=12)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=Cc1c(Oc2ccccc2)ncnc1Oc1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1-n1ncc2c(Oc3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.7 %

Procedure:
(2-(trifluoromethyl)phenyl)hydrazine (CAS no. 365-34-4) (102 mg, 0.58 mmol) was added to 4,6-diphenoxypyrimidine-5-carbaldehyde (Intermediate Z2) (169 mg, 0.58 mmol) in THF (2 mL) the resulting solution was stirred at room temperature for 5 minutes. 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (526 mg, 1.16 mmol) was added and sealed into a microwave tube. The reaction was heated to 150° C. for 10 hours in a microwave reactor and cooled to RT. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by flash silica chromatography, eluting with 10 to 80% ethyl acetate in isohexane to afford the product (88 mg, 42.7%). 1H NMR (400 MHz, CDCl3) δ 7.29-7.33 (2H, m), 7.34-7.39 (1H, m), 7.49-7.58 (3H, m), 7.67-7.71 (1H, m), 7.74-7.78 (1H, m), 7.90-7.92 (1H, m), 8.08 (1H, s), 8.56 (1H, s); m/z (ES+) (M+H)+=357; HPLC tR=2.66 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+](C1C=CC([C:28](Cl)=[O:29])=CC=1)([O-])=O.[CH3:33][S:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([C:46]1[CH:51]=[C:50]([O:52][CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[N:49]=[CH:48][N:47]=1)[CH2:41][CH2:40]2)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:28]([N:56]2[CH2:57][CH2:58][CH:53]([O:52][C:50]3[CH:51]=[C:46]([N:42]4[C:43]5[C:39](=[CH:38][C:37]([S:34]([CH3:33])(=[O:36])=[O:35])=[CH:45][CH:44]=5)[CH2:40][CH2:41]4)[N:47]=[CH:48][N:49]=3)[CH2:54][CH2:55]2)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)N2CCC(Oc3cc(N4CCc5cc(S(C)(=O)=O)ccc54)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.37 g, 2 mmol) was dissolved in 4 mL of DCM with triethylamine (0.28 mL, 2 mmol). 4-Nitro-benzoyl chloride (0.4 g, 2 mmol) was added and the mixture was stirred at room temperature for 12 h. It was then diluted with DCM and washed with saturated NaHCO3 (3×20 mL). The organic layer was dried, filtered and evaporated. The residue was dissolved in DCM (4 mL) with triethylamine (0.36 mL, 2.6 mmol) and 4b (0.49 g, 1.3 mmol) was added. The mixture was stirred at room temperature for 8 h, diluted with DCM and washed with saturated NaHCO3. The organic layer was evaporated to afford 21a, LCMS 588.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].COCCOC>O.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>[C:12]([O:16][C:17]([C:19]1[CH:24]=[C:23]([C:9]2[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[N:10]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(C(=O)O)c(Cl)n2)c1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
2,6-Dichloronicotinic acid (1.20 g, 6.25 mmol), 3-(tert-butoxycarbonyl)benzene boronic acid (2.08 g, 9.10 mmol), potassium carbonate (2.60 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol), degassed 1,2-dimethoxyethane (30 mL) and water (0.5 mL) were combined under an argon atmosphere and the mixture heated at 90° C. overnight. The reaction mixture was then cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The aqueous layer was acidified to pH 3-4 using 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 20% methanol/dichloromethane) and the product containing fractions concentrated to give a solid, which was triturated with 2:1 heptane/ethyl acetate to give pure 6-(3-(tert-butoxycarbonyl)phenyl)-2-chloronicotinic acid (1.4 g, 67%) as an off-white foam. 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.59 (t, 1H), 1.60 (s, 9H); m/z 334 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH2:21])=[NH:20])[N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C:32](Cl)=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.[OH-].[Na+]>C(#N)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:21][C:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:33])=[NH:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(N)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N=C(NC(=O)c1cccc2ccccc12)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.75 gram, 2.50 mmol) and 1-naphtoyl chloride (0.4 ml, 2.70 mmol) in acetonitrile (15 ml) was added triethylamine (1 ml). The resulting mixture was stirred at room temperature for 1 hour. After addition of a 2 N sodium hydroxide solution and extraction with ethylacetate, the ethylacetate layer was concentrated in vacua. The resulting crude residue was further purified by means of flash chromatography (petroleum ether/diethyl ether=3/1 (v/v), followed by ethylacetate). Subsequent concentration in vacuo afforded 3-(4-chlorophenyl)-4,5-dihydro-N-(1-naphtoyl)-4-phenyl-1H-pyrazole-1-carboxamidine (0.94 gram, 83% yield). Melting point: 206-207° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]([CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CC1CC(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)C1CC(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-(3-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino) cyclobutyl)acetate from step 2 in a mixture of MeOH and H2O was added 1N NaOH (8 mL). The resultant reaction mixture was stirred at RT overnight. Half of the solvents were removed under reduced pressure and 1N HCl was added to adjust pH of the solution to 4. The aqueous phase was extracted with EtOAc for three times. The combined organic phase was then dried and concentrated in vacuo to afford the acid (0.9 g).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1Cn2c(=O)cnc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 103.3 %

Procedure:
(1S)-1-(Hydroxymethyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (750 mg, 3.42 mmol) was suspended in dry DCM (100 ml) at room temperature under argon and then treated with Et3N (0.572 ml, 4.11 mmol). The mixture was then cooled using an ice-water bath. Methanesulfonyl chloride (0.293 ml, 3.76 mmol) was then added and the reaction was allowed to warm up to room temperature. After 50 minutes there was no starting material left so the mixture was washed with saturated NaHCO3 (100 ml). The aqueous layer was extracted with 20% MeOH/DCM (2×100 ml); the combined organic extracts were dried over MgSO4, filtered and evaporated to afford the product as a brown foam (1.05 g, 90% purity by LCMS).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[C:17]2[C:12](=[C:13]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[O:11][C:10](=[O:26])[CH:9]=1.[Cl:27][C:28]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([Cl:36])[C:29]=1[NH2:30].OP([O-])(O)=O.[K+]>CS(C)=O>[CH:21]1([O:20][C:13]2[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[C:17]3[C:12]=2[O:11][C:10](=[O:26])[CH:9]=[C:8]3[NH:30][C:29]2[C:31]([Cl:36])=[CH:32][CH:33]=[C:34]([CH3:35])[C:28]=2[Cl:27])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: Cc1ccc(Cl)c(N)c1Cl
Agent: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)ccc(C)c3Cl)cc(=O)oc2c1OC1CCCC1
Reaction time: 14 h

Procedure:
Potassium t-butoxide (35 mg, 0.3 mmol) was added to a solution of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (29 mg, 0.1 mmol, Example 7, Step 1), 2,6-dichloro-3-methylaniline (26 mg, 0.15 mmol), and DMSO (1 mL). After 14 h, the reaction was poured into 1M KH2PO4 (20 mL), and extracted with ethyl acetate (20 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→0:1; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-4-(2,6-dichloro-3-methylphenylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 7.95 (d, 1H), 7.58 (d, 1H), 7.48 (d, 1H), 7.18 (d, 1H), 4.82 (m, 1H), 4.33 (s, 1H), 3.90 (s, 3H), 2.40 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 433.9.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][C:13]([OH:15])=O)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH2:52][C:53]1[CH:54]=[CH:55][C:56]([Cl:63])=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:58]=1>C(OCC)(=O)C.CN(C=O)C>[Cl:63][C:56]1[CH:55]=[CH:54][C:53]([NH:52][C:13](=[O:15])[CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([N:6]3[CH:7]=[C:3]([Si:2]([CH3:1])([CH3:20])[CH3:19])[N:4]=[N:5]3)[CH:9]=2)=[CH:58][C:57]=1[C:59]([F:60])([F:61])[F:62]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)c1cn(-c2cccc(OCC(=O)O)c2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cn(-c2cccc(OCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL recovery flask was added [3-(4-Trimethylsilanyl-[1,2,3]triazol-1-yl)-phenoxy]-acetic acid 6 (483 mg, 1.66 mmol, 1.0 eq.) and a stirbar. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g, 3.3 mmol, 2.0 eq.), DMF (8 mL), and N-methylmorpholine (503 μL, 4.98 mmol, 3.0 eq.) were added. The mixture was stirred at room temperature for 30 min. 5-amino-2-chlorobenzotrifluoride (649 mg, 3.3 mmol, 2.0 eq.) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a succession of 10% aq. LiCl (3×50 mL), H2O (50 mL), and sat'd aq. NaCl (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a grayish solid. The solid was recrystallized in hot MeOH to give a light gray solid, which by LC/MS was a mixture of product and the corresponding de-silylated material (200 mg). The mixture was taken on to the next step without further purification. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 469.1 (M+H)+1
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[N:15][OH:16])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[Br:26][CH2:27][C:28](=[CH2:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl[O-].[Na+]>ClCCl.O>[Br:26][CH2:27][C:28]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:16][N:15]=[C:14]([C:13]2[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:9]3[CH:19]=[N:18][N:17]([CH2:20][CH3:21])[C:10]3=[N:11][CH:12]=2)[CH2:34]1
Reactant: C=C(CBr)C(=O)OCC
Reactant: CCn1ncc2c(NC3CCCCC3)c(C=NO)cnc21
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1(CBr)CC(c2cnc3c(cnn3CC)c2NC2CCCCC2)=NO1
Reaction time: 8 h
Yield: 66 %

Procedure:
4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (200 mg, 0.0006 mole) (example 8) was taken in dichloromethane: chloroform mixture (10 ml: 5 ml). Ethyl 2-(bromomethyl)acrylate (0.2 ml, 0.00103 mole) was added. Sodium hypochlorite (2.5 ml) was added drop wise. The reaction mixture was stirred overnight. Water was added, the mixture was extracted with chloroform, washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude compound obtained was purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csnn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csnn1
Yield: 43.7 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)-acetic acid (syn isomer) (0.6 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.1 g.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g.), mp 90° to 98° C. (dec.).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[N:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[N:42]=[CH:41][C:40]([NH:43][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN1CCN(Cc2ccc(N)cn2)C(C)(C)C1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4(C)C)nc3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 6-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 114.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.2 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30]([C:34]1[CH:39]=[CH:38][C:37](OB=O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([O:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1ccc(OB=O)cc1
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 57.7 %

Procedure:
4-(6,7-Dimethoxy-4-quinolyloxy)phenol (starting compound 8) (24 mg) was dissolved in chloroform (2 ml) to prepare a solution. Triethylamine (0.3 ml), 4-tert-butylphenylboranic acid (50 mg), and copper(II) acetate (90 mg) were added to the solution, and the mixture was stirred at room temperature for 4 days. The insolubles were removed by filtration, and the solvent was then removed by evaporation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel using chloroform/acetone for development to give the title compound (20 mg, yield 58%).