Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:34])=[CH:36][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Prepared using General Procedure 3: To the solution of (S)-methyl 2-amino-3-(4-cyanophenyl)propanoate (789.2 mg, 3.32 mmol) in DCM (15 mL) and DIEA (1.29 g, 9.96 mmol) was added 4-(tert-butyl)benzoyl chloride (981.3 mg, 4.99 mmol) at room temperature. The reaction was stirred for 2 h and the reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over mgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 1.06 g (88%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate. LCMS-ESI (m/z calculated for C22H24N2O3: 364.2. found 365.3 [M+H]+, tR=3.55 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=8.0 Hz, 1H), 7.85-7.60 (m, 4H), 7.49 (dd, J=15.1, 8.4 Hz, 4H), 4.85-4.60 (m, 1H), 3.65 (s, 3H), 3.30-3.23 (m, 1H), 3.18 (dd, J=13.7, 10.6 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.COC(OC)(OC)C1C=CC=CC=1>O.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:12])[C:4]=1[C:5]([C:18]1[C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:15]([O:14][CH3:13])=[CH:16][C:17]=1[CH3:25])=[O:7]
Reactant: Cc1c(F)ccc(F)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: COC(OC)(OC)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(F)ccc(F)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
9.3 g (54.3 mmol) of 3,6-difluoro-2-methylbenzoic acid and 9.88 g (54.3 mmol) of 3,4,5-trimethoxytoluene were introduced into 250 ml of absolute dichloromethane, and 54 g (380 mmol) of pulverulent phosphorus pentoxide were then added. The mixture was stirred for 16 hours at room temperature. According to HPLC check, the trimethoxytoluene had not been reacted completely. A further 13.5 g of phosphorus pentoxide were added. After a further four hours, the reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were then dried and concentrated. The crude product was purified by reversed-phase MPLC (eluent acetonitrile/water 7:3). This gave 12.2 g of the compound I.5-02 (36 mmol, 67% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CC(C)=O.O.CCOC(C)=O>[Cl:24][CH2:23][CH2:22][CH2:21][N:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1oc2ccc([N+](=O)[O-])cc2n1CCCCl
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
5-Nitro-3H-benzoxazol-2-one (5.35 g, 29.7 mmol) in Acetone (300 mL) was treated with Potassium carbonate (6.99 g, 50.6 mmol) then 1-Bromo-3-chloropropane (10.0 mL, 101 mmol) was added. After 45 min, the mixture was heated to 55° C. overnight. The reaction was cooled, diluted with 100 mL water and 150 mL EtOAc. The layers were separated, the org. washed with brine (50 mL), dried over sodium sulfate, filtered through a ½″h×2″w pad of SiO2 and conc. in vacuo. to near dryness. The oily remainder was suspended in 100 mL 5% EtOAc:Hexane, resulting in precipitation of the product. The solids were triturated for 2 h to break up the solids, collected by filtration and washed with hexane (2×60 mL). After drying, 3-(3-Chloro-propyl)-5-nitro-3H-benzoxazol-2-one was isolated as yellow solids (7.52 g, 99%). 1H-NMR (DMSO): 8.27 (d, 1H, J=2.2 Hz), 8.10 (dd, 1H, J=2.2, 8.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 4.04 (t, 2H, J=6.7 Hz), 3.75 (t, 2H, J=6.5 Hz), 2.17 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CCCCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperazine-1-carboxylate (0.0945 g, 0.177 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[4-(piperazin-1-yl)butyl]benzofuran-3(2H)-one (0.0524 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:25][CH2:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1S2
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Yield: 93.9 %

Procedure:
A mixture of 3.30 g of 2-chloro-11-(1-piperazinyl)dibenzo[b,f][1,4]thiazepine and 1.20 g of ethyl acrylate in 17 ml of ethanol was refluxed for 3 hrs. The reaction mixture was concentrated and the residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give 4.04 g of yellow crystals, which were recrystallized from isopropyl ether to give colorless needles, mp 79°-80° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: OCCOCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.8 %

Procedure:
A mixture of ethylene glycol monobenzyl ether (36 ml, 252 mmol), 60% sodium hydride (11.0 g, 275 mmol) and N,N-dimethylformamide (300 ml) was stirred at room temperature for 1.5 hours. To the resulting suspension was added dropwise a solution of ethyl bromoacetate (34 ml, 302 mmol) in N,N-dimethylformamide (50 ml), followed by stirring at room temperature for another 3 hours. The reaction mixture was poured into a 10% aqueous sodium chloride solution and extracted with ethylacetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate : n-hexane= 9:95) to obtain 18.5 g of ethyl (2-benzyloxyethoxy)acetate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[C:26]1([C:31]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: O=C(Cl)C1=CCCC1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#N)c(N)c(OC(=O)C2=CCCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (200 mg, 0.83 mmol) was dissolved in acetonitrile (10 ml), and cooled to 0° C. Triethylamine (195 μl, 1.4 mmol) and cyclopentenecarbonyl chloride (162 mg, 1.24 mmol) were dropwise added to the solution, followed by stirring at room temperature for 1 hour. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography, and the eluate with ethyl acetate/hexane (1:3, v/v) gave the entitled compound (180 mg, 77%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=Cc1ccnc(NC(N)=O)c1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1C(Cc1ccnc(NC(N)=O)c1)c1ccccc1
Yield: 14 %

Procedure:
[4-(2-Phenyl-2-o-tolyl-vinyl)-pyridin-2-yl]-urea (140 mg, 0.43 mmol) is dissolved in methanol (2 mL) and DCM (2 mL). Then 5% palladium on carbon (90 mg, 0.043 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Purification by Gilson preparative HPLC affords 20 mg of the titled product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:14]=1)=O)([OH:3])=[O:2].Cl.[NH2:35][OH:36]>>[C:1]([C:4]1[CH:5]=[C:6]([C:7](=[N:35][OH:36])[C:9]2[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:14]=2)[CH:31]=[CH:32][CH:33]=1)([OH:3])=[O:2]
Reactant: NO
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1CCC(=O)O
Agent: Cl
Product: CCCCCCCCCCOc1ccc(C(=NO)c2cccc(C(=O)O)c2)cc1CCC(=O)O
Yield: 81 %

Procedure:
The title product was also prepared in 81% yield directly from 5-(3-carboxybenzoyl)-2-(decyloxy)benzenepropanoic acid upon treatment with hydroxylamine hydrochloride according to the procedure of Example 51.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:2]1=2.C1C=CC2N(O)N=[N:20]C=2C=1.N.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH2:20])=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (3.54 g) in DMF (80 mL) were added HOBt-NH3 (4.48 g) and EDCI HCl (5.65 g) at room temperature. The reaction mixture was stirred at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with hexane to give the title compound (1.10 g).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH2:24])=[S:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:25][I:26]>CC(C)=O.O1CCCC1>[IH:26].[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22](=[NH:24])[S:23][CH3:25])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: NC(=S)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: I
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-thiourea (600 mg, 1.8 mmol) was dissolved in 20 mL acetone and 10 mL tetrahydrofuran. Methyliodide (306 mg, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was recrystallized from dichloromethane and diethylether. The title compound (720 mg, 84%) was obtained as a yellow solid; MS: m/e=349.4 (M+H+).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9](C(OC(C)(C)C)=O)[C:10]2[C:15]([C:16]=1[CH:17]([CH:19]1[C:23](=O)N(C(OC(C)(C)C)=O)[N:21]([CH:32]3C4CC5CC(C[CH:33]3C5)C4)[CH2:20]1)O)=[C:14]([Cl:42])[CH:13]=[C:12]([Cl:43])[CH:11]=2)=[O:7])(C)(C)C.[OH2:51].[OH-].[Li+]>C(O)C>[Cl:42][C:14]1[CH:13]=[C:12]([Cl:43])[CH:11]=[C:10]2[C:15]=1[C:16](/[CH:17]=[C:19]1/[C:20](=[O:51])[NH:21][CH2:32][CH2:33][CH2:23]/1)=[C:8]([C:6]([OH:5])=[O:7])[NH:9]2
Reactant: O
Reactant: CC(C)(C)OC(=O)c1c(C(O)C2CN(C3C4CC5CC(C4)CC3C5)N(C(=O)OC(C)(C)C)C2=O)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCCC/C1=C\c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12
Reaction time: 0.5 h
Yield: 176.8 %

Procedure:
Example 4 (490 mg) and lithium hydroxide monohydrate (200 mg) were dissolved in ethanol (95%) (20 ml) and the resulting solution refluxed for 1.5 h. The solvent was evaporated and the residue treated at 50° with 6 M hydrochloric acid for 30 min, then at room temperature for further 30 min. The resulting white solid was filtered, washed and vacuum dried to yield the title compound (400 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH2:17][OH:18])[O:14][N:13]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.O>C(Cl)Cl>[N:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc(-c2ccncc2)no1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nc(-c2ccncc2)no1
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.50 ml, 6.50 mmol) was added to a stirred solution of (3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)methanol (1 g, 5.65 mmol) and triethylamine (0.953 ml, 6.78 mmol) in CH2Cl2 (30 ml) at 0° C. After 10 min, water (20 ml) was added and the aqueous phase extracted with CH2Cl2 (20 ml). The combined organic phases were dried (MgSO4) and evaporated to afford the title compound: RT=2.32 min; m/z (ES+)=256.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21](O)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 84 h
Yield: 93.5 %

Procedure:
A mixture of 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 213 μmol), pyrrolidine (70.5 μl, 853 μmol), propylphosphonic anhydride (50% in ethyl acetate, 314 μl, 533 μmol) and diisopropylethylamine (112 μl, 640 μmol) in tetrahydrofurane (4 ml) is stirred for 3.5 days at 25° C. The solvent is evaporated and the residue stirred for 1 hr with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording N-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (76 mg, 93.5%) as a white solid. Mp.: 141-3° C. MS: m/z=380.3 (M−H+).
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:32]2[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([CH3:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (855.1.1 mg, 8.45 mmol, 1.178 mL) and para-methylbenzylamine (465.3 mg, 3.84 mmol, 0.489 mL) resulting in the formation of a bright yellow precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Recrystallisation of the cream/yellow residue from a minimum amount of boiling ethyl acetate and excess petrol yielded the title product as a fine pale yellow crystalline solid (1.090 g, 3.10 mmol, 81%). 1H NMR: (300 MHz, DMSO) δ ppm 2.21 (s, 3H, HO, 4.20 (d, 1H, J=15.62 Hz, H9), 4.40 (d, 1H, J=15.36 Hz, H9′), 6.95 (d, 2H J=7.97 Hz, H11, H13), 7.04 (d, 2H J=8.00 Hz, H10-H14) 7.27 (m, 5H, H1-H5), 7.55 (m, 2H, H6-H7) 7.74 (d, 1H, H8). 13C NMR: (75 Hz, DMSO) δ 20.90 (CH3), 42.53 (N—CH2), 90.57 (O—C—N), 122.89, 123.15, 128.36, 128.38, 128.61, 129.66, 130.85, 132.91, 133.03, 135.37, 135.84, 139.51 (Ar), 167.10 (C═O). IR: 1398, 1468, 1660, 2921, 3138 cm−1.
Reaction SMILES: C(OC([N:8]([CH:19]1[C:44](=[O:45])[N:21]2[C:22]([C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12)[C:9](=[O:18])[CH:10]([C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1)[NH2:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[NH2:17][C:14]1[S:15][CH:16]=[C:12]([CH:10]([C:9]([NH:8][CH:19]2[C:44](=[O:45])[N:21]3[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]23)=[O:18])[NH2:11])[N:13]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
To a suspension of benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (3.9 g) in methylene chloride (20 ml) were added trifluoroacetic acid (13.7 g) and anisole (3.8 g) under ice-cooling, and the mixture was stirred at ambient temperature for an hour. After evaporation of the reaction mixture, to the residue were added water (100 ml) and ethyl acetate, followed by adjusting to pH 7 with 2N aqueous solution of sodium hydroxide. The precipitated solid was removed by filtration and the aqueous layer was separated out. Thereto was added ethyl acetate, followed by adjusting to pH 5 with 10% hydrochloric acid. After separating out the aqueous layer, the organic solvent was completely removed therefrom by evaporation, and then the resultant aqueous solution was adjusted to pH 4 with 10% hydrochloric acid under cooling, followed by subjecting to column chromatography on a nonionic adsorption resin "Diaion HP-20" (120 ml). After washing with water (270 ml), elution was carried out with 10% isopropyl alcohol and then 30% isopropyl alcohol, and the fractions containing the desired compound were collected and evaporated under reduced pressure to give a residue, which was lyophilized to obtain 7-[2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylic acid (0.8 g).
Reaction SMILES: [CH3:1][CH2:2]OCC.[CH3:6][C:7]([CH3:9])=O.[C:10]1([CH3:16])[CH:15]=[CH:14]C=[CH:12][CH:11]=1>>[CH2:7]([C:9]12[CH2:16][CH:10]([CH2:11][CH2:12]1)[CH:15]=[CH:14]2)[CH2:6][CH2:1][CH3:2]
Reactant: Cc1ccccc1
Reactant: CCOCC
Reactant: CC(C)=O
Product: CCCCC12C=CC(CC1)C2
Temperature: 80 °C
Yield: 3 %

Procedure:
A 50 weight percent solution of butylnorbornene (5.0 g, 0.033 mol) was prepared in toluene. Lithium tetrakis(pentafluorophenyl)borate·2.5 Et2O (0.0012 g, 0.0014 mmol) was combined with (allyl)platinum(tricyclohexylphosphine)triflate (100 μl of a 2.8 mmol solution in toluene) in toluene and added to the monomer mixture. The mixture was heated to 80° C. for 18 hours. The mixture was poured into acetone to precipitate the polymer. After filtering and drying, 0.15 g of polymer was isolated (3% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:21]([NH:20][C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:12]=1)=[O:19])[CH3:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCNC(=O)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1cccc(-c2cnc3cc(-c4cnn(C)c4)ccn23)c1

Procedure:
A solution of 1-[3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-ethyl urea (200 mg, 0.636 mmol, 1 equivalent, made using procedure F1a), 1-methylpyrazole-4-boronic acid pinacol ester (commercially available, 265 mg, 1.272 mmol, 2 equivalents), potassium carbonate (527 mg, 3.816 mmol, 6 equivalents), and bis(tri-t-butylphosphine)palladium(0) (16 mg, 0.032 mmol, 0.05 equivalents) in ethanol (10 ml), toluene (10 ml) and water (10 ml) was heated at 70° C. for 24 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated brine solution, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 25S, flow rate 25 ml/min, gradient 0% to 20% methanol in ethyl acetate) to give 1-ethyl-3-{3-[7-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea as a white solid (35 mg). MS: [M+H]+ 361.