Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]#[CH:17]>CC(C)=O>[CH2:17]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Hydroquinone (49.6 g; 450 mM) was dissolved in 700 ml of anhydrous acetone in a two liter, 3-necked, round bottom flask equipped with reflux condensor, air stirrer and nitrogen bubbler. Potassium carbonate (65.6 g; 460 mM) was ground finely and then added to the reaction followed by propargylbromide (53.6 g; 450 mM). The reaction was heated at reflux for three days, cooled to room temperature, filtered and the solvent removed. The residue was taken up in ether and extracted three times with 2.5N aqueous sodium hydroxide. The basic layers were acidified with concentrated hydrochloric acid while adding ice and extracted twice with ether. The combined ethereal layers were dried over magnesium sulfate, charcoal was added, and the mixture was filtered through celite. The solvent was removed in vacuo and the remaining dark brown sludge was purified by chromatography in two portions on a Waters Prep 500 equipped with two silica gel cartridges and eluted with 20% ethyl acetate in hexane after injecting in ether solution. This produced 21.4 g (64% of theory) of the desired p-propargyloxyphenol.
Reaction SMILES: CO[C:3](=[O:25])/[C:4](=[N:22]/[O:23][CH3:24])/[C:5](/[CH3:21])=[CH:6]\[CH2:7][O:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]=1.[CH3:26][NH2:27]>C1COCC1.O>[CH3:26][NH:27][C:3](=[O:25])/[C:4](=[N:22]/[O:23][CH3:24])/[C:5](/[CH3:21])=[CH:6]\[CH2:7][O:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]=1
Reactant: CN
Reactant: CO/N=C(C(=O)OC)\C(C)=C/COc1ccn(-c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=N/OC)/C(C)=C\COc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
120 mg (0.33 mmol) (Z)-5-[1-(4-chloro-phenyl)-1H-pyrazol-3-yloxy]-2-[(E)-methoxyimino]-3-methyl-pent-3-enic acid methyl ester and 0.99 ml (1.98 mmol) of a 2-molar solution of methyl amine in THF have been stirred overnight at ambient temperature in 2.0 ml of THF and 0.5 ml of water. After removal of the solvent in vacuo the product (120 mg) was collected in quantitative yield and good purity. Melting point 129-130° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C=O)C.[Cu]>[O:7]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1cccc(Oc2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 157 %

Procedure:
A mixture of potassium carbonate (5.53 g, 0.04 mol) and 3-phenoxyphenol (15 g, 0.08 mol) in DMF (60 ml) was heated at 80° C. with stirring for 30 minutes. 2-Chloro-3-cyanopyridine (11.08 g, 0.08 mol) and copper bronze (0.8 g) were added and the resulting mixture heated at reflux for 90 minutes. GC analysis indicated the formation of a single product (96%). The reaction mixture was cooled and filtered, and then poured into water (300 ml) and allowed to stand over the weekend. The yellow-brown oily precipitate was extracted into dichloromethane and dried. The dichloromethane solution was then filtered and evaporated to yield crude 2-(3-phenoxyphenoxy)-3-cyano-pyridine (36.2 g, contaminated with DMF) which was used in the next stage without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:32][CH3:33])=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([NH2:45])=[CH:40][CH:41]=2)[CH2:36]1.Cl>CC(O)C>[CH3:33][O:32][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:39]4[CH:38]=[C:37]5[C:42]([CH2:43][CH2:44][N:35]([CH3:34])[CH2:36]5)=[CH:41][CH:40]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:22][C:21]=1[NH:23][C:24](=[O:31])[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN1CCc2ccc(N)cc2C1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C)CC4)n2)cc1NC(=O)Cc1cccs1
Temperature: 180 °C
Yield: 53.5 %

Procedure:
To a solution of N-{5-[3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-methoxyphenyl}-2-(2-thienyl)acetamide (110 mg, 0.23 mmol) (see Example 48, step F) in anhydrous i-PrOH (3 mL) was added 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (39 mg, 0.24 mmol), followed by catalytic 12M HCl. After heating for 10 min in the microwave at 180° C., the reaction was quenched with saturated NaHCO3 (25 mL), the solvent removed by rotary evaporation, and the aqueous layer extracted with DCM (25 mL). The organic layer was concentrated and purified by column chromatography (1-10% MeOH in DCM) to provide the product (74 mg, 53%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.28 (s, 3H), 2.53-2.55 (m, 2H), 2.70-2.72 (m, 2H), 3.36 (s, 2H), 3.87 (s, 3H), 3.97 (s, 2H), 6.49 (d, 1H, J=5.1 Hz), 6.94-6.95 (m, 2H), 7.05-7.13 (m, 2H), 7.25-7.27 (d, 1H, J=8.1 Hz), 7.35-7.43 (m, 3H), 7.48 (s, 1H), 8.19 (d, 1H, J=5.3 Hz), 8.31 (s, 1H), 8.43 (d, 1H, J=8.6 Hz), 8.78 (d, 1H, J=6.8 Hz) 9.38 (s, 1H), 9.45 (s, 1H) ppm. ES-LC/MS m/z=602 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](OCC)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:17][O:16][C@@H:14]1[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@H:12]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]1
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](OC)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (2S,4S)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (3.0 g, 0.01 mol) in methanol (40 mL0 and diethyl ether (20 mL) was added (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 6.4 mL, 0.013 mol) dropwise under ice-bath. The reaction mixture was stirred at room temperature for 1 h. Concentration of the reaction mixture gave (2S,4S)-1-benzyl 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate 18B (3.2 g, 100%) as an oil which was used in the next step without purification. 1H NMR (CDCl3, 400 MHz) δ 7.27-7.36 (m, 5H), 5.04-5.19 (m, 2H), 4.39-4.50 (m, 1H), 3.91-3.94 (m, 1H), 3.53-3.72 (m, 5H), 3.24 (s, 3H), 2.21-2.35 (m, 2H).
Reaction SMILES: C1(OC(=O)NC)C2C(=CC=CC=2)C=CC=1.[CH3:16][NH:17][C:18](Cl)=[O:19].C1(O)C2C(=CC=CC=2)C=CC=1.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[OH:42].C(Cl)(Cl)=O.Cl>C1(C(C)C)C=CC=CC=1>[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[O:42][C:18](=[O:19])[NH:17][CH3:16]
Reactant: CNC(=O)Cl
Reactant: Oc1ccc2ccccc2c1
Agent: CNC(=O)Oc1cccc2ccccc12
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: CC(C)c1ccccc1
Product: CNC(=O)Oc1ccc2ccccc2c1

Procedure:
A process for the manufacture of α-naphthyl-N-methylcarbamate by the reaction of methylcarbamyl chloride and α-naphthol containing β-naphthol as an impurity, which comprises reacting methylcarbamyl chloride, which is essentially free from phosgene and hydrogen chloride, in the absence of an acid-binding agent, with α-naphthol containing β-naphthol as an impurity at a temperature in the range of 60° to 130° C in, as solvent, cumene, the starting concentration of said naphthol in the cumene being in the range of 20 to 40% by weight, based on the cumene, and cooling the reaction mixture to precipitate the α-naphthyl-N-methylcarbamate as a pure crystalline solid, the β-naphthyl-N-methylcarbamate formed in the reaction remaining in solution in the cumene when the reaction mixture is cooled.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[CH:11]([CH2:12][N:13]3[CH2:18][CH2:17][N:16](CC4C=CC=CC=4)[CH2:15][CH2:14]3)[O:10][CH2:9][CH2:8][C:7]=2[CH:26]=1.CO>[Pd].O>[CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[CH:11]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:10][CH2:9][CH2:8][C:7]=2[CH:26]=1
Reactant: COc1cc2c(cc1OC)C(CN1CCN(Cc3ccccc3)CC1)OCC2
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)C(CN1CCNCC1)OCC2

Procedure:
A mixture of 53 g of 1-[(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]-4-(phenylmethyl)piperazine, 150 ml of methanol, 150 ml of water and 5 g of 5% Pd on activated charcoal was acidified with 36% hydrochloric acid and hydrogenated at 50 psi until absorption of hydrogen was finished. The catalyst was filtered and the solvent evaporated, after which the residue was basified with sodium hydroxide and extracted with dichloromethane. The dichloromethane phase was washed, dried and evaporated and the product precipitated under diisopropyl ether to obtain 1-[(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]piperazine.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[S:11][CH:12]=1.C1COCC1.[OH-].[Na+]>CCO>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:20])=[O:2])[N:9]=1
Reactant: COC(=O)CCCCc1csc(-c2ccccc2O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCCc1csc(-c2ccccc2O)n1

Procedure:
Combine 5-[2-(2-hydroxy-phenyl)-thiazol-4-yl]-pentanoic acid methyl ester (2.2 g, 7.6 mmol) with THF (2.5 mL), EtOH (2.5 mL) and 2N NaOH (14 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 2.0-3.0 using aqueous HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 5-[2-(2-hydroxy-phenyl)-thiazol-4-yl]-pentanoic acid (1.5 g, 72%). MS (ES): (M+1)+ 278.1 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:27])[C:23]([CH2:25]O)=[CH2:24])[CH:16]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)Cl.CCN(S(F)(F)[F:37])CC>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:27])[C:23]([CH2:25][F:37])=[CH2:24])[CH:16]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: C=C(CO)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=C(CF)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C

Procedure:
To ethyl-4-(3-{[2-(hydroxymethyl)acryloyl]amino}phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (17 mg, 0.045 mmol) was added CH2Cl2 (0.90 mL) and the reaction was cooled to −78° C. before DAST (12 μL, 0.090 mmol) was added. The reaction was allowed to warm to room temperature over 2 hours. The reaction was quenched by pouring into a separatory funnel containing aqueous sodium bicarbonate (saturated) and was extracted with ethyl acetate (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford a residue that was dissolved in 2 mL of DMSO, and was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophilization of the desired fractions affords a colorless solid. LRMS (ESI) calc'd for C19H18N4O3F [M+H]+: 369, found 369. 1H NMR (600 MHz, DMSO-D6) δ 13.02 (bs, 1H), 10.25 (s, 114), 8.97 (s, 1H), 8.36 (m, 1H), 8.09 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.38 (d, 1H, J=7.8 Hz), 6.19 (s, 1H), 5.94 (s, 1H), 5.26 (s, 1H), 5.18 (s, 1H), 3.90 (q, 2H, J=7.2 Hz), 0.90 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[CH3:12])=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2.C(O)C.N1CCCC1>C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])/[C:17]/2=[CH:1]\[C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[CH3:12]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40% acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40% acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79% yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.48, 2.50 (2×s, 6H, 2×CH3), 6.80, 6.88, 7.68, 7.72 (4×m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M−1].
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:16])(=O)=O.O.[OH-].[Na+]>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([Cl:16])[CH:10]=[C:11]([CH3:12])[C:2]=1[NH2:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cccc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
The solution prepared in Step A (195 g, 475 mmol) was diluted with acetonitrile (50 mL), and heated to 50° C. Then a solution of sulfuryl chloride (70.6 g, 523 mmol) in acetonitrile (100 mL) was added over 3.25 h at 50-55° C. Immediately after completion of the addition, the mixture was cooled to 5° C., water (150 g) was added, and the pH of the solution was adjusted to 6.0 by slow addition of 50% aqueous sodium hydroxide (103 g). After stirring for 10 minutes at this temperature, the organic layer was separated, and the aqueous layer was extracted with acetonitrile (50 mL). The organic layers were combined, dried (MgSO4), and partially evaporated to a weight of 193.7 g. Quantitative HPLC of this solution showed 41.5 wt % of the title compound (80.4 g, 84.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][C:26]1([CH3:38])[CH2:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35](Cl)=[O:36])[C:28]=2[O:27]1.CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:35]([C:34]2[C:28]3[O:27][C:26]([CH3:38])([CH3:25])[CH2:30][C:29]=3[CH:31]=[CH:32][CH:33]=2)=[O:36])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC1(C)Cc2cccc(C(=O)Cl)c2O1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OC(C)(C)C3)Cc2ccccc2C1
Yield: 77.9 %

Procedure:
A test tube (25×150 mm) containing a stirring bar and 2-amino-indane-2-carboxylic acid ethyl ester (0.5 g, 2.436 mmol) is charged with dry DCM (3 mL). Stirring is initiated. After dissolution, the DIPEA (1.50 mL, 8.6 mmol) and 4-dimethylaminopyridine (2 mg, 17 μmol) are added. A solution of 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride (0.73 g, 3.47 mmol) in dry DCM (4 mL) is added to the reaction tube. After stirring for 18 h, tlc analysis (silica, 10% CH3OH in DCM) indicates complete consumption of the starting amine. The reaction mixture is diluted with DCM (10 mL) and washed with 5% aqueous HCl (2×5 mL) and brine (5 mL), dried over MgSO4 filtered and evaporated by pumping to constant weight gives 0.72 g of a light brown gum. This material is purified by chromatography (silica, 0% to 20% EtOAc in DCM) on the ISCO Companion using a 40 g cartridge (silica). Fractions 17-22 are combined, evaporated and pumped to a constant weight to provide 0.62 g (67%) of a glassy solid.
Reaction SMILES: [C:1]1([N:7]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH3:18])[C:15]([SH:17])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1>C(O)C>[C:1]1([N:7]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH3:18])[C:15]([S:17][CH2:35][C:36]4[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(S)n2C)c1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(SCc1ccc(C#N)cc1)n2C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 1.30 g (3.4 mmol) of 1-methyl-2-mercaptobenzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, 0.52 g (3.74 mmol) of potassium carbonate and 0.66 g (3.4 mmol) of 4-bromomethylbenzonitrile were dissolved in 40 mL of absolute ethanol, stirred for 4 hours at 60° C. and 16 hours at room temperature. Then the solvent was distilled off in vacuo, the crude product was taken up in 30 mL of methylene chloride, washed with 40 mL of water and dried with sodium sulfate. After filtration and distillation of the solvent, the desired compound was obtained as a beige-white solid. Yield: 1.8 g (100% of theory); Rf value: 0.64 (silica gel; ethyl acetate).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[N+:12]([O-])=O)=[O:4].[H][H]>CO.[Pd]>[NH2:12][C:6]1[C:7]([CH3:11])=[N:8][N:9]([CH3:10])[C:5]=1[C:3]([N:2]([CH3:1])[CH3:15])=[O:4]
Reactant: [H][H]
Reactant: Cc1nn(C)c(C(=O)N(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1nn(C)c(C(=O)N(C)C)c1N
Yield: 98.7 %

Procedure:
19.0 g of N,N,1,3-tetramethyl-4-nitropyrazole-5-carboxamide in 400 ml of methanol are hydrogenated in the presence of 2.0 g of 10% strength palladium-on-charcoal in an autoclave at a hydrogen pressure of from 80 to 110 bars (8,000 to 11,000 kPa) for 8 hours at room temperature. The mixture is filtered, and the solvent is removed by distillation in vacuo to yield 16.1 g of crystalline 4-amino-N,N,1,3-tetramethylpyrazole-5-carboxamide, mp 116° to 118° C. (from ethyl acetate).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[S:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:25]1([CH2:31][C:32]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)=[S:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
For example, p-nitrobenzyl 7-amino-3-methylthio-3-cephem-4-carboxylate is reacted with phenylacetyl chloride in cold aqueous acetone containing an excess of sodium bicarbonate to provide the acylated compound p-nitrobenzyl 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylate. Similarly, diphenylmethyl 7-amino-3-(1-methyl-1H-tetrazole-5-ylthio)-3-cephem-4-carboxylate is reacted with 2-thienylacetyl chloride in aqueous acetone at a temperature of about 5° to about 10° C. in the presence of sodium bicarbonate to provide the 7-[2-(2-thienyl)acetamido]ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH2:26])=[N:3]1>C(OCC)C>[C:4]([NH:5][C:6]([NH:2][CH3:1])=[N:26][CH2:25][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)[N:2]([CH3:1])[N:3]=1)#[N:3]
Reactant: Cn1nc(CN)nc1NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCOCC
Product: CNC(=NCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1)NC#N
Yield: 55.5 %

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanamine (1.0 g) in diethylether (20 ml) was added to a refluxing solution of N-cyanocarbimidothioic acid dimethyl ester (0.45 g) in ether (50 ml) and the mixture heated at reflux for 8 h. After cooling, a colourless solid (0.65 g) precipitated and was collected by filtration, m.p. 121°-122°. This material was added to a solution of methylamine (33% in ethanol, 10 ml) in ethanol (50 ml) and the solution heated at reflux for 16 h. The mixture was evaporated to give a solid which was recrystallized from ethyl acetate to give the title compound as a colourless solid (0.34 g), m.p. 138°-139°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].C(#N)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(Br)c(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)c(C=O)cc1OCc1ccccc1
Temperature: 50 °C
Yield: 83 %

Procedure:
2-Bromo-5-hydroxy-4-methoxybenzaldehyde (25 g, 0.108 mol) and K2CO3 (30 g, 0.216 mol) were added to acetonitrile (250 mL) and flushed with Ar. Benzyl bromide (20 g, 0.12 mol) was added and the mixture was heated under Ar for 20 h at 50° C. After cooling, the mixture was poured into water (200 ml) and extracted with CH2Cl2 (300 mL). The CH2Cl2 was washed with water (3×100 mL), dried and concentrated. Recrystallization with isopropanol: water (3:1) gave 28.8 g (83%) of 2 as a light brown solid. 1H-NMR (400 MHz, CDCl3) dH 3.96 (3H, s, OCH3), 5.16 (2H, s, CH2Ph), 7.07-7.48 (7H, m, ArH+CH2Ph), 10.16 (1H, s, CHO).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[CH3:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:23][C:13]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][O:16][C:12]=2[CH3:11])[CH:9]=1)=[O:4]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1cc(O)n[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a stirred solution of 5-hydroxy-2H-pyrazole-3-carboxylic acid methyl ester (1.30 g, 9.15 mmol) and (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.73 g, 9.15 mmol) in THF (80 mL) at 5° C. under argon was added triphenylphosphine (3.12 g, 11.9 mmol), then diethyl azodicarboxylate (2.07 g, 11.9 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1 then dichloromethane:methanol=9:1) gave a colorless oil (800 mg) which was triturated with diisopropylether and further purified using a 5×50 cm Chiralpak AD column at room temperature using an isopropanol:heptane (2:8) mobile phase with UV detection at 220 nM to afford the title compound (250 mg, 9%) as a white solid. MS: m/e=328.3 [M+H]+.