Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:22]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CCOC(C)=O>[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[CH:8][C:4]=1[C:5]([NH:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:22]=1)=[O:7]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(-c2ccc(F)cn2)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reaction time: 1 h
Yield: 55.8 %

Procedure:
2,4-dichloro-5-(5-fluoropyridin-2-yl)benzoic acid hydrochloride (Preparation 20, 900 mg, 3.15 mmol), ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (683 mg, 2.95 mmol) and diisopropylethylamine (3.28 mL, 18.88 mmol) were added to EtOAc (30 mL) and heated to reflux under an atmosphere of nitrogen. A 50% solution of propylphosphonic cyclic anhydride in EtOAc (9 g, 14.16 mmol) was added dropwise, and the reaction was kept at reflux for 3 hours. After cooling, the reaction was basified with saturated aqueous sodium hydrogen carbonate solution. The organic layer was collected, dried over magnesium sulphate and concentrated in vacuo. The residue was dissolved in ethanol (30 mL) and solid sodium carbonate (˜2 g) was added with rapid stirring for 1 hour. The mixture was filtered and the filtrate concentrated in vacuo. The residue was stirred with dilute aqueous sodium hydrogen carbonate, filtered, washed with water and dried in vacuo. The resulting solid was triturated with TBME to afford the title compound (822 mg, 52%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])[C:25](O)=[O:26])(=[O:22])[CH3:21]>>[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])[C:25]([NH:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19])=[O:26])(=[O:22])[CH3:21]
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: CC(=O)S[C@H](C(=O)O)[C@@H](C)C(C)C
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)[C@@H](SC(C)=O)[C@@H](C)C(C)C)CCc2ccccc21
Yield: 49 %

Procedure:
0.500 g (1.91 mmol) of (3S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one and 0.430 g (2.1 mmol) of (2S,3S)-2-acetylthio-3,4-dimethylpentanoic acid were treated by the same method as that of Example 101(h). Thus, 0.420 g of the title compound was obtained.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6](O)[CH2:7][CH2:8][OH:9]>P(=O)(O)(O)O.O>[CH2:2]([CH:1]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH2:3][CH3:4]
Reactant: OCCCO
Reactant: CCCC=O
Agent: O=P(O)(O)O
Solvent: O
Product: CCCC1OCCCO1
Yield: 56 %

Procedure:
This example illustrates the limitations of conventional synthesis methods. A 500 mL round bottom is charged with 191 g normal butyraldehyde, 101 g of 1,3-propanediol, and 4 drops 85% phosphoric acid. The round bottom is fitted with a Dean-Stark trap and condenser and the entire apparatus is placed into an electric heating mantle and brought to reflux. The aldehyde/water azeotrope condenses and separates into the trap. Heating is maintained until 24 mL of water has evolved (1 hr). The mixture is cooled and poured into a separatory funnel. The solution is washed twice with 50 mL of saturated sodium bicarbonate solution and once with 50 mL of distilled water. The organics are dried over MgSO4 and the residue distilled. A fraction collected at 150° C. is 99.6% acetal and has a mass of 95.7 g. This corresponds to a yield of 56%, lower than the yields reported in Table II.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH2:30])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH:30][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCn1c2ccccc2c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)NC(=O)OC(C)(C)C)ccc21
Yield: 77.3 %

Procedure:
A solution of 2-((tert-butoxycarbonyl)amino)propanoic acid (200 mg, 1.06 mmol), (9-ethyl-9H-carbazol-3-yl)methanamine (237 mg, 1.06 mmol), HATU (522 mg, 1.37 mmol) and TEA (0.442 mL, 3.17 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 60% ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give tert-butyl (1-(((9-ethyl-9H-carbazol-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (324 mg, 0.819 mmol, 78%) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[N:7]=1.[OH-].[Na+]>CO.O>[C:14]([NH:13][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:17])=[O:2])[CH:11]=[C:10]([CH3:12])[CH:9]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)CCc1cc(C)cc(NC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cc(C)cc(CCC(=O)O)n1
Reaction time: 18 h
Yield: 92 %

Procedure:
6.15 g of 3-(6-acetylamino-4-methyl-pyridin-2-yl)-propionic acid methyl ester (compound C5) is dissolved in 100 ml methanol and 70 ml water. Subsequently, 30.44 ml of a 1.0 M solution of NaOH is added while stirring is continued for 18 h at r.t. 2.0 g of amberlite IR-120 [H+] is added and the suspension is stirred for 10 min to neutralize the reaction mixture. The ion exchange resin is removed by filtration and 7.1 g of the crude product is isolated as a colourless solid after evaporation of solvent. Purification by chromatography on silica gel (eluent: dichloromethane/ethanol 10:1) affords 5.32 g of the title compound. M.p. 202° C. ESI-MS: 223.1 (MH+). TLC: Rf=0.13 (cyclohexane/ethyl acetate 1:1+1.0 vol % acetic acid).
Reaction SMILES: [Br: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=O.[NH:13]1[C:17]([C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25])=[CH:20][CH:19]=2)=[N:16][N:15]=[N:14]1>C(O)(=O)C>[Br: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:27][NH:26][C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:28]=[CH:29][C:18]([C:17]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: NNC(=O)COc1ccc(-c2nnn[nH]2)cc1
Solvent: CC(=O)O
Product: O=C(COc1ccc(-c2nnn[nH]2)cc1)NN=C1C(=O)Nc2ccc(Br)cc21
Temperature: 100 °C
Yield: 68 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added 2-[4-(1H-tetrazol-5-yl)phenoxy]acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 40 mg of the title compound (68%) as a orange Solid in 94.9% purity by HPLC (Rt: 3.34, gradient of 8 mini, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([N:12](CC)CC)C>C(#N)C>[C:10]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)#[N:12]
Reactant: COc1ccc[n+]([O-])c1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: COc1cccnc1C#N

Procedure:
3-Methoxypyridine-1-oxide (25.2 g, 209 mmol) was dissolved in acetonitrile (260 mL). Trimethylsilycyanide (66.35 g, 669 mmol) and triethylamine (45.13 g, 446 mmol) were added and the reaction mixture heated at reflux for overnight. The cooled solution was concentrated in vacuo to give a brown solid which was partitioned between CH2Cl2 and 3M Na2CO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chomatography using 1:1 EtOAc/hexanes as eluent. Compound 762B was isolated (17.63 g, 63%) as a light yellow solid. HPLC: 96.2% at 1.37 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 134.88 [M+H]+.
Reaction SMILES: C(CCCCC1C=C(/[C:14](=[CH:48]\[CH:49]=[C:50]2/[C:51]([CH3:69])([CH3:68])[C:52]3[C:53](=[N:67]/2)[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH:55]=[C:56]([Cl:58])[CH:57]=3)/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:46])=[O:45])C=CC=1)(O)=O.[Na+:70].[Na+].[Na+].B([C:76]1[CH:77]=[C:78]([CH2:82][CH2:83][C:84]([OH:86])=[O:85])[CH:79]=[CH:80][CH:81]=1)(O)O>>[C:84]([CH2:83][CH2:82][C:78]1[CH:77]=[C:76](/[C:14](=[CH:48]\[CH:49]=[C:50]2/[C:51]([CH3:69])([CH3:68])[C:52]3[C:53](=[N:67]/2)[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:64])=[O:65])[CH:55]=[C:56]([Cl:58])[CH:57]=3)/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:45])=[O:46])[CH:81]=[CH:80][CH:79]=1)([OH:86])=[O:85].[Na+:70].[Na+:70].[Na+:70]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)O)c1
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCC(=O)O)c1

Procedure:
Compound 30 is prepared analogously to compound 28 (Example 37), except that 3-(3-boronophenyl)propionic acid is used as a starting material.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:8]=[C:9]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH2:3]1.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][CH:6]2[CH2:2][CH2:3][C@@H:4]([C:7]3[CH:8]=[C:9]([CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=3)[O:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:5]2)[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc([C@@H](C)N)ccc1F
Reactant: CCOC(=O)COc1cc([C@@H]2CCC(=O)C2)cc(C(F)(F)F)c1
Agent: Cl
Product: COc1cc([C@@H](C)NC2CC[C@@H](c3cc(OCC(=O)O)cc(C(F)(F)F)c3)C2)ccc1F

Procedure:
General procedure A was followed using ethyl 2-[3-[(1R)-3-oxocyclopentyl]-5-(trifluoromethyl)phenoxy]acetate as the ketone and (R)-1-(4-fluoro-3-methoxyphenyl)-ethylamine hydrochloride as the amine. The resulting mixture of isomeric esters was purified and separated by flash chromatography (gradient of 0-80% EtOAc in heptane containing 2.5% NEt3). The faster eluting peak was isolated and subjected to hydrolysis following general procedure B to afford the title compound. 1H NMR (300 MHz, DMSO) δ 7.40 (d, J=8.5 Hz, 1H), 7.17 (dd, J=11.4, 8.3 Hz, 1H), 7.11-6.97 (m, 3H), 6.94 (s, 1H), 4.46 (dd, 2H), 4.10 (q, 1H), 3.84 (s, 3H), 3.16-2.86 (m, 2H), 2.21-2.07 (m, 1H), 1.94-1.58 (m, 5H), 1.45 (d, J=6.6 Hz, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:14]2[N:10]([C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:12]3[C:18](=[O:19])[N:17]([CH3:20])[C:16](=[O:21])[N:15]([CH3:22])[C:13]3=2)[CH2:9][CH:8]=1)(=O)=O.[Br-].[Li+].C([Sn](CCCC)(CCCC)[C:38]1[O:39][C:40]([CH3:43])=[CH:41][CH:42]=1)CCC>C1COCC1.CCOCC>[CH3:22][N:15]1[C:13]2=[C:14]3[N:10]([C:11]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[C:12]2[C:18](=[O:19])[N:17]([CH3:20])[C:16]1=[O:21])[CH2:9][CH:8]=[C:7]3[C:38]1[O:39][C:40]([CH3:43])=[CH:41][CH:42]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CC3
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C2=CCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1

Procedure:
1,3-Dimethyl-2,4-dioxo-5-phenyl-2,3,4,7-tetrahydro-1H-pyrimido[4,5-a]pyrrolizin-9-yl trifluoromethanesulfonate (step 4) (100 mg, 0.227 mmol), Cul (4.31 mg, 0.023 mmol), lithium bromide (39.4 mg, 0.453 mmol), tributyl(5-methylfuran-2-yl)stannane (168 mg, 0.453 mmol) in THF (2 ml) and Pd-118 (14.77 mg, 0.023 mmol) were heated to reflux for 10 mins. The reaction mixture was filtered through a glass filter paper and the filtrate concentrated in vacuo. The crude product was dissolved in the minimum amount DCM/EtOAc and loaded onto a 12 g silica cartridge and eluted with 0-80% EtOAc in iso-hexane. The desired product was eluted at 30% EtOAc. The relevant fractions were combined and concentrated to yield a yellow solid. The isolated solid was suspended in Et2O and the solid filtered to yield the title product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]I)=[CH:5][CH:4]=1)#[N:2].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[K]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(CCCI)cc1
Agent: [K]
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCN2CCNCC2)cc1
Yield: 66.2 %

Procedure:
A solution of 250 mg of 3-(4-cyanophenyl)propyl iodide, 0.85 g of anhydrous piperazine and 0.5 g of potassium carbonated in 10 ml of tetrahydrofuran was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and, after addition of saturated aqueous solution of sodium chloride, the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 140 mg of 1-[3-(4-cyanophenyl)propyl]piperazine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[CH2:11][C:10]=2[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:19]([S:18][C:17]3[C:16]([C:22]4[O:23][C:24]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:25][C:26](=[O:28])[CH:27]=4)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [5-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl]-carbamic acid tert-butyl ester (19) (1.08 g, 2.19 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (2 ml) and left under stirring at room temperature overnight. The solvent was dried in vacuo revealing a viscous dark brown liquid. Saturated sodium bicarbonate solution (20 ml) was added to the residue, which was left to stir for 20 mins. The brown precipitate was filtered, washing with water and left to dry in the vacuum oven overnight (0.77 g, 90%). 1HNMR (300 MHz, DMSO-d6): δH=3.40 (4H, t), 3.70 (4H, t), 3.77 (2H, s), 5.23 (2H, bs), 5.50 (1H, d), 6.17 (1H, d), 6.44 (1H, dd), 6.65 (1H, d), 7.09 (1H, d), 7.35 (1H, t), 7.47-7.59 (2H, m); m/z (LC-MS, ESP), RT=3.51 minutes, (M++1)=392.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:20]=O)[S:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:22][NH2:23].CO.CO>O1CCCC1>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH2:20][NH:23][CH3:22])[S:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: O=Cc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(2-fluoropyridin-3-yl)-5-[(pyridin-2-yl)thio]thiophene-2-carbaldehyde (270 mg) in tetrahydrofuran (2 mL) were added 40% methylamine-methanol solution (0.9 mL) and methanol (2 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (3 mL), and sodium tetrahydroborate (222 mg) was added at 0° C. The mixture was stirred at room temperature for 1 day and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 286 mg, yield quantitative).
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)=[O:11])=[C:6]([Cl: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)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12

Procedure:
For example, p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate is reacted with phenylacetyl chloride in cold aqueous acetone containing sodium bicarbonate to provide p-nitrobenzyl 7-phenylacetamido-3-chloro-3-cephem-4-carboxylate.
Reaction SMILES: CN.N.[CH3:4][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][N:8]([CH:10]([CH2:14][CH2:15][CH3:16])[C:11](O)=[O:12])[CH:9]=1.C[CH:24]([N:28]1C=C(C)C(C2C=CC=CC=2)=N1)C(O)=O>>[CH3:24][NH:28][C:11](=[O:12])[CH:10]([CH2:14][CH2:15][CH3:16])[N:8]1[CH:9]=[C:5]([CH3:4])[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7]1
Reactant: CCCC(C(=O)O)n1cc(C)c(-c2ccccc2)n1
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Agent: CN
Agent: N
Product: CCCC(C(=O)NC)n1cc(C)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 68, but substituting aqueous methylamine for aqueous ammonia, and 4-methyl-3-phenyl-α-propylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid, there was obtained N,4-dimethyl-3-phenyl-α-propylpyrazole-1-acetamide having a melting point of 84°-86° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([NH2:15])=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:15][C:7]2=[O:8]
Reactant: NC=O
Reactant: O=C1OC(=O)c2c(F)cccc21
Product: O=C1NC(=O)c2c(F)cccc21
Temperature: 0 °C

Procedure:
Under argon, 10.0 g (60.2 mmol) of 4-fluoro-2-benzofuran-1,3-dione were stirred at 130° C. in 50 ml of formamide for 1 h. The cooled reaction mixture was then added to ice-water. A solid precipitated out. This solid was filtered off with suction and washed with water. The product was dried under high vacuum. This gave 8.3 g (83% of theory) of the target compound.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][C:18](=[O:23])[C:19]#[C:20][CH2:21][CH3:22])[CH3:16]>CN(C)C=O>[CH2:15]([O:17][C:18]([C:19]1[C:20]([CH2:21][CH3:22])=[N:2][N:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=12)=[O:23])[CH3:16]
Reactant: CCC#CC(=O)OCC
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 8.8 %

Procedure:
To a solution of amino-pyridinium iodide (22 g, 99 mmol) and anhydrous potassium carbonate (17.8 g, 128.7 mmol) in dimethylformamide (225 mL) was added ethyl-2-pentynoate (24.98 g, 198 mmol). The solution was stirred at room temperature for 24 h. The reaction mixture was poured into 1.2 L of ice water. The resulting light brown precipitate was collected by vacuum filtration and air-dried for 16 h to yield crude product (1.9 g, 55%), which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([O:13][C:12]1[CH:11]=[CH:10][C:9]([CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)CCCl)cc1
Reaction time: 24 h
Yield: 54.6 %

Procedure:
3-Chloropropionyl chloride (12.5 ml, 0.131 mol) was added for three minutes to a solution of p-cresol (12.90 g, 0.119 mol) in pyridine (9.5 ml, 0.12 mol) and CH2Cl2 (53 ml) at 0° C. After stirring the reaction mixture for one day at 0° C. to room temperature, solvent was removed by rotary evaporation. The concentrate was treated with brine (50 ml) and 0.5 M citric acid (150 ml) and extracted with EtOAc (3×100 ml). The organic extracts were washed with 100 ml; 1 N HCl, H2O, cold 0.1 N NaOH, H2O and brine. After solvent removal, the residue was purified by silica gel flash column chromatography eluting with 7.5% EtOAc/hexane to give 12.90 g (55%) of 19 as a colorless liquid: NMR δ 2.34 (s, 3H), 3.03 (t, 2H, J=7), 3.86 (t, 2H, J=7), 6.95-7.01 (m, 2H), 7.17 (d, 2H, J=8).
Reaction SMILES: C[O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].C(N(C(C)C)CC)(C)C.[N:18]1[NH:19][N:20]=[N:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([CH:36]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:37](O)=[O:38])[CH:34]=[N:35][C:31]=2[CH:30]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[O:38]=[C:37]([NH:5][C@H:4]([C:3]([OH:2])=[O:8])[CH2:6][OH:7])[CH:36]([N:33]1[C:32]2[CH:46]=[CH:47][C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]3[N:18]=[N:19][NH:20][N:21]=3)=[CH:30][C:31]=2[N:35]=[CH:34]1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C(=O)N[C@@H](CO)C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Yield: 10.6 %

Procedure:
Serine methyl ester (1.0 moles, 0.119 g), diisopropylethylamine (1.0 mmoles, 0.206 g), 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.0 mmoles, 0.405 g), hydroxybenzotriazole (1.0 mole, 0.135 g), and dicyclohexylcarbodiimide (1.0 moles, 0.206 g) were reacted as in Example 37. The resulting ester (0.19 moles, 0.097 g) was hydrolyzed as in Example 37 to yield 0.052 g of N-[1-oxo-2-[5-[2-(2H-tetrazol-5-yl]phenyl]-1H-benzimidazol-1-yl]octyl]-L-serine (MS).