Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:16]([NH2:18])=O>O>[C:5]12[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=1[S:3][C:2]1[N:1]=[CH:16][N:18]=[C:7]([OH:8])[C:6]2=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: NC=O
Solvent: O
Product: Oc1ncnc2sc3c(c12)CCCC3
Temperature: 160 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Into a 100-mL round-bottom flask containing a solution of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (4.06 g, 18.02 mmol, 1.00 equiv) in 100 mL of formamide was stirred for 8 h at 160° C. in an oil bath under nitrogen. The reaction mixture was cooled to 0° C. and diluted with water. The solids were filtered and precipitated with ethyl acetate to provide 8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-ol (3.0 g, 81%) as a light yellow solid.
Reaction SMILES: [CH3:1][Si:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])OCC.[Mg].Br[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1>O1CCCC1>[CH3:1][SiH:2]([O:6][CH2:7][CH2:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]1[CH:11]=[CH:10][C:9]([SiH:2]([CH3:1])[O:6][CH2:7][CH2:8][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCO[Si](C)(OCC)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C[SiH](OCCc1ccccc1)c1ccc([SiH](C)OCCc2ccccc2)cc1
Reaction time: 3 h
Yield: 147.5 %

Procedure:
21.0 g of methylphenyldiethoxysilane, 2.43 g of magnesium and 100 ml of tetrahydrofuran were charged into a 500-ml, three-necked flask provided with a stirrer, a cooler, and a dropping furnel and stirred in a nitrogen gas stream, while 100 ml of a tetrahydrofuran solution containing 11.8 g of p-dibromobenzene was dropwise added thereto from the dropping furnnal over about 3 hours. After the dropwise addition, the mixture was further stirred and refluxed for about 5 hours. After the refluxing, the resulting polymer was separated by filtration, and the solvent was removed therefrom by distillation. The residues were subjected to distillation under reduced pressure, whereby 15 g of p-bis(methylphenylethoxysilyl)benzene was obtained (yield: 78%, boiling point: 213°-215° C./3 mmHg).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C>CO>[CH3:20][O:19][C:17]([C:16]1[NH:7][C:1]2[C:6]([C:15]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:18]
Reactant: COC(=O)CCC(=O)C(=O)OC
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1c(C(=O)OC)[nH]c2ccccc12
Temperature: 75 °C

Procedure:
Phenyl hydrazine (5.7 ml), dimethyl 2-oxoglutarate (10 g) and acetic acid (1.0 ml) in methanol (100 ml) were heated at reflux for 1 hour, then concentrated in in vacuo. The crude hydrazone (13 g) was dissolved in saturated methanolic hydrochloric acid (350 ml) and heated to 75° C. for 16 hours with continual stirring. The reaction was diluted with water (200 ml) and extracted with dichloromethane. Combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate solution, water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo to give a yellow crystalline solid (7.0 g); NMR d (CD3SOCD3) 3.59 (s, 3H), 3.83 (s, 3H), 4.12 (s, 2H), 7.06 (t, 1H), 7.26 (t, 1H), 7.41 (d, 1H), 7.63 (d, 1H), 11.76 (brs, 1H); M/z (−) 246 (M−H+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>CCCCCC.O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:12]([OH:17])[OH:13])=[CH:3][C:4]=1[CH2:10][CH3:11])#[N:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCc1cc(Br)ccc1C#N
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3.66 ml of n-butylithium solution (1.6M in hexane) are added dropwise to a solution of 1.14 g of 4-bromo-2-ethylbenzonitrile in 20 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 20 minute, 1.51 ml of triisopropyl borate are added. After 45 minutes, 12 ml of 1N HCl are added to the reaction mixture, which is warmed to room temperature. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1.1) each time. The combinred organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remainig oil is mixed with 40 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in the title compound as a yellow solid. Rt=3.27.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[OH:37].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:37][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: Oc1cc(F)ccc1F
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cc(F)ccc2F)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2,5-difluorophenol (0.23 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.29 g, 52%).
Reaction SMILES: [H-].[Na+].Cl.[Br:4][C:5]1[CH:9]=[N:8][NH:7][C:6]=1[O:10][CH3:11].CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[Br:4][C:5]1[C:6]([O:10][CH3:11])=[N:7][N:8]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: COc1[nH]ncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
Sodium hydride (354 mg, 60% dispersion in oil) was added portionwise to a solution of 4-bromo-3-methoxy-2H-pyrazole, hydrochloride salt (755 mg) in degassed DMF (12 ml) under argon at room temperature. The resulting suspension was stirred at room temperature for 10 minutes. tert-butyl 4-methylsulphonyloxypiperidine-1-carboxylate (1.087 g) was added to the stirred suspension. The resulting mixture was stirred at 90° C. for 20 hours. The reaction mixture was allowed to cool to room temperature, quenched with water, diluted with ethyl acetate then water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromo-3-methoxy-pyrazol-1-yl)piperidine-1-carboxylate (670 mg). NMR Spectrum: (CDCl3) 1.47 (s, 9H), 1.78 (dd, 1H), 1.83 (dd, 1H), 2.03-2.10 (m, 2H), 2.78-2.93 (m, 2H), 3.93 (s, 3H), 3.99-4.07 (m, 1H), 4.13-4.31 (m, 2H), 7.24 (s, 1H)
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:6][C:7]=1[CH:8]([OH:10])[CH3:9])[CH3:2].[CH3:21][O:22][C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][C:27]=1[CH3:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:21][O:22][C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:10][CH:8]([C:7]2[O:6][C:5]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:4][C:3]=2[CH2:1][CH3:2])[CH3:9])=[CH:28][C:27]=1[CH3:33]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)Oc1ccc(CCC(=O)OC)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 1-[4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.114 g, 0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.0789, 0.400 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine (0.200 mL, 0.800 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.800 mmole) in toluene (2 mL). The reaction is stirred overnight, then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0–15%) and concentrated to provide the titled compound as a white solid. Mass [EI+] 462 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][C:33]1[C:37](B(O)O)=[C:36]([CH3:41])[O:35][N:34]=1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:37]3[C:33]([CH3:32])=[N:34][O:35][C:36]=3[CH3:41])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3,5-dimethylisoxazol-4-yl)boronic acid gave 244. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.47 (s, 1H), 7.83 (s, 1H), 5.01 (d, J=50.4 Hz, 1H), 4.84 (d, J=10.2 Hz, 1H), 4.24-4.06 (m, 1H), 4.06-3.88 (m, 1H), 3.78 (s, 3H), 3.45-3.31 (m, 1H), 2.77 (s, 3H), 2.56 (s, 3H), 2.09-1.84 (m, 3H), 1.76-1.68 (m, 1H). LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:12]1([C:10]2[N:9]=[CH:8][N:7]=[C:6]([C:4]([C:23]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:5])[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1cc(-c2ccccc2)ncn1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cc(-c3ccccc3)ncn2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of 38b (0.243 g, 1 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.6 mL, 1.4 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1b (52.3%). NMR (CDCl3) δ 9.40 (d, 1H, J=1.5 Hz), 8.29 (d, 1H, J=1.5 Hz), 8.22-8.18, 7.57-7.54 (m, 5H), 7.46 (s, 2H), 3.96 (s, 3H), 3.91 (s, 6H); MS (ESI) adz 351.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCc3c(sc(N)c3C(=O)c3ccccc3)C2)cc1

Procedure:
To a well-stirred and ice-cooled solution of 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.78 mmol, 0.2 g) in dichloromethane (20 ml) under an argon atmosphere, was added triethylamine (0.162 ml) and then p-toluenesulphonyl chloride (0.93 mmol, 177 mg) portionwise. The suspension was stirred a room temperature for 24 h and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give a solid residue which was chromatographed on silica gel eluting with an ethyl ether and petroleum ether mixture to afford 2-amino-3-benzoyl-6-(4-methylphenylsulphonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.[NH3:34]>O1CCOCC1>[NH2:34][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Solvent: C1COCCO1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(N)nc3)nc3c2CCC3)n[nH]1

Procedure:
To a solution of (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (250 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was added aqueous ammonia (5 mL) and the reaction mixture was allowed to reflux in steel bomb at 130° C. for 18 h. The reaction mixture was concentrated under vacuum to obtain an oily crude product which was purified by reverse phase HPLC to afford 8 mg of (S)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.20 (d, 6H), 2.00-2.20 (m, 4H), 2.75-2.95 (m, 5H), 3.50-3.90 (m, 4H), 4.90-4.98 (m, 1H), 6.40 (s, 1H), 6.50 (d, 1H), 7.40 (s, 1H), 7.90 (s, 1H). The other enantiomer is prepared using the chiral (R) starting material.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[O:3]1.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([NH:20][C:21]([NH:14][S:11]([C:10]1[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:13])=[O:12])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Yield: 84.3 %

Procedure:
A solution of 19 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide prepared in Example 2 and 9.9 g of n-butyl isocyanate in 200 ml of 2-butanone was refluxed with 11.5 g of anhydrous potassium carbonate for 7 hours. The resulting mixture was concentrated to dryness in vacuo. The residue was taken up in 400 ml of water and extracted once with 100 ml of ethyl ether. The aqueous layer was acidified with 2N HCl and the resulting mixture was filtered and suction dried. The still slightly wet solid was washed once with 100 ml of hot acetonitrile, then suction dried an additional 8 hours to give 23 g of N-(butylaminocarbonyl)-2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide, m.p. 200°-203° C.
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.O.[NH2:19][NH2:20]>C(O)C>[O:3]=[C:4]1[C:5]2[NH:20][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1CCCC2=O
Yield: 70 %

Procedure:
1 g (4.2 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in mL of ethanol, 0.21 mL of hydrazine hydrate were added and the solution stirred at reflux for a day. The solvent was then evaporated and the residue redissolved with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give (70% yield) the title compound.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15]I>O1CCCC1>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:15])[C:11]([O-:13])=[O:12].[Na+:2]
Reactant: CI
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C(=O)C(=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) and 30 ml of tetrahydrofuran were added to 1.64 g (10.0 mmoles) of phenylpyruvic acid to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated, and ether was added to the resulting pale yellowish white semi-solid. The precipitated sodium 2-oxo-3-phenylbutanoate as a white solid (0.68 g, yield 68 %) was isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][C:5]([C:6]([N:8]([CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:7])=[C:4]([F:22])[CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O.C1COCC1>[NH2:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([CH:17]=1)[C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:7]
Reactant: Cc1ccccc1N(C)C(=O)c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1N(C)C(=O)c1cc(N)c(Cl)cc1F

Procedure:
To 4-chloro-2-fluoro-N-methyl-5-nitro-N-o-tolyl-benzamide (6.6 g, 20.3 mmol) was stirred vigorously in a mixture of water (30 mL) and THF (30 mL) containing Na2S2O4 (17.6 g, 101.2 mmol) for 12 hrs. The organic layer was then separated and the water layer was further extracted with ethyl acetate. The combined organic solutions were washed with brine and dried over MgSO4. Concentration yielded 5-amino-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide as a crude solid which was washed with ether to give a light yellow product (3.3 g). MS: 292.9 (M+H)+: tR=1.90 min (method 1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.Cl.[NH2:17][C:18]1[NH:23][CH2:22][CH2:21][CH2:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:17]=[C:18]3[NH:23][CH2:22][CH2:21][CH2:20][N:19]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCCN2
Yield: 75.4 %

Procedure:
A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate and 8.0 g (46.5 mmol) of 2-amino-3,4,5,6-tetrahydropyrimidine dihydrochloride (prepared according to J. Org. Chem. 1955, 20, 829.) and 19.3 g (139.5 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 18 h. The solution cooled, was evaporated to remove solvent. The residue was treated with water and extracted with dichloromethane. The extracts were dried and evaporated to give 8.0 g (75%) of product as a white powder. Mp: 219° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.CN(C=O)C.[CH2:23]([O:25]/[CH:26]=[CH:27]/B1OC(C)(C)C(C)(C)O1)[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH:12]1([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2](/[CH:24]=[CH:23]/[O:25][CH2:26][CH3:27])[C:3]=3[CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCO/C=C/c1nc(C)nc2sc(C3CCCCC3)cc12
Temperature: 85 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a mixture of 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (1.0 g) and DMF (40 mL) were added (E)-1-ethoxyethene-2-boronic acid pinacol ester (900 mg) and K3PO4 (4.3 g), and Pd(PPh3)4 (500 mg) was added thereto under an argon atmosphere, followed by heating and stirring at 85° C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, then concentrated under reduced pressure, and purified by silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-[(E)-2-ethoxyvinyl]-2-methylthieno[2,3-d]pyrimidine (885 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][C@H:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH3:36][N:37]1[C:42](=[S:43])[CH:41]=[CH:40][CH:39]=[CH:38]1.[I-].[Na+].C(=O)([O-])O.[Na+]>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][C@H:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][S:43][CH2+:42]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH3:36])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Cn1ccccc1=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O[C@H]3CCNC3=O)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CN1C=CC=C[CH2+]1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O[C@H]3CCNC3=O)c3csc(N)n3)[C@H]2SC1
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 33.3 %

Procedure:
To 4.8 ml of water are added 341 mg of 7β{(Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-oxopyrrolidin-3-yl)oxyimino]acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid, 125 mg of 1-methyl-2-thiopyridone and 900 mg of sodium iodide. The mixture is adjusted to a pH of 6.63 with an aqueous solution of sodium hydrogencarbonate. The mixture is stirred in an argon atmosphere at 65° C. for 3.5 hours. The reaction mixture is concentrated under reduced pressure. The concentrate is introduced into a column packed with HP-20 and is eluted with 20% and 25% methanol solutions. The fractions containing the contemplated compound are collected and concentrated. The residue is lyophilized, giving 128 mg of 7β-{(Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-oxopyrrolidin-3-yl)oxyimino]acetamido}-3-(1-methyl-2-pyridinio)thiomethyl-3-cephem-4-carboxylate as a pale brown compound.