Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]1[C:15]([S:16](Cl)(=[O:18])=[O:17])=[C:14]([F:20])[C:13]([F:21])=[C:12]([F:22])[C:11]=1[F:23].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]1[C:11]([F:23])=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=1[S:16]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: COC(C)(C)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)(C)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 163 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (1.07 g, 9 mmol) and TEA (0.61 g, 6 mmol) in CH2Cl2 (12 mL) was added pentafluorobenzenesulfonyl chloride (0.99 g, 3.7 mmol). The solution was stirred at rt for 2 h. Saturated aqueous NaHCO3 (12 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (75 mL) and washed with 1 M HCl (2×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (2.1 g, 81%). 1H NMR (400 MHz CDCl3) δ 4.42 (t, 2H, J=7.3 Hz), 3.13 (s, 3H), 1.97 (t, 2H, J=7.4 Hz), 1.17 (s, 6H); 19F NMR (400 MHz CDCl3) δ −137.9 (m, 2H), −146.65 (m, 1H), −161.01 (m, 2H). Anal. Calcd. For C12H13F5O4S: C, 41.38; H, 3.76. Found: C, 41.37; H, 3.77.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.[OH:15][CH2:16][CH2:17][NH:18][NH2:19].Cl>C(O)C>[OH:15][CH2:16][CH2:17][NH:18][NH:19][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Reactant: NNCCO
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(NNCCO)nn2)n1

Procedure:
A mixture of 2.09 g (0.01 moles) of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 30 ml of ethanol and 1.52 g (0.02 moles) of hydroxyethyl hydrazine is reacted and worked up in the same way as described in Example 42. Yield: 0.3 g (10.5%); the hydrochloride melts at 302°-305° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: NC1CC1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NC2CC2)cn1
Yield: 84 %

Procedure:
As described for example 168, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (90 mg, 0.26 mmol) was converted using cyclopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (81 mg, 84%) which was obtained as an off white solid. MS: m/e=367.4 [M+H]+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[C:26]3[C:38]([NH2:39])=[N:37][CH:36]=[N:35][C:27]=3[N:28]3[C:33]=2[CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]3)[CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:39][C:38]1[C:26]2[C:25]([C:17]3[CH:16]=[N:15][C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:33]3[N:28]([C:27]=2[N:35]=[CH:36][N:37]=1)[CH2:29][CH:30]([NH:34][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:31][CH2:32]3
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(N)CC1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Reaction time: 0.25 h

Procedure:
N,N-diisopropylethylamine (0.033 ml) and acryloyl chloride (0.0154 ml) were added to a solution of 5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-4,8-diamine (68 mg) obtained in Step 11 in chloroform (2.5 ml) under ice-cooling. After stirring at the same temperature for 15 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a yellow solid (35.4 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[O:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:25]4[CH:26]=[CH:27][O:23][CH:24]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccoc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccoc4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of 3-furaldehyde to form 4-(3-chloro-phenylamino)-3-[(fur-3-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)-3-[(fur-3-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 207-209° C.; HPLC: tRet(grad20-100/20)=8.4; MS: (M)+=340, (M−H)+=339.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]([N:23]([CH3:37])[C:24](=[O:36])[CH2:25][CH2:26][CH2:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[CH2:16]([N:23]([CH3:37])[C:24](=[O:36])[CH2:25][CH2:26][CH2:27][C:28]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:5][C:3]([OH:4])=[CH:2][C:1](=[O:6])[O:35]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C(=O)CCCC(=O)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)CCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 5.6 mmol of methyl acetoacetate, 6.1 mmol of NaH 60% dispersion in oil, 5.9 mmol of 1.6M n-butyl lithium in hexane, 5.6 mmol of 5-oxo-5-phenylpentanoic acid benzyl-methyl amide and 25 mL of tetrahydrofuran. The product was flash chromatographed using CH2 Cl2 /MeOH (98/2) to give a solid (m.p. 47°-51° C.). 1H NMR (DMSO-d6) δ 1.1-1.3 (m, 1 H), 1.4-1.6 (m, 1 H), 1.8-2.0 (m, 2 H), 2.2-2.4 (m, 2 H), 2.75/2.81 (s/s 3 H), 2.85-3.1 (m, 2 H), 4.4/4.5 (s/s, 2 H), 4.85/4.9 (s/s 1 H), 7.1-7.4 (m, 10 H), 11.36/11.38 (s/s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]nc(I)c2cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.83 h

Procedure:
A solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.874 g, 6.71 mmol) in THF (20 mL) was treated with NaH (60% in mineral oil; 0.402 g, 10.06 mmol) at 0° C. and the mixture was stirred for 50 min. Trityl chloride (2.244 g, 8.05 mmol) was added at 0° C. and the mixture was stirred for 16 h at room temperature, quenched with saturated NH4Cl, and extracted with EtOAc. The organic phase was washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified via flash chromatography (0-10% EtOAc-hexanes) to yield 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C25H18ClIN3[M+1]+ 522. found 522.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:28]=[C:29]([C:35]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[CH:40]=2)=[CH:36][C:37]#[N:38])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])(C(C)(C)C)(C)C.CCOCC>C1COCC1>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C:35]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([OH:26])[CH:28]=2)=[CH:36][C:37]#[N:38])[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(O)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in THF, 1.49 ml, 1.49 mmol) was added at rt to a stirred solution of 3-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-3-(3,5-dimethoxyphenyl)acrylonitrile (0.53 g, 1.25 mmol) in THF (15 ml). The colorless clear solution immediately turned into brown/red wine color. The reaction should be done within one hour. Ice water (10 ml) was poured into the reddish solution, followed by addition of ether (50 ml). The mixture was washed with water (2×80 ml), dried over MgSO4, filtered and concentrated to a yellow oil, which was lyophilized to give 3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-acrylonitrile as a foamy solid (0.35 g, 90%): mp, 43-45° C.; 1HNMR (DMSO-d6) δ 9.36 (s, 1H, OH group of one isomer), 9.28 (s, 1H, OH group of the other isomer), 7.07 (d, J=8 Hz, 1H, Ar), 7.00 (d, J=8 Hz, 1H, Ar), 6.91-6.82 (m, 4H, Ar), 6.69-6.65 (m, 2H, Ar), 6.49 (t, J=2 Hz, 4H, Ar), 6.19 (s, 1H, double bond proton of one isomer), 6.17 (s, 1H, double bond proton of the other isomer), 3.87 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 3.78 (s, 6H, 2OCH3), isomer ratio based on 1HNMR was 45%: 55%; 13C NMR (CDCl3) δ 162.8, 162.6, 160.8, 160.8, 148.7, 148.2, 145.7, 145.5, 141.4, 139.1, 131.9, 130.2, 122.3, 121.3, 118.2, 118.1, 116.0, 114.4, 110.4, 110.4, 107.8, 107.1, 102.2, 94.2, 93.5, 56.2, 56.1, 55.6; Anal. Calcd. For C18H17NO4: C, 69.12; H, 5.53; N, 4.48. Found: C, 68.76; H, 5.69; N, 4.22.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:26]([CH:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:27])[F:28])=[CH:23][CH:22]=1)[CH3:25])[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: CC(N)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(c1ccc(OC(F)(F)F)cc1)N1Cc2cc(Br)cc(Cl)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.409 g, 1.2 mmol), 1-(4-trifluoromethoxy-phenyl)-ethyl-amine (0.288 g, 10.4 mmol), and K2CO3 (0.331 g, 2.4 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-Bromo-7-chloro-2-[1-(4-trifluoromethoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.202 g, 39%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.67 (d, 3H), 3.96 (d, 1H), 4.20 (d, 1H), 5.77 (q, 1H) 7.21 (d, 2H), 7.41 (m, 3H), 7.58 (s, 1H). GC-MS: m/z 434 (M)+, 420 (M−14)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[Cl:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:17]1[CH:18]=[C:14]([Cl:13])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16]1
Reactant: FC(F)(F)c1n[nH]cc1Cl
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(Cl)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 83 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.82 g), 4-chloro-3-trifluoromethyl-1H-pyrazole (0.63 g) and potassium carbonate (0.61 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-chloro-3-trifluoromethyl-1H-pyrazole (0.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][O:19][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Yield: 98.7 %

Procedure:
Into a 200 cc glass reactor equipped with a stirrer, 26.3 g of ethyl 2-chloro-4,5-difluorobenzoylacetate, 23.7 g of ethyl ortho-formate and 40 ml of acetic anhydride were charged, and reacted at a reaction temperature of from 120° to 135° C. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure to obtain 31.5 g of the desired compound as the residue.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CCCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added butanoyl chloride (0.42 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml) and filtered to give 0.55 g (80%) of product as an off-white solid: mp 171-173° C.; 1H NMR (DMSO-d6) d 11.14 (s, 1H), 9.68 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 5.15 (dd, J=5.2 and 12.6 Hz, 1H), 2.96-2.84 (m, 1H), 2.65-2.42 (m, 4H), 2.11-2.06 (m, 1H), 1.73-1.58 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR (DMSO-d6) d 172.70, 171.84, 169.72, 167.70, 166.63, 136.54, 136.07, 131.41, 126.17, 118.23, 116.89, 48.90, 30.91, 21.96, 18.25, 13.46; Anal. Calcd. For C17H17N3O5: C, 59.47; H, 4.99; N, 12.24. Found: C, 59.45; H, 4.82; N, 12.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:24]([O-])=O)=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.[In].[C:28](O)(=O)[CH3:29].C(OC)(OC)(OC)C>C1C=CC=CC=1.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]3[N:24]=[C:28]([CH3:29])[O:23][C:16]=3[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Reactant: CC(=O)O
Agent: COC(C)(OC)OC
Agent: [In]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C)oc12
Yield: 51.8 %

Procedure:
To a solution of methyl 2-[(2,6-dichlorophenyl)amino]-6-hydroxy-7-nitro-1H-benzimidazole-5-carboxylate (0.150 g, 0.370 mmol) in benzene (5 mL), indium (0.172 g, 1.51 mmol), acetic acid (0.468 g, 7.54 mmol) and trimethyl orthoacetate (0.480 g, 2.96 mmol) were added under N2 atmosphere. The reaction mass was refluxed for 3-4 h. A mixture of MeOH:DCM (15%) was added to the reaction mixture. The reaction mass was filtered. The organic layer was concentrated. The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH: DCM to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 2.63 (s, 3H), 3.88 (s, 3H), 7.40 (m, 1H), 7.61-7.69 (m, 3H), 9.56 (s, 1H), 11.56 (s, 1H); MS [M+H]+: 391.33.
Reaction SMILES: [OH:1][CH:2]([CH:12]1[C:16](=[O:17])[CH:15]=[CH:14][CH:13]1[CH:18]=[CH:19][CH:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[OH:34]O.[OH-].[Na+]>CO>[O:34]1[CH:14]2[CH:15]1[C:16](=[O:17])[CH:12]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:13]2[CH:18]=[CH:19][CH:20]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OO
Reactant: CCCCCC(C=CC1C=CC(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(C=CC1C2OC2C(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A solution of 3.30 g of 5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone in methanol (25 ml) was cooled to 0° C., and 48 ml of an aqueous 30% hydrogen peroxide and 0.48 ml of an aqueous 1N sodium hydroxide were dropwise added thereto. After stirring at 0° C. for 3 hours, the reaction mixture was extracted with an addition of ethyl acetate and saturated aqueous ammonium chloride, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 2.54 g (yield 74%) of 2,3-epoxy-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)cyclopentanone.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered potassium hydroxide (144.4 g) was added carefully to a mechanically stirred mixture of 6-fluoroindole (49.23 g, 0.364 mol) and 4-piperidone monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml). The mixture was then heated under reflux under nitrogen for 18 hr and then more potassium hydroxide (40 g) was added and the reaction mixture heated under reflux for a further 4 hr. The reaction mixture was allowed to cool to room temperature and poured onto ice-water (3 l) and stirred for 1 hr and the precipitated solid isolated by filtration and dried at 50° C. in vacuo to give a solid. (WO 9747302).
Reaction SMILES: [CH3:1][C:2]([O:7]/[N:8]=[C:9](\[C:16]([NH:18][C@@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][S:27][C@H:20]12)=[O:17])/[C:10]1[N:14]=[C:13]([NH2:15])[S:12][CH:11]=1)([C:4]([OH:6])=[O:5])[CH3:3]>C(O)=O>[CH3:3][C:2]([O:7]/[N:8]=[C:9](/[C:16]([NH:18][C@@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][S:27][C@H:20]12)=[O:17])\[C:10]1[N:14]=[C:13]([NH2:15])[S:12][CH:11]=1)([C:4]([OH:6])=[O:5])[CH3:1].[OH2:5].[OH2:5].[OH2:5].[OH2:5].[OH2:5]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Solvent: O=CO
Product: CC(C)(O/N=C(/C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Product: O
Temperature: 5 °C

Procedure:
A second 128 ml aliquot of the ceftazidime solution prepared as described above was cooled and maintained at 5° C., while the pH was adjusted from 5.8 to 3.6 with 10.5 ml of 5.9M formic acid. The stirred solution was seeded with ceftazidime pentahydrate crystals and crystallization commenced. After 5 hours the crystals were harvested by filtration, washed with 150 ml of chilled water and 100 ml of chilled acetone and air dried to give 20.8 g of ceftazidime pentahydrate. The material assayed as follows: HPLC potency 84.4% (as is); polymer (stressed material) 0.66%; related substances, 1.07%; Karl Fischer 14.1%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:38][CH:39]=1
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3s2)CC1

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (265 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 113 mg of 183. MS (Q1) 484.3 (M)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[F:7][C:8]1[S:12][C:11]([NH2:13])=[N:10][CH:9]=1.[S:14](Cl)(Cl)(=[O:16])=[O:15]>C(Cl)Cl.CCCCCCC>[F:7][C:8]1[S:12][C:11]([NH:13][S:14]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:16])=[O:15])=[N:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1ncc(F)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=S(=O)(Nc1ncc(F)s1)n1ccnc1
Reaction time: 0.17 h

Procedure:
A solution of 1H-imidazole (6.17 g, 91 mmol) and 5-fluorothiazol-2-amine hydrochloride (Milestone Pharmatech, Brunswick, N.J., 3.50 g, 22.64 mmol) in 100 mL DCM was cooled to −78° C. sulfuryl chloride (1.841 ml, 22.64 mmol) was added, and the reaction mixture was allowed to stir for 10 minutes. The reaction mixture was then transferred to a 0° C. cooling bath, and was allowed to stir for an additional hour. LC/MS showed mostly product, so the reaction mixture was diluted with a small amount of heptane, and the solvent was decanted off. The resulting solid was dried (kept under vacuum) and used without further purification. [M+H]+=249.0