Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)c3ccccc3)cccn2n1
Yield: 67.3 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (50.0 mg, 0.248 mmol) and triethylamine (41.6 μL, 0.298 mmol) in tetrahydrofuran (2.5 mL) was added benzoyl chloride (31.7 μL, 0.273 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) 15 and silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (51.0 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:55]1([CH2:60][C@@H:61]2[CH2:66][CH2:65][CH2:64][NH:63][CH2:62]2)[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:63]2[CH2:64][CH2:65][CH2:66][C@@H:61]([CH2:60][N:55]3[CH2:56][CH2:57][CH2:58][CH2:59]3)[CH2:62]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: C1CNC[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H](CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.2 g, 0.4 mmol), HOBt (54 mg, 1 eq.), EDAC (77 mg, 1 eq.) in DMF (1.5 mL) was stirred at rt for 10 mins. To the mixture was added (R)-3-pyrrolidin-1-ylmethyl-piperidine (0.2 g, 3 eq.). After stirring at rt for over the weekend, the precipitate was collected by vacuum filtration, washed with water, sodium bicarbonate and water. The solid was then purified on a silica gel column to give 101 mg (46%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][OH:18]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC[C@@H]2CO)c(F)c1
Temperature: 75 °C
Yield: 96.4 %

Procedure:
A suspension of 3,4-difluoronitrobenzene (1.57 g, 9.8 mmol), (R)-2-pyrrolidinemethanol (1.0 g, 9.8 mmol) and K2CO3 (1.36 g, 9.8 mmol) in 30 mL DMF was heated at 75° C. for 20 h, whereupon the mixture was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (19:1 CH2Cl2:MeOH) afforded 2.27 g (96%) of (R)-[l-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol, an orange solid. Data for (R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol: Rf 0.17 (7:3 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, 1H, J=9.1, 2.6), 7.89 (dd, 1H, J=14.4, 2.6), 6.68 (t, 1H, J=9.0), 4.25-4.32 (m, 1H), 3.60-3.75 (m, 3H), 3.40-3.50 (m, 1H), 1.95-2.15 (m, 4H), 1.43 (t, 1H, J=5.8).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[C:21]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH3:37])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH2:37][Br:8])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(CBr)nc2ccccc21
Reaction time: 21 h

Procedure:
NBS (8.43 g, 47.4 mmole) and AIBN (2.1 g, 12.8 mmole) were added to a solution of 1-BOC-2-methylbenzimidazole (10.0 g, 43.1 mmole) in CCl4 (120 mL) at reflux. After 21 hr, the reaction was cooled and filtered. The filtrate was concentrated, and the resulting brown oil was chromatographed on silica gel (15% EtOAc/hexanes) to afford the title product: 1H NMR (400 MHz, CDCl3) δ 7.94-8.01 (m, 1 H), 7.70-7.75 (m, 1 H), 7.31-7.44 (m, 2 H), 4.96 (s, 2 H), 1.75 (s, 9 H),
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(N4CCCCC4)ccc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI/CI): predicted mass C21H24N6O3, 408.2.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[O:24]1[CH2:27][C:26]([CH2:30][NH2:31])([CH2:28][NH2:29])[CH2:25]1>>[NH2:29][CH2:28][C:26]1([CH2:30][NH:31][C:15]2[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=[C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:1])[CH2:3][CH2:4]3)[N:14]=2)[CH2:27][O:24][CH2:25]1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Reactant: NCC1(CN)COC1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(CN)COC3)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and 3,3-oxetanedimethanamine. MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.74 (t, J=8.7 Hz, 2H), 7.43-7.51 (m, 2H), 6.83 (s, 1H), 5.21 (d, J=15.2 Hz, 1H), 4.68-4.75 (m, 1H), 4.64 (d, J=6.6 Hz, 2H), 4.50 (t, J=6.2 Hz, 2H), 4.01 (br. s., 2H), 3.09 (s, 2H), 2.56 (s, 3H), 2.06 (s, 4H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:10](=[C:11]([CH3:23])[N:12](COCC[Si](C)(C)C)[N:13]=3)[CH:9]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)=[CH:4][C:3]2[CH:33]=[CH:34][CH:35]=[CH:36][C:2]1=2.B([O-])[O-].C(OC([N:47]1[C:55]2[CH:54]=[N:53][C:52]([N:56]=CN(C)C)=[N:51][C:50]=2[C:49](I)=[CH:48]1)=O)(C)(C)C>>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:49]3[C:50]4[N:51]=[C:52]([NH2:56])[N:53]=[CH:54][C:55]=4[NH:47][CH:48]=3)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[C:11]3[CH3:23])=[CH:4][C:3]2[CH:33]=[CH:34][CH:35]=[CH:36][C:2]1=2
Reactant: Cc1c2cc(B3OC(C)(C)C(C)(C)O3)cc(-c3cc4ccccc4s3)c2nn1COCC[Si](C)(C)C
Reactant: CN(C)C=Nc1ncc2c(n1)c(I)cn2C(=O)OC(C)(C)C
Agent: [O-]B[O-]
Product: Cc1n[nH]c2c(-c3cc4ccccc4s3)cc(-c3c[nH]c4cnc(N)nc34)cc12
Yield: 18.9 %

Procedure:
A mixture of 7-benzo[b]thiopen-2-yl-5-bromo-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (Preparation #24, 1.0 g, 2.18 mmol) in tetrahydrofuran (15 mL) was cooled to about −65° C. then a solution of n-butyllithium (1.6 M, 1.5 mL, 2.4 mmol) was added dropwise. After about 5 minutes methyliodide (0.37 g, 2.6 mmol) was added then the solution was warmed to about −20° C. Saturated ammonium chloride (1 mL) was added then the mixture was diluted with ethyl acetate (25 mL) and water (10 mL). The layers were separated then the organic layer was dried over magnesium sulfate, filtered and evaporated to give the crude 7-benzo[b]thiophen-2-yl-5-bromo-3-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole which was converted to 7-benzo[b]thiophen-2-yl-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (0.29 g, 25% over 2 steps) using general procedure E. The boronate (200 mg, 0.385 mmol) was coupled with 2-(dimethylamino-methyleneamino)-7-iodo-pyrrolo[3,2-d]pyrimidine-5-carboxylic acid tert-butyl ester (0.135 g, 0.32 mmol) using general procedure F and the resulting product deprotected using general procedure G to give 7-(7-benzo[b]thiophen-2-yl-3-methyl-1H-indazol-5-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamine (24 mg, 19%); (DMSO-d6, 400 MHz) δ 12.48 (bs, 1H), 11.44 (s, 1H), 8.50 (m, 3H), 8.18 (d, 1H), 8.07 (bs, 1H), 8.02 (d, 1H), 7.90 (d, 1H), 7.43 (m, 2H), 5.94 (bs, 2H), 2.61 (s, 3H); RP-HPLC (Table 1, Method e) Rt 1.76 min; m/z: (M−H)− 394.9.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[CH:6][N:7]=1.C(Cl)Cl.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CCOCC3)cnc2N)cc1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.8 %

Procedure:
To a suspension of tert-butyl 4-(3-amino-6-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (15 g, 40.4 mmol) in MeOH (800 mL) was added DCM (100 mL) until the suspension turned to a homogeneous solution. After degassed by N2 stream for 15 min, Pd/C (10 g, 9.40 mmol) was added to the reaction mixture. To this mixture, hydrogen balloon was equipped after flushed with hydrogen gas three times. The reaction mixture was stirred for 6 h. After the reaction mixture was filtered through Celite® pad, the volatile materials were removed in vacuo. The residue was dissolved in MeOH (200 mL) by heating and cooling down to room temperature and standing overnight. The brown precipitate was filtered off, which afforded 4.5 g of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate. The filtrate was concentrated and dissolved in EtOH (200 mL) by heating. The second brown precipitate was filtered off to afford 3.9 g of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (55.7% combined yield). LCMS (m/z): 374.7 (MH+), 0.90 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:29]=[C:20]1[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:24])[N:19]1[O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate 69 (0.9 g, 3.67 mmol, WO 2009/87649 A1) in THF (28 mL) were added N-hydroxyphthalimide (0.9 g, 5.51 mmol), triphenylphosphine (1.44 g, 5.51 mmol) and DIAD (1.07 mL, 5.51 mmol) sequentially at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min and at room temperature for 16 h. Solvent was evaporated off and the residue was subjected to chromatography to give 70 (0.69 g, 48%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:32](=[O:40])[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:32]([CH2:33][N:34]1[CH2:35][CH2:36][N:37]([CH2:14][CH:12]([OH:13])[CH2:11][C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:15])[CH2:38][CH2:39]1)=[O:40]
Reactant: COc1ccc(NC(=O)CC2CO2)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NC(=O)CC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1

Procedure:
To a solution of crude N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide (10) in ethanol (2.5 mL) was added triethylamine (0.5 mL), followed by N-(2,6-dimethylphenyl)-2-piperazinylacetamide, a compound of formula (4) (150 mg), and the mixture was heated to reflux for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and the residue purified by column chromatography on silica gel, eluting with 5% MeOH/dichloromethane, to give 4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}-piperazinyl)-3-hydroxy-N-(4-methoxyphenyl)butanamide, a compound of Formula I as an off-white solid.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].[Br:9]Br.N1C=NC=N1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CC(C)=O>[F:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH2:5][Br:9]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CF
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1nc[nH]n1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)CBr
Yield: 99.9 %

Procedure:
4.18 kg (35.4 mol) of 1-fluoro-2,2-dimethyl-butan-3-one were dissolved in 30 liters of methylene chloride, and 5.67 kg of bromine were added dropwise at 20° C. in the course of 2 hours such that continuous decolorisation occurred. The solvent was distilled off under a waterpump vacuum, a further 15 liters of methylene chloride were added to the residue and the solvent was again distilled off under a waterpump vacuum. The crude 1-fluoro-4-bromo-2,2-dimethyl-butan-3-one (6.97 kg, quantitative yield) was added dropwise to 2.45 kg of 1,2,4-triazole and 4.89 kg of potassium carbonate in 21.4 liters of acetone at 30° to 35° C. in the course of 2 hours, whilst cooling. The mixture was subsequently stirred at room temperature for 15 hours, the insoluble material was filtered off and the solvent was distilled off from the filtrate under a waterpump vacuum. 6.12 kg (93% of theory) of 1-fluoro-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one, which could be further reacted directly, were obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([O:28]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6].FC(F)(F)C([O-])=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([OH:28])=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 4 h

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate.trifluoroacetate (syn isomer)(1.4 g) in methylene chloride (30 ml) were added anisole (1.4 ml) and trifluoroacetate acid (1.83 ml) with stirring under ice-cooling and the stirring was continued for 4 hours at 5° C. The reaction mixture was evaporated and the residual oil was pulverized in diethyl ether, collected by filtration and then dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.trifluoroacetate (syn isomer)(1.1 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].[CH3:11][CH2:12]O.OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:11]([O:8][C:7](=[O:9])[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:12]
Reactant: CCO
Reactant: O=C(O)C(=O)c1ccco1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccco1
Temperature: 63 °C
Yield: 93.9 %

Procedure:
Furan-2-yl-oxo-acetic acid (15 g, 107 mmol), dissolved in CHCl3 (420 ml), was treated with EtOH (9.6 ml, 165 mmol) and H2SO4 (1 ml) and heated to 63° C. for 12 hours. Next, the reaction mixture was transferred to a separatory funnel and washed with sat. NaHCO3 (100 ml). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated providing 16.9 g (66%) of the above subtitle compound, which was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cccnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyridin-3-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and benzenesulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ8.79 (s, 1H), 8.58 (d, 1H), 7.87 (m, 3H), 7.61 (m, 1H), 7.54 (m, 2H), 7.40 (m, 3H), 7.18 (m, 3H), 7.03 (d, 1H), 6.88 (d, 1H), 6.79 (s, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 3.65 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 501 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH:1]1[C:11](=[O:12])[CH2:10][O:8][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]1=2
Reactant: O=C(Cl)CCl
Reactant: Nc1ccncc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cnccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
4-amino-3-pyridinol (650 mg, 5.904 mmol) was dissolved in anhydrous N,N-dimethyl formamide (15 ml) under nitrogen atmosphere, and chloroacetyl chloride (0.52 ml, 6.494 mmol) solution was added thereto dropwise at room temperature and then stirred for 30 minutes. Then, potassium carbonate (2.0 g, 14.760 mmol) was added thereto dropwise at room temperature, and the reaction mixture was heated at 100□ for 18 hours. The reaction mixture was cooled to room temperature and water was added to quench the reaction. The organic layer was extracted with ethyl acetate and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid. The obtained white solid was recrystallized from ethyl acetate and n-hexane to obtain white solid (520 mg, 59%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:30][CH2:29][CH2:28][CH2:27]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[CH:26]1([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: OC1CCCC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OC4CCCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and cyclopentanol instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[ClH:10].Br[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Br>ClC1C=CC=CC=1.C(OCC)C>[ClH:10].[ClH:10].[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: BrCCNCCBr
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Yield: 201.2 %

Procedure:
A mixture of 3,4-difluoroaniline (3.6 g) and bis(2-bromoethyl)amine hydrochloride (5.0 g) in 50 mL of chlorobenzene is warmed to reflux under argon for 48 hours. The mixture is cooled to room temperature, diluted with 100 mL of diethyl ether, and extracted with three 150 mL portions of 1N HCl. The aqueous extracts are backwashed with three 50 mL portions of ether, which are discarded. The combined aqueous fractions are basified to pH 11 with 12N NaOH. The resulting mixture is extracted with three 50 mL portions of methylene chloride, and the combined organic extracts are dried over sodium sulfate. The solvent is removed under reduced pressure, and the resulting residue is taken up in 50 mL of diethyl ether and filtered through Celite. The resulting solution is treated with a 1 M ethereal HCl solution (56 mL), and the resulting precipitate is collected and dried under vacuum to give 5.1 g of the title compound, mp 100-104° C. (decomposes). ##STR7## Preparation of 2-[4-(3,4-difluoro-phenyl)-piperazin-1-ylmethyl]-quinoline
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2[NH:7][CH:8]=[N:9][C:10](=O)[C:5]=2[CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[N:9]=[CH:8][NH:7][C:6]2=[N:12][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc2c(=O)nc[nH]c2[nH]1
Product: CCc1cc2c(Cl)nc[nH]c-2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 3.35 g (20.5 mmol) of 1,7-dihydro-6-ethyl-4H-pyrrolo[2,3-d]pyrimidin-4-one in 187 mL of phosphorous oxychloride was heated to reflux for 4 hours. The reaction was cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in 100 mL of methylene chloride and poured onto 100 g of ice. The mixture was neutralized to pH 7 by the addition of powdered potassium carbonate. After an additional 200 mL of methylene chloride and 200 mL of water were added, some solids remained and were removed by filtration. The solids were shown to be desired product by thin layer chromatography (silica, 19:1 methylene chloride-methanol). The solids were combined with the organic phase and concentrated to 4.0 g of brown residue. The residue was purified by flash chromatography (200 g of silica, 19:1 methylene chloride-methanol) to provide 2.50 g (67%) of 4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, dmso-d6) δ1.27 (t, J=7.5 Hz, 3H), 2.76 (q, J=7.5 Hz, 2H), 6.30 (s, 1H), 8.48 (s, 1H), 12.41 (s, 1H)