Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[C:15]([OH:23])(=O)[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:24]1[O:29][C:27](=[O:28])[NH:26][CH:25]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Li]CCCC>C1COCC1.CCOC(C)=O.CCCCCC>[CH2:30]([C@@H:25]1[CH2:24][O:29][C:27](=[O:28])[N:26]1[C:15](=[O:23])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH3:21])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: CCCCC=CC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCC/C=C/C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
Triethylamine (6.85 g, 49.15 mmol) and trimethyl acetyl chloride (6.05 mL, 49.15 mmol) were added dropwise (5 min) to a −78° C. solution of 2-heptenoic acid (6 g, 46.81 mmole) in THF (80 mL). The slurry was stirred at −78° C. for 5 min and then replaced with a 0° C. cooling system. It was stirred at this temperature for 1 h. In a separate flask, a solution of R-(+)-4-benzyl-2-oxazolidinone (8.295 g, 46.81 mmol) was cooled to −78° C. and nBuLi (1.6M, 46.8 mmol) was added dropwise over 10 min. The colorless solution was stirred at this temperature for 45 min and transferred via cannula to a −78° C. solution of the ester. The yellowish slurry was warmed to 25° C. overnight (19 h). An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete. It was cooled to 0° C. and the reaction was quenched by addition of H2O (20 mL). It was diluted with ethyl acetate (200 mL) and the organic layer was separated. The organic layer was dried over MgSO4, filtered, and concentrated to obtain a crude yellow oil (13.69 g). The crude product was purified by column chromatography, silica gel 230 to 400 mesh, eluent: 1:4 EtOAc-hexane to obtain (4R)-4-benzyl-3-[(E)-2-heptenoyl]-1,3-oxazolidin-2-one as a colorless oil (12.1 g, 92.80%). Mass Spectrum (−ESI): 288 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (548 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>ClCCl>[Cl:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([F:1])[CH:3]=2)=[O:6])=[CH:23][CH:22]=1
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: ClCCOc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OCCCl)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 3-fluoro-4-methoxybenzoyl chloride from the last step and anhydrous AlCl3 (1.30 g, 9.76 mmol) in dry dichloromethane (18 mL) was added (2-chloroethoxy)benzene (1.53 g, 9.76 mmol) in 2 mL dichloromethane at 0° C. After stirring at rt for 25 min, the mixture was poured into 3 N HCl. The mixture was extracted with dichloromethane. The extract was washed with sat. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated to give the subtitle compound, which would be used for the next step directly.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH:3]1C(OC)=O.[ClH:24].O>>[ClH:24].[CH2:10]1[C:5]2([CH2:18][CH2:19][C:2](=[O:1])[CH2:3][CH2:4]2)[CH2:6][CH2:7][NH:8][CH2:9]1
Reactant: COC(=O)C1CC2(CCC1=O)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: O
Product: O=C1CCC2(CCNCC2)CC1

Procedure:
To 3-tert-butyl 8-methyl 9-oxo-3-azaspiro[5.5]undecane-3,8-dicarboxylate (450 mg, 1.38 mmol) was added HCl—H2O (5 ml, 1:1) at 0° C. and the mixture was refluxed overnight. LCMS revealed complete consumption of the starting material and the mixture was concentrated to dryness. The crude product thus obtained was used directly in next step.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=[O:3])[CH3:2].Br[C:38]1[N:39]=[C:40]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([CH:54]3[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]3)=[CH:50][CH:49]=2)[C:41]2[N:42]([CH:44]=[CH:45][N:46]=2)[CH:43]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[N:39]=[C:40]([NH:47][C:48]4[CH:49]=[CH:50][C:51]([CH:54]5[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]5)=[CH:52][CH:53]=4)[C:41]4[N:42]([CH:44]=[CH:45][N:46]=4)[CH:43]=3)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:30]=[CH:29]2)([CH3:33])([CH3:32])[CH3:34]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: CN1CCC(c2ccc(Nc3nc(Br)cn4ccnc34)cc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cn3ccnc3c(Nc3ccc(C4CCN(C)CC4)cc3)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Yield: 91.3 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (491.3 mg, 1 mmol), (6-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(1-methyl-piperidin-4-yl)-phenyl]-amine (200 mg, 0.52 mmol), K2CO3 (137 mg, 1 mmol), Pd2(dba)3 (45.4 mg, 0.05 mmol), X-phos (94.5 mg, 0.2 mmol) in 30 mL dioxane and 10 mL water was stirred at 90° C. overnight. The reaction mixture was filtered. The filtrate was evaporated and the residue was purified through a silica-gel column (ethyl acetate:petroleum ether=1:2) to give the desired product as a yellow oil (320 mg, 92% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[CH2:30][CH2:31]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CCc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: CCc1ccccc1N1CCN(C(=O)Nc2nc(C)c(C)nc2OC)CC1
Yield: 70.4 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH2:26][NH2:27])[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18].C(N(CC)CC)C>CO.C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:27]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=2)[CH:10]=1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Reaction time: 24 h
Yield: 19.5 %

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in methanol (5 ml) was added a solution (3 ml) of 1-[3-(methylsulfonyl)phenyl]methanamine hydrochloride (1.4 g) and triethylamine (0.9 ml) in ethanol at room temperature, and the mixture was stirred for 24 hr. The reaction solvent was evaporated under reduced pressure, DMSO (5 ml) was added, and the mixture was stirred at 80° C. for 4 hr. The solvent was evaporated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=4/1-1/0). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the precipitated crystals were filtered and recrystallized to give the title compound (78 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)N>>[F:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2F)cn1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCO)c34)cc2F)cn1
Yield: 50.1 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (900 mg, 4.03 mmol) and 3-fluoro-4-[(6-methylpyridin-3-yl)oxy]aniline (967 mg, 4.43 mmol) to give the title compound as a white solid (800 mg, 50%); NMR Spectrum: 2.44 (s, 3H), 3.81 (br t, 2H), 4.34 (t, 2H), 5.13 (br s, 1H), 7.24-7.31 (m, 3H), 7.55 (dd, 1H), 7.98 (dd, 1H) 8.24 (d, 1H), 8.35 (s, 1H), 8.61 (br s, 1H); Mass Spectrum: 397 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH2:35])=[CH:4][N:3]=1.O=[C:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH:35][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:4][N:3]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: COc1cc(-c2csc3c(/C=C/CN)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC/C=C/c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of N-(4-{4-amino-7-[(1E)-3-aminoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.050 g, 0.104 mmol) and ethyl 4-oxo-1-piperidinecarboxylate (0.017 g, 0.087 mmol) in dichloroethane (1.5 mL) was added sodiumtriacetoxy borohydride (0.036 g, 0.173 mmol). The resulting solution was allowed to stir at room temperature for 12 hours. Upon completion, the reaction solution was treated with an aqueous solution of 10% sodium hydroxide (3 mL) and dichloromethane (3 mL). The two layers were stirred for 15 minutes, followed by filtration through an Empore™ cartridge, and removal of the solvent. The resulting crude product was purified by trituration of the residue in ethanol and collection of the title compound (0.030 g, 45%) as a white powder. LCMS (Conditions a) Rt 3.57 minutes, 639.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.01 (dd, J=8.2 Hz, J=7.8 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.35 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.08 (dd, J=8.2 Hz, 1.9 Hz, 1H), 6.67 (d, J=16.0 Hz, 1H), 6.29 (td, J=16.4 Hz, J=5.9 Hz, 1H), 5.61 (s (br), 1H), 4.04 (s, 3H), 4.02 (q, J=7.02 Hz, 2H), 3.91 (s, 3H), 3.88 (m, 2H), 3.42 (d, J=5.5 Hz, 2H), 2.87 (m, 2H), 2.67 (m, 1H), 1.83 (m, 2H), 1.19 (m, 2H), 1.18 (t, J=7.02 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([CH3:17])=[N:15][NH:14][N:13]2[CH3:18])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:20]([O:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[N:34]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][C:43]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:47][CH2:46][NH:45][CH2:44]2)[CH2:36][CH2:35]1)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([CH3:17])=[N:15][NH:14][N:13]2[CH3:18])=[CH:8][C:4]=1[C:5]([N:45]1[CH2:46][CH2:47][C:43]([CH2:42][CH2:41][N:37]2[CH2:38][CH2:39][CH2:40][N:34]([C:26]3[N:25]([CH2:24][CH2:23][O:22][CH2:20][CH3:21])[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=3)[CH2:35][CH2:36]2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:44]1)=[O:7]
Reactant: COc1ccc(C2C(C)=NNN2C)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C5C(C)=NNN5C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:5]1)[CH2:2][CH3:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C.Cl>O1CCCC1.C(OCC)C>[ClH:29].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]3)=[CH:15][CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN1CCCC(c2ccc(N)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCN1CCCC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.2 %

Procedure:
4-(1-Propyl-piperidin-3-yl)-phenylamine (600 mg, 1.65 mmol) and 4-isopropyl-phenylsulfonyl chloride (397 mg, 1.81 mmol) were dissolved in tetrahydrofuran (25 ml). Triethylamine (760 μl, 5.44 mmol) was added and the reaction mixture stirred for 72 hours at room temperature. The solvent was evaporated under reduced pressure, the residue treated with diethyl ether (50 ml) and three times extracted with water (3×30 ml). The organic phase was treated with 1 molar HCl solution. The acidic aqueous solution was made alkaline with NaOH solution to pH 9-10 and then extracted with ethyl acetate (25 ml). The organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the crude product (580 mg). The crude product was purified via silica gel chromatography with ethyl acetate. Fractions containing the product were combined, the solvent evaporated to yield the pure product which was then converted into the hydrochloride salt via adding a solution of 1 N HCl in diethyl ether. The precipitate was filtered off and dried in vacuo to give the pure product (283 mg, 39%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH2:28])[C:23]=1[I:29].[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:24]1[N:25]=[CH:26][N:27]=[C:22]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:23]=1[I:29]
Reactant: Nc1ncnc(Cl)c1I
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Yield: 59.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.55 g, 2.05 mmol) was treated with 6-chloro-5-iodopyrimidin-4-amine (1 g, 3.29 mol), cesium fluoride (0.62 g, 4.08 mmol), N,N-diisopropylethylamine (1.79 mL, 10.28 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 0.59 g (59% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][N:9]=[C:10]([C:14]1[S:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]=1[O:19][CH3:20])[C:11](O)=[O:12]>>[CH3:7][O:8][N:9]=[C:10]([C:14]1[S:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]=1[O:19][CH3:20])[C:11]([Cl:4])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C(C(=O)O)c1sc2ccccc2c1OC
Product: CON=C(C(=O)Cl)c1sc2ccccc2c1OC

Procedure:
Oxalyl chloride (0.72 ml, 8 mM) were reacted with 530 mg (2 mM) of α-methoxyimino-α-(3-methoxy-2-benzothienyl)acetic acid according to the method of Example 6 to give α-methoxyimino-α-(3-methoxy-2-benzothienyl)acetyl chloride. The acid chloride was dissolved in 20 ml of acetone and added dropwise to a cold (0° C.) stirred solution of 428 mg (2 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 20 ml of acetone and 20 ml of water containing 420 mg (5 mM) of sodium bicarbonate. The reaction mixture was stirred for thirty minutes at 0° C. and then was warmed to 25° C. and stirred for an additional three hours. The reaction mixture was concentrated to a volume of about 20 ml and then was washed with ethyl acetate. The aqueous layer was layered with fresh ethyl acetate and the slurry was diluted with 1N hydrochloric acid to pH 2.4. The organic layer was separated, washed with water, dried, and the solvent was removed by evaporation to give 670 mg (72% yield) of 7-[α-methoxyimino-α-(3-methoxy-2-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[N:23]([CH:29]([CH3:33])[C:30](=[O:32])[CH3:31])[C:22]4=[O:34])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+].Br>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[N:23]([CH:29]([CH3:33])[C:30](=[O:32])[CH3:31])[C:22]4=[O:34])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(N4C(=O)N(C(C)C(C)=O)C(C)(C)C4=O)cc3)CC2)cc1
Agent: Br
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)C(C)N1C(=O)N(c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)C(=O)C1(C)C
Reaction time: 6 h
Yield: 86 %

Procedure:
A mixture of 25.6 parts of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-1-(1-methyl-2-oxopropyl)-2,4-imidazolidinedione, 3 parts of sodium disulfite and 375 parts of a hydrobromic acid solution 48% in water was stirred for 6 hours at reflux temperature. After cooling. the crystallized product was filtered off, washed with 2-propanone and suspended in a mixture of water, trichloromethane and 1-butanol. The whole was treated with potassium carbonate (pH 8~9). The separated organic layer was set aside and the aqueous phase was extracted twice with the same mixture. The combined extracts (see above) were evaporated in vacuo. The residue was crystallized from 1-butanol. The product was filtered off and dried, yielding 21.3 parts (86%) of 3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-1-(1-methyl-2-oxopropyl)-2,4-imidazolidinedione; mp. 225.9° C. (intermediate 21).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:30]>C(O)C>[ClH:30].[C:27]([N:24]1[CH2:23][CH2:22][CH:21]([O:20][C:13]2[CH:12]=[C:11]([O:10][CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[CH:16]=[CH:15][C:14]=2[NH2:17])[CH2:26][CH2:25]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(OC3CCN(C(C)=O)CC3)c2)CC1
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CCC(Oc2ccc(N)c(OC3CCN(C(C)=O)CC3)c2)CC1

Procedure:
1,3-Di(1-acetyl-4-piperidyloxy)-4-nitrobenzene (3.7 g) was dissolved in a mixed solution of ethanol (30 ml) and conc. hydrochloric acid (1 ml) and then catalytic reduction was conducted according to the same manner as that described in Example 1, (2). After completion of the reaction, the catalyst was removed and then the solvent was distilled off to obtain 2,4-di(1-acetyl-4-piperidyloxy)aniline hydrochloride (3.9 g) as an amorphous solid. The amorphous solid (1.23 g) was dissolved in dimethylformamide (5 ml) and potassium carbonate (1.24 g) and 1,4-dibromobutane (0.36 ml) were added to the mixture, which was heated with stirring at 100° C. for one hour. After completion of the reaction, water (50 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residual oily compound was separated and purified by silica gel column chromatography (developing solvent: methanol/dichloroethane=1/19 (v/v)) to obtain an oily compound (0.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:29][C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:22][C:21](=[O:30])[C:20]=2[CH:31]=1)(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C.CO.C(Cl)(Cl)Cl>CN(C)C=O>[C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:29][C:23]3([CH2:24][CH2:25][N:26]([CH2:8][C:7]4[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:27][CH2:28]3)[CH2:22][C:21](=[O:30])[C:20]=2[CH:31]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(Cc3ccc([N+](=O)[O-])cc3)CC1)O2
Yield: 59.6 %

Procedure:
A solution of 4-nitrobenzyl bromide (0.73 g, 3.4 mmol), 3,4-dihydro-6-acetamido spiro[(2H)-benzopyran-2,4'-piperidine]-4-one (0.94 g, 3.4 mmol) and diisopropylethylamine (0.61 ml, 3.5 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 3 hr. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with methylene chloride and washed with saturated sodium bicarbonate solution, water and brine. Drying and solvent evaporation gave an oil; flash chromatography (silica gel, methanol-chloroform 2/98) gave 3,4-dihydro-6-acetamido-1'-(4-nitrobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (0.83 g, 59%); 75 mg converted to hydrochloride; mp>250° C.