Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:12](=[O:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:42]>C(OCC)(=O)C>[ClH:42].[NH2:8][CH2:9][C:10]1[N:11]([CH2:38][CH:39]([CH3:40])[CH3:41])[C:12](=[O:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2
Reactant: CCOC(=O)c1sc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)nc1C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Ethyl 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate (0.14 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give ethyl 2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylate hydrochloride (0.11 g, 91.7%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: COC(=O)c1cc(I)c(C(C)F)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)F)cc1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
To a solution of 2-amino-4-(1-fluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.339 g, 1.05 mmol) in dioxane (5 mL) were added 1-methyl-5-tributylstannanyl-1H-pyrazole (0.842 g, 2.14 mmol) and Pd(PPh3)2Cl2 (75.1 mg, 0.105 mmol) and the resulting mixture was stirred at 90° C. for 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 4:6)) to give 2-amino-4-(1-fluoro-ethyl)-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (280 mg, 0.982 mmol, 93%). ES-MS: m/z 278 [M+H]+, rt 4.66 min.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([CH2:16][CH3:17])[CH2:5]1)=[N+]=[N-].[CH:18]1([S:21](Cl)(=[O:23])=[O:22])[CH2:20][CH2:19]1>CCO.[OH-].[OH-].[Pd+2]>[CH:18]1([S:21]([NH:1][C@@H:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([CH2:16][CH3:17])[CH2:5]2)(=[O:23])=[O:22])[CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
To a slurry of 20 wt % Pd(OH)2 on C (0.044 g, 0.062 mmol) in EtOH (30 mL) was added a solution of (2R,4S)-tert-butyl 4-azido-2-ethylpyrrolidine-1-carboxylate (1.5 g, 6.2 mmol, synthesized as described in Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med. Chem. 1988, 31, 1598-1611) in EtOH (10 mL). The reaction mixture was sparged with hydrogen and an atmosphere of hydrogen was maintained via balloon. The reaction mixture was stirred for about 4 h at ambient temperature and then was filtered and concd in vacuo. The residue was dissolved in pyridine (30 mL) and cyclopropanesulfonyl chloride (1.05 g, 7.49 mmol) was added. The reaction mixture was stirred for about 15 h at ambient temperature and then was partitioned between EtOAc (50 mL) and saturated aqueous CuSO4 (50 mL). The organic layer was separated, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, concd in vacuo, and purified by chromatography on silica gel (80 g) eluting with 20-80% EtOAc in heptane to provide (2R,4S)-tert-butyl 4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate (0.95 g, 48%) as an oil: LC/MS (Table 1, Method a) Rt=2.12 min (ELSD); MS m/z: 319 (M+H)+.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].P([O-])([O-])(O)=[O:8].[Na+].[Na+].[Cl:14][C:15]1[C:16]([O:23][C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=2)=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]>CC(C)=O>[Cl:14][C:15]1[C:16]([O:23][C:24]2[N:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:28]([O:30][CH3:31])[N:29]=2)=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]([OH:8])=[O:19]
Reactant: COc1cc(OC)nc(Oc2c(Cl)cccc2C=O)n1
Reactant: O=P([O-])([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2c(Cl)cccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
An aqueous solution of potassium permanganate (1.3 g) and disodium hydrogenphosphate (1 g) was dropwise added to a solution of 3-chloro-2-(4,6-dimethoxypyrimidin-2-yl)oxy benzaldehyde (1.7 g) in acetone (50 ml). The mixture was stirred at room temperature for 12 hours, and the precipitated manganese dioxide was filtered off. The filtrate was adjusted with hydrochloric acid to a pH of about 4 and then extracted with chloroform. The chloroform layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized from carbon tetrachloride to obtain the above identified compound as a white solid (1.1 g). (Melting point: 151°-152° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH3:5].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[O:21][C:20](=[O:23])[CH:19]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CCCNC
Product: CCCN(C)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from N-methylpropan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.42 (br s, 1H), 8.58 (s, 2H), 7.86 (d, 1H), 7.06 (d, 1H), 4.24 (br s, 1H), 3.97 (t, 2H), 3.87 (s, 3H), 2.75-2.40 (br, 4H), 2.38 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.49 (m, 4H), 0.83 (t, 3H); MS (ESI): 494.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C(CN1CCOCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of morpholine (16.0 g) in toluene (100 ml) is slowly added to a solution of 2-bromo-1-(4-fluorophenyl)-ethanone (20.0 g) in toluene (250 ml). The mixture is stirred overnight at room temperature and extracted with a 1-N aqueous solution of hydrochlorid acid (3×250 ml). The mixed aqueous phases are alcalinized with a 50% aqueous solution of sodium hydroxide (55 ml) and extracted with ethyl acetate (3×250 ml). The mixed organic phases are washed with water (3×100 ml) and dried over magnesium sulphate. The solvent is distilled in vacuo and the residue is dried in vacuo to constant weight to give 1-(4-fluorophenyl)-2-morpholino-ethanone which is a liquid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[OH:38][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: CCCCCC(O)Br
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCCO)C(C)(C)CCC2(C)C
Yield: 52 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 540 μl (4.1 mmol) of 1-bromohexanol, 850 mg (50%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[CH3:34][O:33][C:31]([N:15]1[CH2:16][CH2:17][CH:12]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]1)=[O:32]
Reactant: NC(=O)C(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N1CCC(C(C(N)=O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of α,α-bis(4-fluorophenyl)-4-piperidineacetamide (7.65 g, 0.023 mol) and sodium bicarbonate (3.36 g, 0.023 mole) in methylene chloride was prepared. To this mixture was added a solution of methyl chloroformate (2.17 g, 0.023 mole) in methylene chloride. The resulting mixture was stirred overnight at room temperature. The mixture was extracted successively with water, 5% sodium hydroxide, and water. The methylene chloride layer was dried (sodium sulfate). The organic layer was filtered, and solvent was removed to provide a fluffy, white residue (5.95 g, 66.6% yield). A 0.5 g sample was crystallized from methylene chloridehexanes. This provided a white solid which was dried in vacuo overnight at 80° C., mp 126°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:33][CH:32]([O:35][CH3:36])[O:31][CH3:30])[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(CBr)OC
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21)OC
Temperature: 50 °C
Yield: 136.2 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 1 mmol) in DMF (1 mL) was added KHMDS (0.5 M in THF, 1.1 mL) was dropwise at room temperature. The mixture was stirred for half an hour before adding bromoacetaldehyde dimethyl acetal (95 mg, 0.55 mmol). The mixture was warmed to 50° C. and stirred at that temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate (3×15 mL), dried and concentrated under reduced pressure. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) gave the desire product as colorless oil (268 mg, 75%). LC/MS m/e calcd. for C20H20ClNO3: 3570, observed (M+H)+: 358.7.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5]CCNC)=[O:4].CCN(C(C)C)C(C)C.[CH2:21]([O:28][C:29]([N:31]1[C:35](=O)[CH2:34]C[C:32]1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29](=[O:30])[N:31]([CH3:32])[CH2:35][CH2:34][NH:5][C:3](=[O:4])[C:2]([F:11])([F:10])[F:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CNCCNC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A solution of compound A (96.8 g, 340.7 mmol) and DIEA (59.3 ml, 340.7 mmol) in THF (350 ml) was cooled to ˜5° C., followed by addition of a solution of N-(benzyloxycarbonyl)succinimide (84.0 g, 337.3 mmol) in THF (150 ml) dropwise over the period of 20 min The temperature of reaction mixture was raised to room temperature and stirring was continued for an additional 30 min, followed by the solvents being evaporated. The resultant residue was dissolved in EtOAc (600 ml). EtOAc was extracted with 5% aq. NaHCO3 (2×150 ml) and brine (150 ml). The organic layer was separated and evaporated to provide compound B as yellowish oil (103.0 g, 340.7 mmol). LC-MS [M+H] 305.3 (C13H15F3N2O3+H, calc: 305.3). Compound B was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8](O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1cccc2c1OC(C)(C)C2O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1OC(C)(C)C2N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (29 ml) is added to a stirred solution of the product obtained in Step 4. (25.4 g) in methylene chloride (560 ml) at RT under nitrogen. Methanesulfonyl chloride (11.1 ml) is added dropwise to the mixture which is cooled to 0° C. The mixture is stirred for 3 hours at RT, cooled to 0° C., piperidine (128 ml) added and stirring continued at RT overnight. Sat'd aq. sodium bicarbonate is added to the mixture, the phases separated and the organic phase washed with sodium bicarbonate, sat'd NaCl, dried, filtered and evaporated in vacuo. The residue is dissolved in toluene and evaporated in vacuo affording the desired product as the hydrochloride salt.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>CS(C)=O.CCOCC>[C:10]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)#[N:11]
Reactant: N#CCc1ccccn1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccccn2)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersed in oil) (4 g, 0.1 m) in DMSO (70 mL) under nitrogen at 15° C. was added dropwise a solution of 2-pyridyl acetonitrile (6 g, 51 mmol) and 1,5-dibromopentane (6.81 mL, 51 mmol) in ether (40 mL) and DMSO (10 mL) over 1 hour. The mixture was allowed to warm to room temperature and stirred for a further 24 hours under nitrogen. The reaction mixture was carefully quenched by the addition dropwise of isopropanol (10 mL), followed by water (100 mL) 10 minutes later. The reaction solution was taken up in EtOAc and washed with water. The aqueous layer was re-extracted with EtOAc, and the two organic layers were combined, dried (MgSO4), and concentrated in vacuo. The residue was purified on silica with a gradient of heptane to 9:1 heptane/EtOAc to give 1-cyano-1-(2-pyridyl)cyclohexane (6.77 g, 72%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O1CCOCC1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10][NH:24][CH:21]([CH3:23])[CH3:22])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)CNC(C)C)cc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
In a reactor, 21 g (0.1 mol) of 4-acetylaminophenacyl chloride are introduced into a mixture comprising 100 ml of dioxane, 26 ml (0.3 mol) of isopropylamine and 20 ml of water. The reaction medium is stirred at 30°-40° C. for 2 hours. After the addition of 500 ml of iced water, a precipitate is collected, washed and dried. Recrystallization from ethyl acetate gives 21 g of N-(4-acetylaminophenacyl)isopropylamine, which is in the form of a white powder. Melting point (inst.)=156° C.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:35]([O:38][C:39]([N:41]1[CH2:45][C@@H:44]([SH:46])[CH2:43][C@H:42]1[CH:47]1[N:51]([C:52]([O:54][CH2:55][CH:56]=[CH2:57])=[O:53])[NH:50][C:49](=[O:58])[CH2:48]1)=[O:40])[CH:36]=[CH2:37]>>[CH2:35]([O:38][C:39]([N:41]1[CH2:45][C@@H:44]([S:46][C:18]2[CH2:19][C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:43][C@H:42]1[CH:47]1[N:51]([C:52]([O:54][CH2:55][CH:56]=[CH2:57])=[O:53])[NH:50][C:49](=[O:58])[CH2:48]1)=[O:40])[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1NC(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCC=C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C3CC(=O)NN3C(=O)OCC=C)N(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 65.6 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (195 mg, 0.40 mmol) and (2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)-4-mercaptopyrrolidine (162 mg, 0.40 mmol) to obtain allyl (5R,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (155 mg, yield: 65.4%).
Reaction SMILES: [OH:1][C:2]1[C@H:11]2[C@H:6]([C@H:7]3[CH2:12][C@@H:10]2[CH2:9][CH2:8]3)[N:5]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[C:36](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[OH:1][C:2]1[C@H:11]2[C@H:6]([C@H:7]3[CH2:12][C@@H:10]2[CH2:9][CH2:8]3)[N:5]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:29]([CH3:36])[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1
Reactant: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
(1R,2S,7R,8S)—N-{3-[6-Hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 22, 90 mg, 0.172 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). Potassium carbonate (0.04 g, 0.344 mmol) was added followed by iodomethane (0.027 g, 0.189 mmol). The mixture was stirred at 25° C. for 5 h. The reaction mixture was extracted with ethyl acetate (2×100 mL) and water (100 mL). The organic layer was washed with saturated aqueous brine solution (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (Teledyne Isco RediSep column; 40% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)—N-{3-[6-hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.052 g, 0.097 mmol, 56.4%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.92 (6H, d, J=6.4 Hz), 1.21-1.26 (1H, m), 1.28-1.33 (1H, m), 1.39-1.63 (7H, m), 2.54 (1H, bs), 2.63-2.67 (1H, m), 3.00 (3H, s), 3.06-3.17 (1H, m), 3.29 (3H, s), 3.63-3.72 (2H, m), 7.62 (1H, d, J=8.5 Hz), 7.70-7.73 (1H, m), 7.85 (1H, s). LC-MS (ESI) calcd for C24H32N4O6S2 536.18, found 537.6.6 [M+H+].
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:24]>>[Cl:14][C:15]1[C:16]([OH:24])=[C:17]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Product: O=c1cc(N2CCN(Cc3cc(Cl)cc(Cl)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3,5-Dichloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,5-dichlorosalicylaldehyde. Mass spectrum (ES) MH+=355.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH2:8][CH2:9][CH3:10])(=[O:6])O)[CH3:2].[C:11](#[N:14])[CH:12]=[CH2:13].[Na].C(O)(=O)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][CH2:12][C:11]#[N:14])([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH3:2]
Reactant: C=CC#N
Reactant: CCCCP(=O)(O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCP(=O)(CCC#N)OCC
Temperature: 25 °C

Procedure:
15.0 g of n-butylphosphonic acid ethyl ester and 5.3 g of acrylonitrile are dissolved under argon in 25 ml of ethanol. The solution is cooled to 10°, and a solution of 1.15 g of sodium in 50 ml of ethanol is added dropwise, whereupon an exothermic reaction takes place. The mixture is then heated under reflux for one hour and cooled to room temperature, and 3.3 g of glacial acetic acid are added. The solvent is removed and the residue is taken up in dichloromethane. The resulting solution is washed with water, dried over sodium sulfate and concentrated by evaporation. The oil that remains is distilled, yielding 2-cyanoethyl(n-butyl)phosphinic acid ethyl ester having a boiling point of 120° (10-1 bar).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13]C=CN=1)=O>CO.C(Cl)Cl>[CH:3]1([CH2:4][CH2:5][CH2:6][NH2:1])[CH2:2][CH2:7][CH2:9][CH2:14][CH2:13]1
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: NCCCC1CCCCC1
Yield: 335.5 %

Procedure:
Prepared as above from 464.9 mg (1.11 mmol) of the pyridyl ketone and 1.00 g (2.21 mmol) of the Wittig salt. Flash chromatography with 15% MeOH-CH2Cl2 afforded 526.0 mg (92%) of the product (E/Z=~4:1 by 1H NMR): 1H NMR (DMSO) δ 8.66 (s, 1H), 8.52(m, 1H), 8.40 (dd, J=4.5, 1.1 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.47 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 6.20 (t, J=7.4 Hz, 1H), 3.57 (br t, J=4.4 Hz, 4H), 3.28 (br dt, J=~6.2, 5.8 Hz, 2H), 2.30 (br s, 6H), 2.02 (m, 4H), 1.63 (br t, J=6.6 Hz, 2H), 1.40 (m, 4H); FDMS 519 (M+1). 97.5% pure by HPLC.