Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22]CC)=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:9][CH2:8][CH2:7][C:6]2=1.Cl>O.C(O)C.[OH-].[Na+]>[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([OH:22])=[O:21])[CH2:17][CH2:18][CH2:19]3)[NH:9][CH2:8][CH2:7][C:6]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Temperature: 50 °C

Procedure:
A suspension of 1 g of the compound of Example 1 in 15 ml of water, 30 ml of ethanol and 5 ml of 1 M sodium hydroxide solution is heated at 50° C. for 10 hours. The reaction mixture is then cooled and 5 ml of 1M HCl are added. The resulting precipitate is suction-filtered off, washed with water and then dried in vacuo, enabling the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.COCCN1C=CC(N)=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][O:24][CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: COCCn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 469 mg, 1.42 mmol,) was suspended in methylene chloride (7 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (710 mL, 1.42 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (331 μL, 2.84 mmol) was added dropwise. The reaction continued to stir at 0° C. for 10 min. The 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (200 mg, 1.42 mmol) was added as a pre-dissolved reaction in methylene chloride (7 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (262 mg, 41%) as a white powder: ESI-LRMS m/e calcd for C21H28ClN3O4S [M+] 453.15, found 454.26 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.23 (m, 2H, CH2), 1.45-1.92 (m, 8H, 4×CH2), 2.14-2.33 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.31 (s, 3H, OCH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.67 (t, J=5.2 Hz, 2H, OCH2), 4.13 (t, J=5.2 Hz, 2H, NCH2), 6.65 (d, Jo=2.3 Hz, 1H, Ar), 7.33 (d, Jo=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 7.81 (s, 1 H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[N:20]=1)[CH2:9][CH2:10][NH:11][C:12](=O)OC(C)(C)C.N.CO.C(Cl)Cl>>[CH3:12][NH:11][CH2:10][CH2:9][CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[N:20]=1)[OH:7]
Reactant: CCCC(CCC)COc1cccc(C(O)CCNC(=O)OC(C)(C)C)n1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: CCCC(CCC)COc1cccc(C(O)CCNC)n1

Procedure:
LiAlH4 reduction of tert-butyl (3-hydroxy-3-(6-((2-propylpentyl)oxy)pyridin-2-yl)propyl)carbamate following the method described in Example 1 gave after flash chromatography purification (30%-40% 7N NH3/MeOH—CH2Cl2 gradient) Example 43 as a colorless oil; Yield (0.04 g, 62%); 1H NMR (400 MHz, DMSO-d6) δ 7.63 (t, J=8.4 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.69-4.66 (m, 1H), 4.18-4.16 (m, 2H), 2.76-2.72 (m, 2H), 2.40 (s, 3H), 2.10-1.68 (m, 3H), 1.46-1.26 (m, 8H), 0.96-0.88 (m, 6H); RP-HPLC tR=10.66 min; ESI-MS m/z 295.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:24]=1.Br[C:26]1[N:27]=[C:28]([C@@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([C:30]4[NH:29][C:28]([C@@H:31]5[CH2:35][CH2:34][CH2:33][N:32]5[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:27][CH:26]=4)=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Br)c[nH]1
Reactant: CC1(C)OB(c2ccc3c(c2)OCc2cc(Cl)ccc2-3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)OCc2cc(Cl)ccc2-3)[nH]1
Temperature: 85 °C
Yield: 60.9 %

Procedure:
To a solution of 2-(8-chloro-6H-benzo[c]chromen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (773 mg, 2.24 mmol), (S)-tert-butyl 2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (886 mg, 2.8 mmol), tetrakis(triphenylphosphine) palladium(0) (65 mg, 0.05 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (82 mg, 0.11 mmol) in a mixture of 1,2-dimethoxyethane (10.0 mL) and dimethylformamide (2 mL) was added a solution of potassium carbonate (2M in water, 3.5 mL, 7.0 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (S)-tert-butyl 2-(5-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (617 mg, 50%). LCMS-ESI+: calculated for C25H26ClN3O3: 451.96; observed [M+1]+: 452.53.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:12][C:2]([F:1])([F:11])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: OC(c1cccnc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccnc1)C(F)(F)F

Procedure:
13.2 g (0.075 mol) of 2,2,2-trifluoro-1-(3-pyridyl)ethanol and 1.26 g (0.0037 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 250 ml of methylene chloride at room temperature. 46 ml (0.09 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 20 minutes with vigorous stirring and the mixture is stirred for a further 4 hours during which the reaction temperature rises to 35° C. The reaction mixture is added to 250 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product (28 torr, 65°-70°C.), 9.39 g (72% of theory) of 3-trifluoroacetylpyridine are obtained. nD20 : 1.4796.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[C:14]([CH2:20][O:21][CH3:22])[N:13]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH3:22][O:21][CH2:20][C:14]1[N:13]=[C:12]([Cl:11])[N:17]=[C:16]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[C:15]=1[CH3:19]
Reactant: COCc1nc(Cl)nc(Cl)c1C
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
1,2,3,4-tetrahydroisoquinoline(0.9 ml, 6.9 mmol) was added dropwise to a solution of 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) and triethylamine(0.96 ml, 6.9 mmol) in dimethylformamide and stirred for 5 hours at a room temperature. The reaction mixture was diluted with dichloromethane and washed with water and aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to give 1.8 g of the titled compound. (Yield: 94.0%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]1([O:28][S:29]([CH:32]=[CH2:33])(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].[NH4+].[Cl-]>C1COCC1.O>[C:22]1([O:28][S:29]([CH2:32][CH2:33][N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:9]3[C:10]4[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=4[S:7][CH:8]=3)[C:13]2=[O:21])(=[O:31])=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CS(=O)(=O)Oc1ccccc1
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2scc(Cn3c(=O)n(CCS(=O)(=O)Oc4ccccc4)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol) in THF (1.0 mL) are added Ethenesulfonic acid phenyl ester (63 mg, 0.34 mmol) and solid NaOH (14 mg, 0.34 mmol). The resulting suspension is stirred at room temperature for 0.5 hr and it turned into clear solution in about 10 min. Then saturated NH4Cl solution (5.0 mL) is added along with water (5 mL). The mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, dried (MgSO4) and concentrated to give crude product. Purification by flash column chromatography using EtOAc in Hexanes (from 0% to 30%) affords 61 mg (75%) of 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid phenyl ester. LCMS (ESMS): m/z 479.11 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)[CH:2]=[CH2:3].[H-].[Na+].I[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[N:9]([CH3:20])[C:8]=2[CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc2c(cc1OC)COC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc2c(cc1OC)COC(=O)N2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
210 mg of 7-allyl-6-methoxy-1,4-dihydrobenz[d][1,3]oxazin-2-one was dissolved in 6 ml of N,N-dimethylformamide. Thereafter, 46 mg of 60% sodium hydride was added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature for 20 minutes. Thereafter, while cooling on ice, 0.20 g of iodomethane was added to the reaction solution. The obtained mixture was then stirred at room temperature for 2 hours. Thereafter, the reaction solution was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 207 mg of the subject compound.
Reaction SMILES: SCCCCCCCCC1C=C(O)C=CC=1O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Li])CCC.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br>>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:24]1[CH:25]=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(OC)cc1
Reactant: BrCCCCCCCCBr
Agent: Oc1ccc(O)c(CCCCCCCCS)c1
Agent: [Li]CCCC
Product: COc1ccc(OC)c(CCCCCCCCBr)c1

Procedure:
Au microelectrodes (approximately 103 μm2) or Au macroelectrodes (approximately 1 cm2) can be modified with QH2 or Fc by dipping the Au into solutions containing one or both of the thiol reagents. Preparation of 2-(8-mercapto-octyl)hydroquinone involves several steps: 1,4-dimethoxy-benzene was deprotonated with n-butyllithium and added to excess 1,8-dibromo-octane; vacuum distillation afforded 2-(8-bromo-octyl)-1,4-dimethoxybenzene; demethylation was accomplished in quantitative yield with BBr3 ; the bromide was displaced by thioacetate; and subsequent hydrolysis under acidic conditions yields the thiol which was purified by chromatography. Materials were characterized by 1H NMR spectroscopy. Anal. Calcd (Found) for C14H22O2S: C, 66.10 (66.21); H, 8.72 (8.58); S, 12.60 (12.57). The molecules self-assemble onto the Au surfaces when the Au is placed into approximately 1 mM solution of Fc or QH2 in tetrahydrofuran (THF) or ethanol:hexane, 1:1. Mixtures of Fc and QH2 self-assemble onto Au from a QH2 :Fc, 2:1 mixture in THF or in ethanol:hexane, 1:1, at a total thiol concentration of approximately 1 mM. All derivatizations were carried out under argon at 25° C. for approximately 24 hr.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C1(C)C=CC(S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCC(F)(F)F
Temperature: 140 °C
Yield: 86.7 %

Procedure:
A mixture of 2-nitrophenol (18.8 g, 135 mmol), 2,2,2-trifluoroethyl para-toluenesulfonate (34.36 g, 135 mmol), potassium carbonate (18.7 g, 135 mmol) and DMF (200 mL) was heated 16 hours at 140° C. The reaction mixture then was cooled, diluted with water (600 mL) and extracted with ether/hexanes (1:1; 3×400 mL). The combined extracts were washed with saturated sodium bicarbonate (3×100 mL) and brine, dried (Na2SO4), filtered and concentrated to give 1-(2,2,2-trifluoroethoxy)-2-nitrobenzene (27 g, 117 mmol) as an oil.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].[OH:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][N:57]([C:60]([C@@H:62]2[CH2:66][C@H:65]([SH:67])[CH2:64][N:63]2[C:68]([O:70][CH2:71][C:72]2[CH:77]=[CH:76][C:75]([N+:78]([O-:80])=[O:79])=[CH:74][CH:73]=2)=[O:69])=[O:61])[CH2:56][CH2:55]1>C(#N)C>[OH:51][CH2:52][CH2:53][N:54]1[CH2:55][CH2:56][N:57]([C:60]([C@@H:62]2[CH2:66][C@H:65]([S:67][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])[CH2:64][N:63]2[C:68]([O:70][CH2:71][C:72]2[CH:73]=[CH:74][C:75]([N+:78]([O-:80])=[O:79])=[CH:76][CH:77]=2)=[O:69])=[O:61])[CH2:58][CH2:59]1
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(CCO)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 52.5 %

Procedure:
1.82 ml of diphenylphosphoryl chloride and 1.54 ml of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 3.0 g of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 38 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1.54 ml of diisopropylethylamine and a solution of 3.63 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 54) in 30 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 3 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 49(b). The crude product was then purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.4 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound prepared as described in step 54(i), above.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH2:19]1[CH:28]2[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[C:22](=[O:29])[CH2:21][CH2:20]1.[CH2:30]1[O:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCOCC>[OH:32][CH2:31][CH2:30][CH:21]1[C:22](=[O:29])[N:23]2[CH:28]([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:20]1
Reactant: C1CO1
Reactant: O=C1CCCC2CCCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1C(CCO)CCC2CCCCN12
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
A stirred solution of diisopropylamine (2.25 ml, 0.016 mole) in dry THF (20 ml) at -50° C. under nitrogen was treated with 1.6M n-butyllithium in hexane (9.4 ml, 0.015 mole). After 10 minutes the solution was cooled to -65° C. and treated with a solution of quinolizidin-4-one (I. Murakoshi, Yakugaku Zasshi, 1958, 78, 594) (2.0 g, 0.013 mole) in ether (20 ml), stirred for a further 10 minutes and then ethylene oxide (1.23 g, 0.028 mole) bubbled into the solution, which was allowed to warm to room temperature over 1 hour and then heated under reflux for 1.5 hours. The reaction mixture was treated with concentrated potassium carbonate solution (30 ml) and extracted with ethyl acetate (2×60 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with chloroform/methanol (98:2) to afford 3-(2-hydroxyethyl)quinolizidin-4-one as a pale yellow oil (1.4 g, 55%).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:17]=[C:18]([Cl:38])[C:19]([O:22][C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)[C:26](O)=[O:27])=[N:20][CH:21]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1[S:65][CH:66]=[CH:67][N:68]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:17]=[C:18]([Cl:38])[C:19]([O:22][C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)[C:26]([NH:63][C:64]3[S:65][CH:66]=[CH:67][N:68]=3)=[O:27])=[N:20][CH:21]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
DIPEA (0.129 mL) was added to a suspension of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (168 mg), HATU (190 mg) and 2-aminothiazole (40 mg) in DMF (2 mL) and the mixture stirred at RT for 16 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired compound (75 mg).
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10](N(CC)CC)[CH3:11].C(Br)C.O>C1C=CC=CC=1>[CH2:10]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[CH3:1])[CH3:11]
Reactant: CCN(CC)CC
Reactant: Cc1c(N)cccc1Cl
Solvent: CCBr
Solvent: O
Solvent: c1ccccc1
Product: CCNc1cccc(Cl)c1C
Temperature: 25 °C

Procedure:
In 100 ml of benzene is dissolved 14 g of 2-methyl-3-chloroaniline obtained in Reference Example 1 and, after adding 12 g of triethylamine, 13 g of ethyl bromide is added to the solution to conduct the reaction under reflux of benzene for 3 hours. After the completion of the reaction, the mixture is cooled to room temperature and shaken with 200 ml of water. The benzene layer is separated, dried over anhydrous magnesium sulfate, and concentrated. Distillation of the residue results in 12 g of N-ethyl-2-methyl-chloroaniline as the fraction of 125°-126° C./10 mmHg.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:30])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)[C:10](=[O:29])[CH:9]=[CH:8]2)[CH3:2].C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl.CO>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:11]2[C:12]3[C:7](=[N:6][CH:5]=[C:4]([F:30])[C:3]=3[CH2:1][CH3:2])[CH:8]=[CH:9][C:10]2=[O:29])[CH2:20][CH2:19]1
Reactant: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c12
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(N)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[2-(8-ethyl-7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}carbamate (0.234 g, 0.559 mmol) in DCM (2 ml) was added TFA (1 ml) and the reaction was allowed to stirred at rt for 1 h before evaporation of solvent. The residue was dissolved in 1:1 DCM and MeOH (2 ml) and then treated with MP-Carbonate resin until the pH reached 8. The reaction was then filtered, resin washed with MeOH and the filtrate was evaporated to dryness to give a yellow oil (0.176 g, 99%).