Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH2:23][F:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:24][CH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: FCc1cc(Cl)ncn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: FCc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 65 mg, 0.211 mmol), 4-chloro-6-(fluoromethyl)pyrimidine (Intermediate 26, 40 mg, 0.232 mmol) and DIPEA (0.074 mL, 0.423 mmol) were added together in N-methyl-2-pyrrolidone (2 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was heated at 100° C. for 3 hours, allowed to cool to room temperature and diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (6 mg);
Reaction SMILES: Cl[S:2]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3].O.[NH3:18]>C1COCC1>[NH2:18][S:2]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1c(C)nn(C)c1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)nn(C)c1S(N)(=O)=O
Reaction time: 1 h

Procedure:
4.6 g of ethyl 5-chlorosulfonyl-1,3-dimethylpyrazole-4-carboxylate is dissolved in 8 ml of THF, and the solution is added dropwise to 25 ml of ammonia water at 5° C. to 7° C. The reaction mixture is stirred at the same temperature for 1 hour, and then concentrated to dryness under reduced pressure. To the residue is added ethyl acetate, followed by filtration to remove impurities, and the filtrate is concentrated under reduced pressure. The residue is diluted with n-hexane, and then cooled with ice to give crystals. The crystals are filtered and dried to yield 3.6 g of the title compound. mp. 112° to 113° C.
Reaction SMILES: C[O:2][C:3]1[C:11]2[S:10][C:9]([CH3:12])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:12][C:9]1[S:10][C:11]2[C:3]([OH:2])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: COc1cccc2nc(C)sc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc2cccc(O)c2s1
Temperature: 165 °C

Procedure:
7-Methoxy-2-methyl-benzothiazole (400 mg, 2.23 mmol) was mechanically mixed with solid pyridine hydrochloride (6.00 g, 52 mmol) and then heated to 160-170° C. in a sealed vessel for 16 hours. Water (40 mL) was added to the warm mixture, the pH was adjusted to neutrality with NaHCO3 and the mixture was extracted with 1:1 CHCl2 /CHCl3 (4×10 mL). The pooled organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to provide 2-methyl-benzothiazol-7-ol as a waxy yellow solid. (260 mg; GC-MS m/z 165).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:22]1([S:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[N:6]=[C:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[N:9]4[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=34)=[CH:16][CH:17]=2)=[O:36])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Sc4ccccc4)cc3)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(S(=O)c4ccccc4)cc3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-cyclobutyl-1-(4-phenylsulfanylphenyl)-imidazo[1,5-a]pyrazin-8-ylamine (15.0 mg, 0.0403 mmol) in DCM (3 mL, 0.05 mol) at 0° C. was added a solution of m-chloroperbenzoic acid (10.4 mg, 0.0604 mmol) in DCM. The mixture was stirred at 0° C. for 30 min. Sat. aq. NaHCO3 solution was added to quench, and the material was transferred to a separatory funnel. The organic layer was concentrated in vacuo and redissolved in DMF (1 mL) for Gilson HPLC separation. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.98-2.09 (m, 1H), 2.11-2.23 (m, 1H), 2.44-2.53 (m, 2H), 2.55-2.65 (m, 2H), 3.80 (t, J=8.5 Hz, 1H), 7.04 (d, J=5.3 Hz, 1H), 7.13 (d, J=5.3 Hz, 1H), 7.47-7.53 (m, 3H), 7.68-7.71 (m, 2H), 7.79 (s, 4H). MS (ES+): m/z 389.02 (100) [MH+]. HPLC: tR=2.17 min (Open Lynx, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[OH-].[CH2:15]([N+](C)(C)C)[C:16]1[CH:21]=CC=[CH:18][CH:17]=1.ClC(C)(C)C#C>ClCCl.O>[CH3:15][C:16]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([CH3:21])[C:17]#[CH:18]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C#CC(C)(C)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
4-t-butylphenol (10 g) and sodium hydroxide (3.99 g) were added to a stirred mixture of water (60 ml) and dichloromethane (60 ml) followed by benzyltrimethyl-ammonium hydroxide (40% solution in methanol, 150 ml) and 3-chloro-3-methyl-butyne (13.65 g). After stirring at ambient temperature for 11 days, the layers were separated and the aqueous layer extracted with chloroform. The combined organic extracts were concentrated in vacuo and the residue dissolved in diethyl ether. The solution was washed with water, 10% sodium hydroxide solution, then brine, and dried over magnesium sulphate. Removal of drying agent and solvent gave 3-methyl-3-(4-t-butylphenoxy)-but-1-yne as a yellow oil (13.35 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][C@@H:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.O1CCOCC1.O.[F:37][C:38]([F:49])([F:48])[CH2:39][CH2:40]/[CH:41]=[CH:42]/[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CCOC(C)=O>[F:1][C:2]([F:18])([F:19])[CH2:3][CH2:4][C@@H:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:21])=[O:8].[F:37][C:38]([F:48])([F:49])[CH2:39][CH2:40][C@H:41]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([OH:20])[CH:22]=1)[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: OB(O)c1cccc(O)c1
Reactant: CCOC(=O)/C=C/CCC(F)(F)F
Reactant: COC(=O)C[C@@H](CCC(F)(F)F)c1cccc(O)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](CCC(F)(F)F)c1cccc(O)c1
Product: CCOC(=O)C[C@H](CCC(F)(F)F)c1cccc(O)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Methyl (3R)-6,6,6-trifluoro-3-(3-hydroxyphenyl)hexanoate or methyl (3S)-6,6,6-trifluoro-3-(3-hydroxyphenyl)hexanoate (68). A mixture of 3-hydroxyphenylboronic acid (available from Aldrich) (1.8 g, 13 mmol) and hydroxy[(S)-BINAP]-rhodium(I) dimer (0.19 g, 0.13 mmol) in 1,4-dioxane (10 mL, 2.5 mmol) was sparged with N2. To the mixture were added water (1.0 mL, 2.5 mmol) and (E)-ethyl 6,6,6-trifluorohex-2-enoate 68.B (0.56 mL, 2.5 mmol). The resulting red-brown solution was warmed to 45° C. and stirred for 3 hours (sealed vial). The mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-25% EtOAc/hexane) to afford (R)-ethyl 6,6,6-trifluoro-3-(3-hydroxyphenyl)hexanoate and (S)-ethyl 6,6,6-trifluoro-3-(3-hydroxyphenyl)hexanoate 68 as a pale yellow oil (84% e.e.). The enantiomerically enriched mixture was further purified by chiral HPLC (Chiralcel OD, 3% i-PrOH/hexane, 220 nm) to afford 68 as a colorless oil (0.65 g, >99% e.e.). The R enantiomer is believed to be the major product used in the following steps.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[H][H].N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC.[O:26]1[CH2:31]CO[CH2:28][CH2:27]1>O1CCCC1>[C:1]([O:5][CH2:28][CH2:27][O:26][CH3:31])(=[O:4])[CH:2]=[CH2:3]
Reactant: C1COCCO1
Reactant: [H][H]
Reactant: C=CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(=O)OCCOC

Procedure:
Polymethoxyethyl acrylate having a constitutional unit of the above formula (1) in which R1 is hydrogen, R2 is a methyl group and m is 1 was synthesized. Specifically, 15 g of methoxyethyl acrylate was polymerized in 60 g of 1,4-dioxane at 75° C. for 10 hours with nitrogen bubbling by using azobisisobutyronitrile (0.1% by mass) as an initiator. After the polymerization was completed, the resultant was added dropwise to n-hexane to form a precipitate, and thus the product was isolated. The product was dissolved in tetrahydrofuran, the resulting solution was purified with n-hexane twice, and the resultant was dried under reduced pressure for a whole day and night. Thus, a clear and colorless polymer with high viscosity was obtained. The yield rate was 76%. As a result of analysis of the thus obtained polymer by gel permeation chromatography (GPC), the polymer was found to have a number average molecular weight of 15,000 and a molecular weight distribution (Mw/Mn) of 3.4.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C[O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14](I)[CH:13]=[C:12](Br)[CH:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@@:26]2([CH:38]([CH3:40])[CH3:39])[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@@:26]2([CH:38]([CH3:40])[CH3:39])[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:12]4[CH:11]=[C:10]([CH:15]=[C:14]([N:3]5[CH2:4][CH2:5][O:1][C:2]5=[O:6])[CH:13]=4)[C:9]([OH:8])=[O:18])[C:29]3=[O:37])[CH2:27]2)=[CH:24][CH:25]=1
Reactant: CC(C)[C@@]1(c2ccc(Cl)cc2)C[C@@]12C(=O)Nc1ccccc12
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: O=C1NCCO1
Product: CC(C)[C@@]1(c2ccc(Cl)cc2)C[C@@]12C(=O)N(c1cc(C(=O)O)cc(N3CCOC3=O)c1)c1ccccc12

Procedure:
The title compound was prepared in analogy to Example 95 starting from oxazolidin-2-one (commercially available), 3-bromo-5-iodobenzoic methylester (prepared as in Example 92), (1S,2S) and (1R,2R)-2-(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 2. LC/MS m/e calcd. for C29H25ClN2O5: 516, observed (M+H)+: 517.21H NMR (400 MHz, DMSO-d6) δppm 0.77 (d, 3 H) 0.89 (d, 3 H) 2.16 (d, 1 H) 2.28 (d, 1 H) 2.85-3.02 (m, 1 H) 4.07-4.25 (m, 2 H) 4.41-4.59 (m, 2 H) 5.43 (d, 1 H) 6.62-6.75 (m, 1 H) 6.78-6.91 (m, 2 H) 7.11 (t, 1 H) 7.61 (d, 1 H) 7.69 (d, 1 H) 7.79 (s, 1 H) 7.92-8.03 (m, 2 H) 8.21 (s, 1 H) 13.44 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.CN(C=O)C.O[NH:24][C:25](=[NH:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:6]/[N:24]=[C:25](\[NH2:27])/[CH3:26])=[O:5]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: CC(=N)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C/C(N)=N/OC(=O)c1c(F)cccc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
To a heterogeneous mixture of 2-fluoro-6-iodobenzoic acid (1.51 g, 5.66 mmol) at 0° C. in DCM (28 mL) was added oxalyl chloride (0.635 mL, 7.36 mmol) followed by DMF (0.15 mL). Gas evolution commenced immediately and after 5 min the ice bath was removed. When gas evolution had ceased and the mixture was homogeneous an aliquot was removed and quenched with MeOH. Formation of the methyl ester was confirmed by HPLC and the mixture was concentrated in vacuo. The viscous liquid was dissolved in fresh DCM (28 mL) and treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) in several portions followed by TEA (1.2 mL, 8.49 mmol) at 0° C. After stirring for 14 h at ambient temperature the mixture was washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex) afforded the desired product as a colorless oil (1.57 g, 86%). MS (ESI) mass calculated for C9H8FIN2O2, 321.96; m/z found, 323.0. 1H NMR (500 MHz, CDCl3): 7.70-7.65 (m, 1H), 7.15-7.11 (m, 2H), 4.87 (br s, 2H), 2.06 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]([CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])=[CH:4][C:5](=[N:16][OH:17])[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.C(Cl)(Cl)Cl>CC(C)=O>[CH2:1]([C:3]([CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])=[CH:4][C:5](=[N:16][OH:17])[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N+:12]([O-:31])[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:2]
Reactant: CCC(=CC(CNC(=O)c1cccnc1)=NO)C(C)[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCC(=CC(CNC(=O)c1ccc[n+]([O-])c1)=NO)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of N-(4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-yl)-3-pyridinecarboxamide (306 mg), 3-chloroperbenzoic acid (323 mg), chloroform (15 ml) and acetone (40 ml) was stirred at room temperature for 10 hours. The resulting precipitates were collected and washed with acetone to give N-(4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-yl)-3-pyridinecarboxamide 1-oxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH:8][C:9]([CH3:17])([CH3:18])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1N

Procedure:
Mix (4-bromo-2-nitro-phenyl)-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-amine (4 g, 11.1 mmol) and 5% Pt/C(S) (100 mg) in EtOAc (215 mL) and place under 60 psi hydrogen for 18 h. Filter and concentrate to give 3.76 (100%) title compound as a pale yellow oil; MS (es) 328, 330 (M+1), HPLC (ISO80-10M) t=1.57 (95%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([O:31][C:32]1[C:37]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:35]2[CH:36]=[C:37]([NH:38][S:39]([C:42]3[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=3)(=[O:41])=[O:40])[C:32]([O:31][CH2:29][CH3:30])=[N:33][CH:34]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 28 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (54 mg, 0.12 mmol) was treated with N-(2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-hydroxybenzenesulfonamide (116 mg, 0.18 mmol), sodium carbonate (30 mg, 0.28 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (32 mg, 0.04 mmol) according to the method described in Example 3 to give 22 mg (27% yield) of the title compound. Purity 100%. LRMS (m/z): 654 (M+1)+. 1H NMR (400 MHz, CD3OD δ 7.88 (m, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.65-7.42 (m, 7H), 7.38 (dd, J=7.6, 1.2 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.33 (m, 1H), 4.23 (q, J=6.9 Hz, 2H), 2.42 (s, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:50](=[O:51])[N:14]2[C:15]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3C=CC=[CH:40][CH:39]=3)=[O:35])=[C:16](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[CH2:17][S:18][C@H:13]12)=[O:10])C1C=CC=CC=1.[SH-:52].[Na+].O>CN(C)C=O.C(N(C(C)C)CC)(C)C>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:50](=[O:51])[N:14]2[C:15]([C:34]([O:36][CH:37]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:39]=[CH:40][CH:50]=[CH:12][CH:13]=3)=[O:35])=[C:16]([SH:52])[CH2:17][S:18][C@H:13]12)=[O:10])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OP(=O)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: [SH-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S)CS[C@H]12
Reaction time: 0.75 h
Yield: 170.7 %

Procedure:
To a solution of 16.4 g (21.9 mM) of benzhydryl 7β-phenoxyacetamido-3-diphenylphosphoryloxy-3-cephem-4-carboxylate in 128 ml of N,N-dimethylformamide were added at -10° C. a solution of 1.93 g (24.1 mM) of 70% sodium hydrosulfide in 86 ml of N,N-dimethylformamide and 4.25 g (32.9 mM) of diisopropylethylamine, and the mixture was stirred for 45 minutes. After the reaction, 200 ml of water was added and the mixture was extracted with 200 ml of diethyl ether. The aqueous layer was adjusted to pH 2 to 3 with 0.5% hydrochloric acid and extracted with ethyl acetate (300 ml), and the extract was washed with a saturated aqueous sodium chloride solution (200 ml×2) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed over silica gel column (eluent; ethyl acetate:benzene=1:2 to 2:1) to give 10.4 g of benzhydryl 7β -phenoxyacetamido-3-mercapto-3-cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[CH:10]1.[Br:26]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:26][C:10]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:13](=[O:24])[C:12]=2[C:11]=1[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(-c2ccc(Cl)cc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-3-methyl-5-(1-piperidinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (200 mg, 0.529 mmol, Example 16) at 0° C. in dry DMF was added NBS (N-bromosuccinimide) (99 mg, 0.555 mmol). The reaction mixture was stirred 1 h at 0° C., and then water was added. The resulting solution was extracted several times with Et2O, the combined organic extracts were dried over MgSO4 and evaporated. The residue was dissolved in CH2Cl2 and filtered through a pad of silica gel to give the title material (180 mg, 75% yield) as an orange solid, which was used in Example 19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:20]C(OC(C)(C)C)=O)[CH2:5][S:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][S:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[NH:20]1)=[O:28]
Reactant: COC(=O)C(CSCC(=O)c1ccc(OC)c(OC)c1)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CSCC(c2ccc(OC)c(OC)c2)N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice chilled solution of 2-tert-butoxycarbonylamino-3-[2-(3,4-dimethoxy-phenyl)-2-oxo-ethylsulfanyl]-propionic acid methyl ester (2.00 g, 9.34 mmol, 1.0 equivalents) in dichloromethane (9 ml) was added trifluoroacetic acid (9 ml). The reaction solution was stirred on ice for 4 hours. The solution was concentrated, coevaporated with toluene. The residue was dissolved in dichloromethane (30 ml) and chilled on ice. To this was added sodium triacetoxyborohydride (2.97 g, 14.02 mmol, 1.5 equivalents) followed by dichloromethane (7 ml). The reaction was stirred 18 hours at room temperature. Saturated sodium bicarbonate was added, and the reaction mixture was extracted with dichloromethane. The dichloromethane extracts were dried with MgSO4, filtered and concentrated. 5-(3,4-Dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid methyl ester was obtained as an oil (1.63 g, 59% yield). Analysis H1 NMR (400 MHz, CDCl3): 6.92 (2H, m), 6.83 (1H, d), 3.95 (3H, s), 3.93 (3H, s), 3.87 (2H, m), 3.85 (3H, s), 2.77 (3H, m), 2.42 (1H, m). MS (LC-MC): Calculated for C14H19NO4S 297.10, found 298.17.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.CN.[C:28]([BH3-])#[N:29].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:29][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.228 g, 0.65 mmol) and methylamine (2M in THF; 0.5 mL, 0.84 mmol) in CH2Cl2 (3.4 mL) was added sodium cyanoborohydride (0.061 g, 0.97 mmol), followed by acetic acid (1 drop). The reaction was stirred at room temperature overnight, until no starting material was seen by analytical LCMS. The solution was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH:18]=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[C:20]1([C:26](=O)[C:27](=O)[CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[NH4+:35].[NH4+:36].[OH-]>CC(O)=O>[CH3:28][C:27]1[NH:36][C:18]([CH:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)=[N:35][C:26]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C=O
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1[nH]c(C2Cc3ccccc3CN2)nc1-c1ccccc1
Temperature: 0 °C

Procedure:
3-Formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.83 g, 7 mmol) was combined with AcOH (25 mL) to which was immediately added 1-phenyl-propane-1,2-dione (3.11 g, 21 mmol) and NH4OAc (13.49 g, 175 mmol). The reaction mixture was then placed on a steam bath and heated under an argon atmosphere for 20 minutes. The reaction mixture was cooled in an ice bath and then added to an ice slurry (44 g). The resulting mixture was basified by addition of concentrated NH4OH (50 mL) and then extracted twice with diethyl ether (150 mL each). The combined organic phases were dried over MgSO4, filtered and concentrated to yield crude product. This material was purified by preparative HPLC to yield the title compound as a white solid.