Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][CH2:23][C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:17][C:16]=3[C:30]3[C:31]([C:38]([OH:40])=[O:39])=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.O1C=C[N:44]=C1NC.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][CH2:23][C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:17][C:16]=3[C:30]3[C:31]([C:38]([OH:40])=[O:39])=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)(=[NH:44])[NH2:2]
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3ncco3)cc2-c2ccc(OC)cc2C(=O)O)c2ccc(C#N)cc21
Reactant: CNc1ncco1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCn1cc(Cc2ccc(C(=O)NCc3ncco3)cc2-c2ccc(OC)cc2C(=O)O)c2ccc(C(=N)N)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
Part A. 2′-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-4-methoxy-5′-[(oxazol-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid: A mixture of the compound of Example 15, Part F (75 mg, 0.138 mmol), oxazol-2-yl-methylamine hydrochloride (28 mg, 0.208 mmol) NMM (0.012 mL, 1.10 mmol) and BOP reagent (76 mg, 0.172 mmol) in DMF (1 mL) was stirred at rt over 3 days. Reaction was worked up and product isolated as described for Example 15, Part G to provide the amide (78.3 mg, 91%). LC/MS m/z 625.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:17])[C:9]=1[NH:10]2.[C:18]([Si](C)(C)C)([F:21])([F:20])[F:19].[F-].[Cs+]>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8]([C:18]([F:21])([F:20])[F:19])([OH:17])[C:9]=1[NH:10]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCCc2c1[nH]c1c(Cl)cc(Cl)c(Cl)c21
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(Cl)c(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 5,6,8-trichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.3 mmol) in anhydrous THF (5 mL), cooled to 0° C., CF3TMS (0.5 mL) followed by CsF (0.026 g, 0.17 mmol) were added. The reaction mixture was stirred at 0° C. for 1 h, cooled to room temperature and stirred for an additional 16 h, quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to afford the title compound as a yellow solid (0.042 g, 32%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.42 (s, 1H), 7.52 (s, 1H), 6.69 (s, 1H), 3.02 (m, 2H), 2.21 (m, 1H), 1.96 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[C:26](Cl)(=[O:28])[CH3:27].C(OC(=O)CC1C=C(C2C=CC(F)=CC=2CN(C(OCC2C=CC=CC=2)=O)CC)C(OC)=CC=1)C.[Li+].[OH-]>C1COCC1>[C:26]([N:22]([CH2:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[CH:7]=1)[CH2:23][CH3:24])(=[O:28])[CH3:27]
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: CC(=O)Cl
Agent: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(F)ccc1-c1cc(CC(=O)O)ccc1OC)C(C)=O

Procedure:
{2′-[(Acetyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-184) was prepared by reacting (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and acetyl chloride according to the procedure described in Example 1, Step 6 and then hydrolyzing the ester with aqueous LiOH in THF at room temperature.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[O:4].[OH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH3:18])[C:14]1=O>C(#N)C>[Br-:1].[OH:12][CH:13]1[CH2:17][CH2:16][N+:15]([CH3:18])([CH2:2][C:3](=[O:4])[NH:5][C:6]2[CH:11]=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:14]1
Reactant: CN1CC[C@@H](O)C1=O
Reactant: O=C(CBr)Nc1cnccn1
Solvent: CC#N
Product: C[N+]1(CC(=O)Nc2cnccn2)CCC(O)C1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-Bromo-N-pyrazin-2-yl-acetamide (Intermediate A)(3.0 g, 13.9 mmol) in acetonitrile (80 ml) is treated with (R)-hydroxy-methyl pyrrolidone (1.4 g, 13.9 mmol). The resulting suspension is stirred at room temperature for 3 hours and then filtered. The solid is washed with acetonitrile and dried in vacuo overnight to yield the titled compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])[CH:23]=2)=[C:18]([OH:35])[CH:17]=1)([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].IC.[C:38]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:33]([NH:32][C:30]([NH:29][CH2:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[O:8])[CH3:15])=[CH:17][C:18]=2[O:35][CH3:38])[CH:27]=[CH:26][CH:25]=1)=[O:31])[CH3:34]
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCC(=O)N3CCOCC3)cc2O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCC(=O)N3CCOCC3)cc2OC)c1
Temperature: 60 °C
Yield: 23 %

Procedure:
A mixture of 20 (0.1 g, 0.208 mmol, 1.0 eq), iodomethane (0.05 mL, 0.832 mmol, 4.0 eq), and K2CO3 (0.115 g, 0.832 mmol, 4.0 eq) in acetone (3 mL) was heated to 60° C. overnight. LC/MS showed SM/product ˜1/1. More K2CO3 (0.2 g, 1.45 mmol, 7 eq) and iodomethane (0.2 mL, 3.21 mmol, 15.4 eq) were added, and the mixture was heated again to 60° C. overnight. Acetone was removed under reduced pressure, and the residue was partitioned in water/ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed by water (20 mL), brine (20 mL) and dried over anhydrous K2CO3. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, 60-100% ethyl acetate in hexane). Yield: 23%, 98% pure. M+1=496
Reaction SMILES: C(NC(=O)[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C@@H:34]([CH3:47])[C:35](N[C@H](C)CC2C=CC=CC=2)=[O:36])[CH:25]=1)[CH2:11][CH3:12])C1C=CC=CC=1.[OH:49]S(O)(=O)=O>O1CCOCC1>[CH2:11]([NH:10][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([C@@H:34]([CH3:47])[C:35]([OH:36])=[O:49])[CH:25]=1)[CH3:12]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)N[C@H](C)Cc2ccccc2)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)cc(C(F)(F)F)c1

Procedure:
(R)-2-[2′-(3-Benzyl-1-ethyl-ureidomethyl)-5,4′-bis-trifluoromethyl-biphenyl-3-yl]-N—((R)-1-methyl-2-phenyl-ethyl)-propionamide (0.08 g, 0.12 mmol) was treated with 5N aqueous H2SO4 in 1,4-dioxane at 100° C. for 24 hours. The mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: Cc1cc(O)cc(C)c1C=O
Solvent: ClCCl
Product: Cc1cc(O)cc(C)c1CN1CCCC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 2,6-dimethyl-4-hydroxybenzaldehyde (8.2 g, 52.1 mmol) in methylene chloride (80 mL) at 0 C (ice/water bath) was added pyrrolidine (6.5 mL, 78.1 mmol) followed by Na(Oac)3BH and then the reaction was warmed to rt. After 2 hr the reaction was quenched with 1 N NaOH and extracted with methylene chloride. The combined organic layers were dried over MgSO4, filtered and concentrated. This material was triterated with diethyl ether and filtered. The filtrate was concentrated and chromatographed by flash column chromatography using a 330 g ISCO column, eluting with a gradient of 10%, 20%, 30%, 50% MeOH/CHCl3. The product containing fractions were collected and concentrated to give the title compound (3.5 g, 33% yield) as a yellow solid. LCMS-data: 392.2, and 206.3 (M+H)+ (calculated for C13H19NO 205.3). 1H NMR data (CDCl3): 7.52 (bs, 1H), 6.17 (s, 2H), 3.57 (s, 2H), 2.67-2.61 (m, 4H), 2.25 (s, 6H), 1.82-1.72 (m, 4H); C13 NMR δ 155.2, 139.0, 127.4, 116.2, 54.8, 53.0, 23.4, 20.5.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=2)[C:7]=1Cl.[Li+].[Cl-].C1COCC1.[CH2:27]([Mg]Cl)[CH:28]([CH3:30])[CH3:29].C1COCC1.C([Mg]Cl)C(C)C.Cl[C:45](=[O:50])[C:46]([O:48][CH3:49])=[O:47]>CCOCC.[Cu]Br>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:11]=[C:5]3[N:4]=[C:3]([CH3:19])[C:2]([C:45](=[O:50])[C:46]([O:48][CH3:49])=[O:47])=[C:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:6]3[N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)C[Mg]Cl
Reactant: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(Cl)c1Br
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a stirred solution of 6-bromo-7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (0.179 g, 0.5 mmol), copper(I) bromide (0.036 g, 0.250 mmol) and 0.5M LiCl/THF (8 ml, 4.00 mmol) was added 2M i-BuMgCl/THF (2.000 ml, 4.00 mmol) over 5 min at rt. After 2 h, LCMS indicated presence of mostly the unreacted starting material. More iBuMgCl (1 ml) was added and continued stirring at rt for additional 4 h and methyl 2-chloro-2-oxoacetate (0.736 ml, 8.00 mmol) added at once to the reaction mixture, and stirred for additional 1 h. Then, the reaction was diluted with Et2O (50 mL), quenched with Na2CO3 (1 mL), washed with 10 mL each water and brine, dried (Na2SO4), filtered and concentrated to give orange paste which was purified by prep-HPLC to afford methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.0772 g, 0.170 mmol, 34.0% yield) as yellow oil which turned to yellow solid overtime and contaminated with about 15% of 2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidine. 1H NMR (500 MHz, CDCl3) δ: 7.98 (d, J=1.8 Hz, 1H), 7.87-7.83 (m, 1H), 7.41-7.31 (m, 2H), 6.87 (s, 1H), 3.97 (s, 3H), 3.13 (d, J=7.3 Hz, 2H), 2.51 (s, 3H), 2.44 (dt, J=13.7, 6.8 Hz, 1H), 0.97 (d, J=6.7 Hz, 6H). LCMS (M+H) calcd for C20H21ClN3O3: 386.13. found: 386.3.
Reaction SMILES: [BH4-].[Na+].C([C:5]1[CH:6]=[C:7]([C:16]#[C:17][C:18]2([OH:26])[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])=O.[CH3:27][OH:28]>>[OH:28][CH2:27][C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:6][C:7]=1[C:16]#[C:17][C:18]1([OH:26])[CH:23]2[CH2:22][CH2:21][N:20]([CH2:25][CH2:24]2)[CH2:19]1
Reactant: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1C=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)c(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (28.4 mg) was added to a solution of 3-[2-(3-formyl-4-(2-methoxyethoxy)phenyl)ethynyl]quinuclidin-3-ol in methanol at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1.5 hours. The reaction mixture was poured onto water (15 ml) and the mixture extracted with ethyl acetate (3×20 ml). The ethyl acetate extracts were combined, washed with brine solution (20 ml), dried (MgSO4) and evaporated. The residue was dissolved in acetonitrile (5 ml) and diethylether was added to give, on cooling, a solid (262 mg). This solid was further purified by crystallisation from acetonitrile to give 3-[2-(2-hydroxymethyl-4-(2-methoxyethoxy)phenyl)ethynyl]quinuclidin-3-ol (217 mg) as a solid, m.p. 98.5-100.0° C.; microanalysis, found C, 67.5%; H, 7.7%, N, 6.9%, C19H25NO4 0.8CH3CN requires: C, 67.9%; H, 7.6%; N, 6.9%; NMR(CDCl3): 1.40(1H,m), 1.65(1H,m), 2.0(3H,s), 2.05(3H,m), 2.8(4H,t), 3.03(1H,d), 3.28(1H,d), 3.45(3H,s), 3.75(2H,t), 4.13(2H,t), 4.72(2H,s), 6.78(1H,m), 7.05(1H,d) and 7.3(1H,t); m/z 332(M+H).
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3([OH:25])[CH2:24][NH:23][CH2:22]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([N:23]1[CH2:24][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:32])[CH3:33])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)([OH:25])[CH2:22]1)(=[O:36])[CH3:35]
Reactant: C[C@@H](c1ccc(C#CC2(O)CNC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC(O)(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)C1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((3-hydroxyazetidin-3-yl)ethynyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and acetic anhydride following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.27 min, m/z=491, 433; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 1.97 (s, 3H), 2.15-2.45 (5H), 2.84 (m, 1H), 4.20 (d, 1H), 4.36 (m, 2h), 4.44 (d, 1H), 5.65 (q, 1H), 6.88 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:8][C:9]3[NH:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 8 h

Procedure:
Potassium carbonate (2.76 g, 20 mmol) and 2-(chloromethyl)benzimidazole (1.70 g, 10 mmol) were added to a solution of 1-(4-methoxyphenyl)piperazine (1.92 g, 10 mmol) in DMF (20 ml) under a nitrogen atmosphere and the mixture was stirred overnight. The mixture was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried (MgSO4) and evaporated in vacuo to give a solid which was recrystallised from toluene to give the title compound as a buff solid (731 mg, 23%). mp 214°-216° C.; (Found: C, 70.80; H, 6.82; N, 17.28. C19H22N4O requires C, 70.78; H, 6.88; N, 17.38%); δH (DMSO-d6) 2.59-2.62 (4H, m, 2×piperazinyl CH2), 3.03-3.05 (4H, m, 2×piperazinyl CH2), 3.67 (3H, s, OCH3), 3.77 (2H, s, CH2N), 6.79-6.82 (2H, m, ArH), 6.85-6.89 (2H, m, ArH), 7.10-7.17 (2H, m, ArH), 7.43 (1H, d, J 6.9 Hz, ArH), 7.55 (1H, d, J 6.9 Hz, ArH), and 12.30 (1H, brs, NH); m/z (CI+, NH3) 323 (M+1)+.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41]([Cl:43])=[O:42].C(N(CC)CC)C>C(Cl)Cl>[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41]([Cl:43])=[O:42].[CH2:1]([C:8]1[C:9]([CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=2)[CH:19]([CH3:20])[CH3:21])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2ccccc2cc1Cc1ccccc1
Agent: Cc1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3ccccc3cc2Cc2ccccc2)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 2-(3-{[1-(3-benzylquinolin-2-yl)-2-methylpropyl]amino}propyl)-1H-isoindole-1,3(2H)-dione 17 (15 mg, 1 eq.) in CH2Cl2 (1 ml), was added 3-fluoro-4-methyl benzoyl chloride 18 (11 mg, 2 eq.). Benzoyl chloride 18 is prepared using conventional means known in the art. Triethylamine (18 μl, 4 eq.) was then added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to yield 19 mg of N-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-3-fluoro-N-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4-methylbenzamide 19.
Reaction SMILES: N[C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:3]=1[C:25]#[N:26].C(O)(=O)C.[CH:31]([NH2:33])=[NH:32]>C(O)C>[CH:7]1([C:6]2[C:2]3[N:32]=[CH:31][N:33]=[C:25]([NH2:26])[C:3]=3[N:4]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[CH:5]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: N=CN
Reactant: N#Cc1c(N)c(C2CCCC2)cn1-c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncnc2c(C3CCCC3)cn(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 85 °C
Yield: 72.6 %

Procedure:
A mixture of the 3-amino-4-cyclopentyl-1-(4-phenoxyphenyl)-1H-2-pyrrolecarbonitrile (185 mg, 0.539 mmol) in absolute ethanol (10 mL) was treated with formamidine acetate (450 mg, 4.33 mmol) then heated at 85° C. for 2 hours. The solvent was evaporated under reduced pressure then the residue was purified by preparative reverse phase HPLC to provide 145 mg (73%) of the title compound as a white solid after lyophilization: 1H NMR (DMSO-d6, 400 MHz) δ 8.19 (s, 1H), 7.44 (m, 5H), 7.19 (t, 1H), 7.13 (m, 4H), 5.79 (bs, 2H), 3.23 (m, 1H), 2.05 (m, 2H), 1.77 (m, 4H), 1.64 (m, 2H); RP-HPLC (Hypersil HS-C18, 5 μm, 100 A, 4.6×250 mm; 5%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 23.3 min.; MS: MH+ 371.5.
Reaction SMILES: COC(=O)C1C=CC(N[C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=CC=1Cl.[OH-:43].[Na+]>CO.O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:15]3([CH:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[CH:13]([C:11]([OH:43])=[O:12])[NH:17][CH:16]3[CH2:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 66 %

Procedure:
In a manner similar to the methods described in Example 16 and Example 22, rac-2-chloro-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 24 (78 mg, 0.12 mmol) was hydrolyzed with aqueous NaOH in methanol and tetrahydrofuran at 78° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (50 mg, 66%), then rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (30 mg, 0.049 mmol) was reacted with EDCI (19 mg, 0.097 mmol), HOBt (13 mg, 0.097 mmol), triethyamine (9.8 mg, 0.097 mmol), and NH4Cl (26 mg, 0.49 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide as a off white solid (Yield, 35 mg, 64%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([C:22](=[N:30][OH:31])[CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)([OH:21])=[O:20].B(F)(F)F.CCOCC.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][C:22]([C:19]([OH:21])=[O:20])=[N:30][OH:31])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)C(Cn1nnnc1S)=NO
Agent: FB(F)F
Agent: N
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=NO)C(=O)O)CS[C@H]12
Reaction time: 0.83 h
Yield: 75.6 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (12.1 g) and 1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazole-5-thiol (9.0 g) in dry acetonitril (60 ml) was added boron trifluoride etherate (25.1 g) and the resulting solution was stirred at 50° for 50 minutes. Water (60 ml) was added and the solution was adjusted to pH 3.5 with conc. aqueous ammonia to give precipitates which were filtered, washed successively with water and acetone, and air-dried to give 7-amino-3-[1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (13.92 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[OH:8].[N:31]1([CH2:36][CH2:37]O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:27])[F:28])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:37][CH2:36][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OCCN4CCCC4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 1, 100 mg, 0.23 mmol), 2-(pyrrolidin-1-yl)ethanol (35 μL, 0.30 mmol), triphenylphosphine (79 mg, 0.30 mmol), and diisopropyl azodicarboxylate (60 μL, 0.30 mmol) in THF (5 mL) was stirred at room temperature for 2 days. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford impure desired product that was repurified by reverse phase HPLC (acetonitrile/water, 0.1% TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 30 mg of 5-(5-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (d, 1H), 8.74 (d, 1H), 7.40 (t, 1H), 7.35 (dd, 1H), 7.22 (d, 1H), 4.24 (t, 2H), 2.86 (t, 2H), 2.65-2.42 (m, 8H), 1.98-1.95 (m, 1H), 1.70 (m, 4H), 1.60-1.54 (m, 1H). LCMS [M+1]+ 534.9.