Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=CC(C=O)=[CH:4][N:3]=1.C[Mg][Br:12].CS(Cl)(=O)=O.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>>[Br:12][CH:19]([C:18]1[CH:22]=[CH:9][C:2]([F:1])=[N:3][CH:4]=1)[CH3:20]
Reactant: C1CCOC1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)nc1
Agent: CS(=O)(=O)Cl
Product: CC(Br)c1ccc(F)nc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A mixture of 6-fluoronicotinaldehyde (10.000 g, 80 mmol) in THF (300 mL) was chilled to −10° C. in a dry ice/acetone bath, then methylmagnesium bromide (3 M soln. in diethyl ether, Aldrich; 27.4 mL, 82 mmol) was added into the reaction mixture via addition funnel After the addition, the ice bath was removed and the reaction mixture was allowed to stir under inert atmosphere 45 min. The mixture was chilled to −10° C. in a dry ice/acetone bath, then methanesulfonyl chloride (6.50 mL, 84 mmol) was slowly added into the reaction mixture via syringe. After the addition, the ice bath was removed and the reaction mixture was allowed to stir under an inert atmosphere for 2 h. The reaction mixture was quenched with water (100 mL) and diluted with chloroform (300 mL). The organic layer was extracted with chloroform (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 5-(1-bromoethyl)-2-fluoropyridine (16.31 g, 80 mmol, 100% yield) as a tan oil. This material was carried into the next step of the synthesis immediately to prevent decomposition. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.35 Hz, 1H) 7.93 (td, J=8.02, 2.54 Hz, 1H) 6.90-7.11 (m, 1H) 5.21 (q, J=6.85 Hz, 1H) 2.06 (d, J=7.04 Hz, 3H). m/z (ESI, +ve ion) 205.9 (M+H)+.
Reaction SMILES: C[NH2:2].C([C:5]1[CH:10]2[CH2:11][CH2:12][CH:7]([CH2:8][CH2:9]2)[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=O.[CH2:21](O)[CH3:22]>ClCCl>[Cl:20][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]3[CH2:8][CH2:9][CH:10]([C:5]=2[NH:2][CH:21]=[CH2:22])[CH2:11][CH2:12]3)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CN
Reactant: O=CC1=C(c2ccc(Cl)c(Cl)c2)C2CCC1CC2
Reactant: CCO
Solvent: ClCCl
Product: C=CNC1=C(c2ccc(Cl)c(Cl)c2)C2CCC1CC2
Reaction time: 1 h

Procedure:
A 33% solution of methylamine in ethanol (250 ml) was added in one lot to 3-formyl-2-(3,4-dichlorophenyl)bicyclo[2,2,2]oct-2-ene (25 g; 0.089 m) in dichloromethane (50 ml) at 0° C. After 1 hour, the solution was evaporated to yield an oil. Yield 26 g. (100%). An infrared spectrum showed complete loss of the carbonyl group. A peak at 1630 cm-1 indicated the presence of an imine (--CH=N--Me group). M+ 293/295.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:23]([F:26])([F:25])[F:24])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:7]([CH:20]1[CH2:22][CH2:21]1)=[CH:6]2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:23]([F:26])([F:25])[F:24])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]([CH:20]1[CH2:22][CH2:21]1)=[CH:6]2)#[N:2]
Reactant: CC(C)(C)OC(=O)Cn1c(C2CC2)cc2c(C(F)(F)F)c(C#N)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2CC(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a suspension of 1,1-dimethylethyl [5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]acetate (Example 362A) (1.23 g, 4 mmol) in dry CH2Cl2 (10 mL) was added TFA (3.1 mL, 40 mmol) at rt. The mixture was stirred at rt overnight. Solvent and excess TFA were removed in vacuo. The residue was tritrated with Et2O-hexanes to afford the title compound (1.05 g, 85%): MS (ES) m/z 309 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:21])[CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:21])[CH:18]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
Using an analogous procedure to that described in Example 4, 3,4-dichlorobenzoyl chloride was reacted with N-(5-amino-2-methylphenyl)quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound in 57% yield; Mass Spectrum: M+H+ 450.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:31][C@H:32]([CH2:36][CH3:37])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:31][C@H:32]([CH2:36][CH3:37])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: CC[C@@H](O)C(=O)O
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.82 mmol) in CH2Cl2 (6 mL) was added triethylamine (227 μL, 1.63 mmol) followed by the addition of (R)-2-hydroxybutanoic acid (110 mg, 1.06 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one (280 mg, 88%). LC/MS: m/z 393.3 (M+H)+ at 2.17 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (m, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.89 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.1 Hz, 1H), 3.88 (m, 8H), 1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][OH:7])[CH2:2][CH3:3].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][OH:7])[S:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])=[O:15])[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCNCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCO)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 5.16 g (50 mmol) of N-propylethanolamine were introduced into 70 ml of methylene chloride, and 9.7 g (55 mmol) of benzenesulfonyl chloride and 7.6 g (75 mmol) of triethylamine were added successively. After 2 hours of stirring at 0° C., the mixture was allowed to warm to room temperature, stirring was continued for a further hour and the mixture was then extracted with 1M hydrochloric acid and subsequently with 2M aqueous sodium hydroxide solution. The organic phase was dried over Na2SO4, filtered, concentrated and the resulting residue (13.2 g) was chromatographed over silica gel (methylene chloride/methanol 19:1). Yield: 7.4 g as an oil which was directly reacted further.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH3:17][O:16][C:14](=[O:15])[CH:13]([CH:4]([OH:5])[C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[F:1])[C:12]([O:19][CH3:20])=[O:18]
Reactant: O=Cc1c(F)ccc(F)c1F
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C(=O)OC)C(O)c1c(F)ccc(F)c1F
Temperature: 80 °C

Procedure:
2,3,6-trifluorobenzoaldehyde (10.2 g, 63.8 mmol) and dimethyl malonate (8.41 g, 63.8 mmol) were dissolved in 50 mL of DMF. 3 g of K2CO3 was added and the reaction mixture was heated to 80° C. for three hours. 500 mL of EtOAc and 500 mL of water were added. The organic layer was washed with saturated NH4Cl solution (200 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hex as the eluent (gradient from 0/100 to 40/60 in 40 min, 13 g, 70%). 1H NMR (CDCl3 400 MHz) δ 7.12 (m, 1H), 6.85 (m, 1H), 5.72 (d, J=9.5 Hz, 1H), 4.17 (d, J=9.5 Hz, 1H), 3.84 (s, 3H), 3.61 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:32])[C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:32])[C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O

Procedure:
A 1.5 g quantity of the N-[2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 16 was dissolved in 50 ml of ethanol, and 0.1 g of 10% palladium carbon powder was added thereto. The mixture was stirred in a hydrogen atmosphere at 50° C. for two hours. The catalyst was removed by filtration, and the filtrate was then concentrated to give 1.3 g of white crystalline N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Fc1cc(-c2cncc(NCC3CCOCC3)n2)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (375 mg, 1.162 mmol), DMSO (3.5 ml) and trans-4-aminocyclohexanol (1204 mg, 10.46 mmol) was stirred at 100° C. for 18 hours and the progress was followed by LCMS. The reaction mixture was let cool, added 300 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (3×), water (2×), saturated salt solution (1×), dried with sodium sulfate, filtered and concentrated to crude solid. The crude material was purified by silica gel chromatography using 40 g column, eluting slowly from (80% ethyl acetate 20% heptane with 2% MeOH) to 100% ethyl acetate with 2% MeOH. The desired fractions are concentrated to a constant mass, lyapholized from 1:1 ACN/water (does not fully dissolve), re-lyophilized from 80 ml of (60/40) ACN/water solution with sonicating to dissolve solid, giving 270 mg of title compound as free base. LCMS (m/z): 418.3 (MH+), retention time=0.52 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.19-1.55 (m, 6H) 1.71 (d, J=12.89 Hz, 2H) 1.85-2.15 (m, 5H) 3.28-3.32 (dMeOH, 2H App.) 3.40 (td, J=11.72, 1.76 Hz, 2H) 3.50-3.73 (m, 2H) 3.94 (dd, J=11.28, 3.08 Hz, 2H) 6.66 (s, 1H) 7.86 (s, 2H) 7.99 (s, 1H)
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][NH:60][C:61]([CH:63]1[CH2:68][CH2:67][CH2:66][N:65]([CH2:69][C:70](O)=[O:71])[CH2:64]1)=[O:62].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:70](=[O:71])[CH2:69][N:65]1[CH2:66][CH2:67][CH2:68][CH:63]([C:61]([NH:60][CH3:59])=[O:62])[CH2:64]1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CNC(=O)C1CCCN(CC(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C1CCCN(CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.45 g, 0.9 mmol) in anhydrous DMF (10 ml) was treated with HBTU (0.48 g, 1.2 mmol), 2-(3-(methylcarbamoyl)piperidin-1-yl)acetic acid (0.20 g, 0.99 mmol) and diisopropylethyl amine (0.47 mL, 2.7 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (100 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to a sticky yellow residue, 0.63 g that was purified by chromatography (silica gel, dichloromethane and methanol gradient) to afford 1-(2-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-2-oxoethyl)-N-methylpiperidine-3-carboxamide (35) as a white solid, 0.17 g (28%), that was pure by LC/MS (+APCI) m/z 682 (M++1), 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.30 (m, 1H), 7.35 (m, 1H), 7.19 (m, 1H), 7.04 (m, 1H), 6.92 (m, 1H), 6.81 (m, 2H), 6.70 (broad m, 1H), 5.67 (s, 2H), 5.29 (s, 2H), 4.21 (two s, 3H), 4.1 to 1.4 (many multiplets, 19H). 13CNMR (100 MHz, CDCl3) δ 174.4, 170.5, 168.8, 156.8, 156.1, 149.6, 149.0, 138.4, 138.2, 137.0, 136.5, 135.8, 135.3, 130.3, 122.6, 121.7, 120.8, 107.3, 103.1, 67.0, 61.6, 57.5, 56.5, 56.2, 54.3, 53.4, 47.7, 45.4, 41.3, 36.0, 30.9, 26.3, 26.1, 24.5. Anal. Calcd for C33H37Cl2N6O5+0.57CH2Cl2: C, 55.16; H, 5.26; N, 13.41. Found: C, 55.18; H, 5.14; N, 13.35.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.CC1C=CC(S([O:22][CH2:23][C@@H:24]2[O:26][CH2:25]2)(=O)=O)=CC=1.C(=O)([O-])[O-:28].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][CH2:5][C@:6]([CH2:8][CH:9]=[O:28])([O:22][CH2:23][CH:24]2[CH2:25][O:26]2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(F)ccc1O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CC[C@@]1(OCC2CO2)C=C(F)C=CC1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
A mixture of 5′-fluoro-2′-hydroxyacetophenone (2.04 g, 13.25 mmol), (2R)-(−)-glycidyl tosylate (2.75 g, 12.05 mmol), potassium carbonate (2.16 g, 15.66 mmol) and N,N-dimethyl formamide (20 ml) was heated to 60° C. After 6 hours the reaction mixture was cooled down, water (20 ml) and ethyl acetate (20 ml) were added and the layers were separated. Organic phase was recovered and water layer was extracted twice with ethyl acetate. Organic phase and ethyl acetate extracts were combined and washed twice with water and evaporated to dryness. The crude product was crystallized from 2-propanol to yield 1.91 g (76%) of the pure title compound.
Reaction SMILES: O[C:2]1([CH:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[N:14]=[CH:13][NH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[N:14]=[CH:13][NH:12][N:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCCCC2)c2nc[nH]n2)cc1
Reaction time: 2 h

Procedure:
7 g of crude 4-[1-hydroxycyclohept-1-yl-1(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 50 ml of dichloromethane at 0° and stirred with 20 ml of thionyl chloride for 1 hour at 0°. Then the mixture is concentrated to dryness under an oil pump vacuum, dissolved in 50 ml of dichloromethane, stirred for 2 hours with 30 ml of triethylamine, diluted with water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus producing 1.9 g of 4-di-cycloheptylidene-1-(1,2,4triazolyl)methyl]benzonitrile as the free base, mp 79°-80°.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.[CH:19](Br)([Br:21])[Br:20]>C1COCC1>[Br:20][CH:19]([Br:21])[C:11]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][C:14]([CH3:15])=[C:9]([O:8][CH3:7])[N:10]=1
Reactant: BrC(Br)Br
Reactant: COc1ncc([N+](=O)[O-])cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1nc(C(Br)Br)c([N+](=O)[O-])cc1C
Yield: 93.9 %

Procedure:
To a 3 neck, 22 L round bottom flask equipped with a mechanical stirrer and an addition funnel was added potassium t-butoxide (450 g, 4.00 mol) and THF (4 L). The mixture was stirred vigorously and a solution of 2-methoxy-3-methyl-5-nitropyridine (100 g, 0.595 mol) from Part I and bromoform (195.4 g, 0.773 mol) in 500 mL of dry THF was added dropwise at such a rate that the temperature did not rise above −74° C. (3 h addition time). The reaction mixture was stirred at −78° C. for an additional 15 min. The reaction mixture was then quenched by the dropwise addition of a mixture of methanol (400 ml) and conc. HCl (600 mL) while maintaining the temperature below −68° C. Water (1 L) was then added and the aqueous layer was extracted with EtOAc (3×4 L). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (0%→7% ethyl acetate in hexanes) to give 2-(dibromomethyl)-6-methoxy-5-methyl-3-nitropyridine (190.0 g, 94% yield) as a red-brown solid: mp 58.7-61.2° C. 1H NMR (300 mHz, CDCl3) δ 8.04 (s, 1H), 7.60 (s, 1H), 4.15 (s, 3H), 2.26 (s, 1H); LRMS, (ESI) m/e 339.0 [(M+H)+, calcd for C8H9N2O3Br2, 338.9].
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])=[O:4]>C(Cl)Cl.CO>[OH:4][CH2:3][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccccc1C1CC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccccc1C1CC1CO
Reaction time: 2 h

Procedure:
Solid sodium borohydride (110 mg, 2.92 mmol) was added portionwise to a solution of 2-(2-formylcyclopropyl)benzonitrile (500 mg, 2.92 mmol) in methylene chloride (6 mL) and MeOH (10 mL). The mixture was stirred for 2 hr. The reaction was concentrated, and the residue was dissolved in ether and water. The ether layer was separated, washed with water and brine, dried over magnesium sulfate, and concentrated to give 2-(2-(hydroxymethyl)cyclopropyl)benzonitrile as a slightly colored wax (425 mg, 84%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.63 (dd, J=7.7, 0.9 Hz, 1H), 7.52 (td, J=7.8, 1.0 Hz, 1H), 7.36-7.24 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 3.87-3.72 (m, 1H), 3.65 (dd, J=11.2, 7.2 Hz, 1H), 2.25-2.13 (m, 1H), 1.82 (br. s., 1H), 1.60 (s, 1H), 1.56-1.45 (m, 1H), 1.12 (ddt, J=15.3, 8.6, 5.3 Hz, 1H). LCMS: M+1=173.1.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=O)[CH2:3][CH2:2]1.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1Br.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:1]1[CH2:2][CH2:3][CH:4]([C:5]([N:25]2[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]2)=[O:7])[CH2:10][CH2:11]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cccc(Br)c1C
Product: Cc1cccc(N2CCC(C(=O)N3CCC(O)CC3)CC2)c1C

Procedure:
The title compound was prepared from commercially available ethyl isonipecotate, 2,3-dimethylbromobenzene as the aryl halide, and 4-hydroxypiperidine as the secondary amine utilizing general procedures A and B described above. 1H NMR (300 MHz, CDCl3) δ 7.06 (d, J=7.7 Hz, 1H), 6.90 (d, J=7.7 Hz, 2H), 4.12 (m, 1H), 3.96 (m, 1H), 3.83 (m, 1H), 3.33-3.13 (m, 4H), 2.70-2.61 (m, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.12-1.43 (m, 8H). ESI MS: 317.4 (MH+).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:53][CH:52]([N:54](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:55]=[NH:56])[CH2:51]2)=[O:49])[CH2:43]1>>[CH:55]([NH:54][CH:52]1[CH2:51][N:50]([C:48]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][N:45]2[CH3:47])=[O:49])[CH2:53]1)=[NH:56]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(N(C=N)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC=N)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 7.2 %

Procedure:
A procedure similar to that described in Example 125 was repeated, but using 0.35 g of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and 0.22 g of (2S,4S)-4-mercapto-1-methyl-2-(3-[N-(4-nitrobenzyloxycarbonyl)-N-formimidoylamino]azetidin-1-ylcarbonyl)pyrrolidine (prepared as described in Preparation 118), to give 17 mg of the title compound as a powder.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:14][NH:15][CH2:16][CH2:17][OH:18].C(O)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([OH:18])(=[O:11])=[O:10].[OH:18][CH2:17][CH2:16][N:15]([CH3:14])[S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10]
Reactant: CNCCO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Yield: 1622.9 %

Procedure:
66 g (0.3 mole) mesitylenesulphonyl chloride in 37.5 ml pyridine were added dropwise at -5° C. to 11.2 g (0.015 mole) 2-methylaminoethanol. The reaction mixture was kept in a cooler (4° C.) overnight and then poured on ice. 20 ml acetic acid were added and the product was washed with water, taken up in diethyl ether, washed with water and dried with Na2SO4. The solvent was removed in vacuum, giving 55.7 g pale yellow crystals of the title compound, m.p. 94° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1.[BrH:14]>>[BrH:14].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCN)cc1
Agent: Br
Product: NCCCCc1ccc(O)cc1
Yield: 90 %

Procedure:
Amine III (2.32 g, 0.012 mol) was stirred in boiling 48% HBr (50 mL) for 3 h. After the reaction was completed, argon was bubbled through the solution and the solvent was evaporated under reduced pressure. The solid residue was dried above KOH to provide 3.1 g (90%) of IV. API MS m/z=166[C10H15NO+H]+