Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46]O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:46][C:45]4[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=4[F:43])[CH:14]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21]
Reactant: OCc1ccccc1F
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(OCc4ccccc4F)c3)cc21
Reaction time: 1 h

Procedure:
An orange solution of 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-179, 70 mg, 0.23 mmol) in Dichloromethane (10 ml) was treated with polymer bound-Triphenylphosphine (177 mg, 0.68 mmol, 3.0 eq) and the 2-Fluorobenzyl alcohol (56.9 mg, 0.45 mmol, 2.0 eq). The mixture was charged, in portions, with Di-tert-butyl azodicarboxylate (104 mg, 0.45 mmol, 2.0 eq) and the resulting maroon-orange solution was stirred at 23 deg C. for 1 h. The reaction mixture was filtered through a frit and the filtrate was purified via flash column chromatography (SiO2: 100% Hex to 75:25% Hex:EtOAc) to afford the title compound, 1-(2,2-dimethylpropyl)-5-{3-[(2-fluorobenzyl)oxy]phenyl}-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (3-1), as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.55 (t, 1H, J=7.0 Hz), 7.38-7.26 (m, 3H), 7.22-7.15 (m, 3H), 7.13-7.06 (m, 3H), 6.97 (d, 1H, J=7.1 Hz), 5.21 (s, 2H), 3.68 (s, 2H), 3.47 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C26H27FN2O2 (M+H) 419.2, found 419.3.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])[C:14](=[O:23])[N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)=[N:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:13]1[C:14](=[O:23])[N:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][N:9]=2)[CH:12]=1)#[N:31]
Reactant: CC(=O)Oc1ccc(-c2cc(-c3ccccc3C#N)c(=O)n(-c3ccccc3)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(-c2ccc(O)cn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
953 mg of 5-(5-acetoxypyridin-2-yl)-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-one and 192 mg of potassium carbonate were added to 50 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. The mixture was further incoporated with 50 ml of methanol, and stirred at 40° C. for 15 minutes. The reaction mixture was diluted with ethyl acetate, and filtered by silica gel. The filtrate was concentrated under a vacuum and washed with a ether/methanol-based solvent, to obtain 786 mg of the subject compound.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[N+:26]([O-:27])=[N:25][C:24]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[N:23][C:22]=2[CH:34]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[N+:26]([O-:27])=[N:25][C:24]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[N+:23]([O-:6])[C:22]=2[CH:34]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
Hydrogen peroxide (70%; 1.1 mL, ca. 22.6 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (3.2 mL, 22.6 mmol) in DCM (15 mL) at 5° C. The solution was stirred at 5° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 5° C. and added to a stirred solution of 1-oxide 8 (597 mg, 2.3 mmol) and trifluoroacetic acid (350 μL, 4.5 mmol) in CHCl3 (15 mL) at 5° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 9 (424 mg, 67%) as a red solid which was dissolved in HCl saturated MeOH, the solvent evaporated and the residue crystallized to give the hydrochloride, mp (MeOH/EtOAc) 170-174° C.; 1H NMR [(CD3)2SO] δ 10.57 (brs, 1 H, NH+Cl−), 8.45 (brs, 1 H, NH), 8.17 (d, J=9.6 Hz, 1 H, H-8), 7.39 (d, J=2.6 Hz, 1 H, H-5), 7.22 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.01 (s, 3 H, OCH3), 3.78-3.82 (m, 2 H, CH2N), 3.33-3.37 (m, 2 H, CH2N), 2.82 [d, J=4.5 Hz, 6 H, N(CH3)2]; 13C NMR [(CD3)2SO] δ 165.6, 150.1, 139.7, 125.7,123.4, 119.4, 92.5, 56.8, 54.9, 42.3 (2), 36.0. Anal. Calcd for C12H18ClN5O3.1½H2O: C, 42.1; H, 6.2; N, 20.4. Found: C, 42.0; H, 5.9; N, 20.0%.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][N:26]=[CH:25]1>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:30](=[O:31])[CH2:29][N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)Cn1ccnc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cn1ccnc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2-(1H-imidazol-1-yl)acetic acid to yield (3aR,4S,7aR)-4-(2-imidazol-1-yl-acetoxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=422; RT=5.152 min; LC-MS Method III
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=1)(=O)C.[OH-]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[OH:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=1
Reactant: CC(=O)Oc1ccc2ncc3c(c2c1)CCCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Oc1ccc2ncc3c(c2c1)CCCC3
Temperature: 60 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of Compound 274 (26.50 g, 110 mmol) in dry methanol (150 mL) was added Dowex 1×8-200 hydroxide form (0.40 g, catalytic), and tetra-n-butylammonium bromide (50 mg, catalytic), and the resulting mixutre was stirred at 60° C. for 24 hours. The reaction mixture was cooled, diluted with ethyl ether (100 mL) and filtered to give 21.47 g (98 percent) of Compound 275: white crystalline solid; mp 284°-286° C. (dec.); Rf =0.25 (silica, 50 percent ethyl acetate in dichloromethane); IR (CHC3) νmax 2933, 2906, 2850, 2582, 1627, 1503, 1421 cm-1 ; 1H NMR (500 MHz, DMSO -d6) δ 9.92 (s, 1 H, OH), 8.34 (s, 1 H, H6), 7.77 (d, J=9.0 Hz, 1 H, H4), 7.19 (dd, J=9.0, 2.6 Hz, 1 H, H3), 7.12 (d, J=2.6 Hz, 1 H, H1), 2.88 (t, J=6.1 Hz, 2 H, H7 or H10), 2.78 (t, J=6.1 H, 2 H, H7 or H10), 1.87-1.74 (m, 4 H, H8 and H9); 13C NMR (125 MHz, DMSO -d6) δ 155.5, 148.8, 141.1, 138.5, 130.9, 129.4, 128.4, 120.0, 104.0, 26.5, 24.3, 22.1, 21.9; MS (FAB+) m/e (rel intensity) 200 (M+H, 100), 124 (8), 107 (14); HRMS for C13H14NO (M+H), calcd 200.1075, found 200.1079.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[OH:23][C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:27]([C:24]4([OH:23])[CH2:26][CH2:25]4)=[O:28])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: O=C(O)C1(O)CC1
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1CNC(=O)C1(O)CC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-hydroxy-1-cyclopropane carboxylic acid similarly to as described in example 2 with non-critical modifications to afford crude 10-bromo-9-fluoro-3-((1-hydroxycyclopropanecarboxamido)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted directly with 2-methyl-3-butyne-ol via General Procedure F to afford 13 mg (32%) of 9-fluoro-3-[[(1-hydroxycyclopropanecarbonyl)amino]methyl]-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=453.2.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:12](OCC)=O)=[C:6]([CH3:11])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:2].C=O>>[CH2:1]([C:3]1[NH:4][C:5]([CH3:12])=[C:6]([CH3:11])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCc1c(CC)[nH]c(C(=O)OCC)c1C
Agent: C=O
Product: CCCc1c(CC)[nH]c(C)c1C

Procedure:
2-Ethyl-3-n-propyl-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2-ethyl-3-n-propyl-4,5-dimethylpyrrole. ##STR95##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC(C)([O-])C.[K+].C(O)(C)(C)C.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[C:26]([O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reaction time: 0.03 h
Yield: 36.5 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.00 g, 40.9 mmol) in DMF (40 mL) was added 1M potassium tert-butoxide in tert-butanol (40.9 mL, 40.9 mmol). The reaction was stirred for 2 minutes and tert-butyl bromoacetate (6.61 mL, 40.9 mmol) was added. The reaction was stirred for 1 hour and was quenched with 200 mL of water. The product was extracted into EtOAc and the organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography on silica gel (9:1 hexanes:EtOAc) afforded the title compound as a clear oil (3.53 g). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.48 (m, 2H), 7.32 (s, 1H), 7.21 (m, 1H), 4.56 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 4-fluorophenethylamine (4.8 mL, 37 mmol) and diisopropylethylamine (6.4 mL, 37 mmol) in dichloromethane (40 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (5.5 mL, 37 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel, extracted with water (35 mL), brine (25 mL), and 1N HCl (25 mL). The dichloromethane layer was separated and formation of more precipitate was observed which was collected by filtration. The solids collected were combined and dried under vacuum to yield N-(4-fluorophenethyl)-4-(trifluoromethyl)benzamide as an off-white solid. MS (ESI pos. ion) m/z: 312 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14]O.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: OCc1cnoc1-c1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2oncc2CCl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of 5-(2,4-difluorophenyl)-4-isoxazolylmethanol (2.50 g) in toluene (50 ml) was added dropwise thionyl chloride (2.11 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(2,4-difluorophenyl)isoxazole (2.20 g, yield 81%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio). NMR (CDCl3) δ: 4.53 (2H, s), 6.95–7.15 (2H, m), 7.6–7.75 (1H, m), 8.43 (1H, s).
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:24]([O:23][C:21]([NH:20][C:18]12[CH2:19][NH:11][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC12CCCCC1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCCC1CNC2

Procedure:
A 10% palladium-carbon catalyst (80.0 mg, 20 wt %) was added to a solution of 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (optical isomer A) (400 mg, 1.07 mmol) in methanol (10.7 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for one hour. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give the title compound quantitatively.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])=[CH:7][CH:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.Cl.Cl.O1CCOCC1>CO>[CH3:28][NH:27][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:6][CH:7]=3)[CH:12]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCCl)cc3)cc12
Reactant: C1COCCN1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCN4CCOCC4)cc3)cc12
Yield: 69.6 %

Procedure:
In a 10 mL microwave vial 6-(4-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (70.0 mg, 0.179 mmol) and morpholine (0.155 ml, 1.791 mmol) were added in methanol (3 mL) to give a yellow suspension. The vial was irradiated at 150° C. in the microwave for 30 min. The volatiles were evaporated in vacuo. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), then dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on basic silica gel (eluted with hexane/ethyl acetate 3:2 to 0:1). The product was obtained as the parent and converted to the HCl salt by addition of 4 M HCl-dioxane, then crystallized from EtOH-H2O to give 55 mg of N-methyl-6-(4-(2-morpholinoethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine as a yellow powder (60% yield), LCMS m/z=442 (M+1) (Method D) (retention time=1.12 min). 1H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 10.41 (s, 1H), 9.63 (s, 1H), 9.10-8.79 (m, 3H), 8.34 (d, J=8.2 Hz, 1H), 8.28-8.12 (m, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.87-7.74 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 4.60-4.46 (m, 2H), 4.06-3.91 (m, 2H), 3.91-3.74 (m, 2H), 3.67-3.41 (m, 4H), 3.38-3.09 (m, J=10.1 Hz, 5H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([N:11]2[CH2:14][CH:13]([S:15][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]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12]2)=[N:7]1>O1CCCC1.P([O-])([O-])([O-])=O.[Zn]>[CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([N:11]2[CH2:12][CH:13]([S:15][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])[CH2:14]2)=[N:7]1
Reactant: COCOC[C@@H]1CSC(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)=N1
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: COCOC[C@@H]1CSC(N2CC(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of 756 mg of Compound (30) obtained in Example 3 in 10 ml of tetrahydrofuran and 30 ml of 0.35 M phosphate buffer (pH 6.0) solution was added 6.0 g of zinc powder, and the reaction mixture was stirred for 2 hours at room temperature. After removal of the zinc powder by filtration, the filtrate was washed with ethyl acetate and the pH of the filtrate was adjusted to 5.5, then the filtrate was concentrated. The resulting residue was purified by using Diaion HP-40R column (10% isopropanol-water) to give 415 mg (71%) of (1R, 5S, 6S )-2-[1-((4R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid [Compound (31)].
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:11])=[CH:32][CH:33]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CCCCC(=O)OC(C)(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)S[C@H]1C[C@@H](CCCCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-(4-t-butyloxycarbonylbutyl)-4-acetylthiopyrrolidine (493 mg) was dissolved in 2.5 ml of trifluoroacetic acid, followed by stirring at room temperature for 15 minutes. The reaction mixture was distilled off to obtain (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(4-carboxybutyl)-4-acetylthiopyrrolidine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-(2-methoxy-3-pyridinyl)alaninate (1.38 g, 3.62 mmol) and trifluoroacetic acid (5 mL, 67.3 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give the crude ethyl glycyl-3-(2-methoxy-3-pyridinyl)alaninate as a colorless oil, which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 90 °C

Procedure:
To a solution of piperidin-4-yl-carbamic acid tert-butyl ester (24 mmol) in anhydrous DMSO (20 mL) is added 1-(4-fluoro-phenyl)-ethanone (24 mmol) and potassium carbonate (24 mmol). The resulting mixture is heated at 90° C. for 36 hr. The reaction mixture is allowed to cool to rt, poured into cold water (100 mL), and extracted with EtOAc (40 mL×3). The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified through silica gel flash chromatography (hexane/ethyl acetate 2:1) to give [1-(4-acetyl-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester, which is refluxed in HCl—MeOH solution. Removing MeOH in vacuo gives the hydrochloride salt of the title compound.
Reaction SMILES: C([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:7]([C:18]#[N:19])[CH2:6]1)(C)(C)C.ClC(OC(Cl)C)=O.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.CO>ClCCCl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C@@H:8]1[CH2:9][NH:5][CH2:6][CH:7]1[C:18]#[N:19]
Reactant: CC(C)(C)N1CC(C#N)[C@H](c2ccc(F)cc2F)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Solvent: CO
Product: N#CC1CNC[C@H]1c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (4R)-1-t-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carbonitrile (4 g, 15.15 mmol) prepared according to the procedure described in WO 2004/09126 in DCE (10 ml) was added dropwise 1-chloroethyl chloroformate (2.45 ml, 22.68 mmol) at 0° C. The reaction solution was heated to 70° C., and maintaining this temperature, 1.8-bis(dimethylamino)naphthalene (4.87 g, 22.72 mmol) in DCE (10 ml) was added dropwise for 2 h. After the reaction finished, methanol (10 ml) was added, and maintaining the temperature, the reaction mixture was stirred for additional 1 h, concentrated in vacuo, and the next reaction was carried out without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH2:19][C:20](=[CH2:24])[C:21]([OH:23])=[O:22].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:10]([F:13])([F:11])[F:12])[CH2:24][C:20](=[CH2:19])[C:21]([OH:23])=[O:22])=[N:6][C:5]=2[CH:15]=1
Reactant: C=C(CBr)C(=O)O
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cl
Agent: [In]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F)C(=O)O

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.30 g; 1.05 mmol), 2-(bromomethyl) acrylic acid (1.80 g; 10.9 mmol) and indium (1.23 g; 10.7 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 50% ethyl acetate/hexanes) to yield the title compound as an off-white solid.