Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30]Cl)[CH2:25][CH2:24]1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:30][C:29]([N:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)=[O:32])[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cc1
Reactant: O=C(CCl)N1CCOCC1
Product: CC(C)c1ccc(N(CC(=O)N2CCOCC2)C(=O)C2CCCc3ccccc32)cc1
Yield: 60 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-morpholino-2-oxoethyl chloride (0.33 g) as starting materials, N-(4-isopropylphenyl)-N-(2-morpholino-2-oxoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained. melting point: 180° C.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[N:7]=1)=[O:5])C.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:11][C:8]1[N:7]=[C:6]([C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[O:5])[O:10][N:9]=1
Reactant: CCOC(=O)c1nc(C)no1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Product: Cc1noc(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)n1

Procedure:
Following the procedure of Example 1A but employing as reactants 3-methyl-1,2,4-oxadiazole-5-carboxylic acid ethyl ester and p-(β-aminoethyl)-benzenesulfonamide, there is obtained p-(β-(3-methyl-1,2,4-oxadiazole-5-carbonylamino)ethyl]-benzenesulfonamide, M.P. 218°-220°C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:16][CH2:15][CH2:13][OH:14])[CH:7]=1
Reactant: NCCO
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NCCO)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A round bottom flask was charged with 2-bromo-4-methoxy-1-nitrobenzene (2.0 g, 8.6 mmol) and ethanolamine (8.1 mL, 135 mmol). The resulting reaction mixture was stirred at 50° C. for 4 h and at rt for 48 h, then water (32.0 mL) was added and the resulting precipitate was filtered off and rinsed with water to yield 2-((5-methoxy-2-nitrophenyl)amino)ethanol as a yellow solid LC-MS conditions B: tR=0.56 min, [M+H]+=213.13.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([OH:19])[CH2:11][CH2:10]1.CN1CCOCC1.N1C=CN=C1>C(Cl)Cl>[C:1]([Si:5]([O:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCOc2ccccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)OC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-chloro-dimethyl-silane (10.54 g, 70 mmol) was added to a CH2Cl2 (200 mL) solution of 4-chromanol (10.00 g, 66.6 mmol), N-methylmorpholine (10.98 mL, 100 mmol) and imidazole (0.20 g, 3 mmol) at 0° C. The mixture was stirred for 3 days at RT. The reaction was diluted with CH2Cl2 (200 mL), washed with dilute HCl and H2O, dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:15][S:16](O)(=[O:18])=[O:17].C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 1.84 g (10.0 mmol) of 4-methyldiphenyl ether (J. Chem. Soc., Perkin Trans. 1; 1992, 407-408) with 2 mL of dichloromethane in an ice-bath was added a solution of chlorosulfonic acid (0.73 mL, 11.0 mmol) in 2 mL of dichloromethane dropwise. The resulting mixture was stirred at 0° C. to room temperature for 2 hours, and then oxalyl chloride (11.14 mL, 13.0 mmol) was added dropwise, followed by 0.15 mL of DMF. The resulting mixture was heated to 40° C. for 1 hour and then allowed to cool to room tempereature over a 2 hour period. The reaction mixture was poured into ice-pH 7 phosphate buffer (50 mL), then extracted with EtOAc:Hexane (4:3) (3×150 mL). The combined organic layers were washed with brine (75 mL). The aqueous layer was extracted with EtOAc/Hexane(4:3) (150 mL). The organic layer was dried over Na2SO4, then evaporated by vacuum to give crude product as white solid. This solid was triturated with hexane and collected by filtration, then dried under high vacuum to give 1.555 g (57%) of 4-(4-methylphenoxy)benzenesulfonyl chloride as white solid: mp 295-300° C.; 1H--NMR (DMSO-d6) δ 2.34 (s, 3H), 6.91-6.99 (dd, J=7.7,8.4 Hz, 4H), 7.24-7.27 (d, J=8.4 Hz, 2H), 7.61-7.63 (d, J=8.1 Hz, 2H).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH:18](O)[CH:17](O)[CH2:16][C:15]=2[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>C(O)C.[Pt]>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCc2ccc3c(n2)CC(O)C(O)C3)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCc2ccc3c(n2)CCCC3)c1

Procedure:
The intermediate 5,8-dihydroquinoline derivative from Example 5 is dissolved in ethanol and hydrogenated over platinum catalyst. Hydrogen uptake is monitored and the reaction stopped when exactly one equivalent of hydrogen is absorbed. The catalyst is removed by filtration and the filtrate concentrated and chromatographed to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[N:10]=[C:9]([C:27]#[N:28])[C:8]=2[N:7]=[CH:6]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.CO>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:27]#[N:28])[C:8]3[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]=3[CH:12]=2)=[CH:15][C:16]=1[C:23]([F:26])([F:25])[F:24])[CH3:22]
Reactant: CCOc1ccc(-c2cc3c(ncn3CCCBr)c(C#N)n2)cc1C(F)(F)F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(-c2cc3c(ncn3CCCN3CCOCC3)c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C

Procedure:
1-(3-Bromo-propyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile was dissolved in DMF (0.5 ml) and morpholine (19 mg, 0.22 mmol) was added. The mixture was heated to 120° C. in a Smith Creator microwave. Mixture was diluted with methanol and passed through an SCX cartridge, then eluted with 2M methanolic ammonia. Mixture was then prep HPLC purified and acetonitrile was removed under reduced pressure. Resulting aqueous solution was made basic with sodium bicarbonate, extracted into DCM (5 ml), then organics were dried and evaporated to afford 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(3-morpholin-4-yl-propyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a white solid (8 mg). 1H NMR (CDCl3) δ 8.25 (d, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.11 (d, 1H), 4.42 (t, 2H), 4.21 (q, 2H), 3.71 (m, 4H), 2.37 (m, 4H), 2.26 (t, 2H), 2.08 (m, 2H), 1.49 (t, 3H). MS m/z 460.6 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([NH2:9])=[N:7][N:8]=1.[CH3:10][C:11](=O)[CH2:12][CH3:13].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([NH:9][CH:11]([CH3:10])[CH2:12][CH3:13])=[N:7][N:8]=1
Reactant: CCC(C)=O
Reactant: COCc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)Nc1nnc(COC)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution (5 mL) of 5-(methoxymethyl)-4H-1,2,4-triazol-3-amine (0.3 g) and butan-2-one (0.25 mL) in acetic acid was added sodium cyanoborohydride (0.6 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.2 g, 45%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[N:23]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=[CH:25][C:17]=23)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][NH2:37].CC(O)=O>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[N:36][NH2:37])[C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[NH:23][CH:24]=[CH:25][C:17]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A mixture of (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (1.45 g, 2.84 mmol), anhydrous hydrazine (0.273 g, 8.53 mmol) and AcOH (0.163 mL, 2.84 mmol) was heated in EtOH (35 mL) at reflux for about 16 h. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (60 mL). The organic phase was washed with brine (40 mL) and concentrated to yield 4-((1-benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.04 g, quantitative) as a brown amorphous solid that was used directly in the next step without further purification: LC/MS (Table 2, Method a) Rt=1.57 min; MS m/z: 368 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]2([C:15]3[NH:32][C:18]4=[N:19][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29](O)=[O:30])[CH2:24]5)=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:14][CH2:13]2)[CH:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]2([C:15]3[NH:32][C:18]4=[N:19][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:1]6[CH2:5][CH:4]=[CH:3][CH2:2]6)=[O:30])[CH2:24]5)=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:14][CH2:13]2)[CH:11]=1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Reactant: C1=CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CC=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
3-Pyrroline (98.5 mg, 1.41 mmol) was added to a solution of (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (500 mg, 1.29 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (541 mg, 1.41 mmol) and diisopropylethylamine (334.7 mg, 2.58 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was triturated with pentane to afford the title compound (510 mg). MS (ES+) (M+H) 438.0; LCMS retention time 4.935 min (Method R1).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:27][CH:26]([OH:28])[CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:14]=1>>[CH2:1]([C:3]1[N:4]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([CH2:23][N:24]4[CH2:25][CH:26]([OH:28])[CH2:27]4)[N:19]3[CH3:22])=[C:15]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:14]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CC(O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(O)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)azetidin-3-ol were reacted to give 524. LCMS m/z: 449.2 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([NH:39][C:40]([CH3:44])([CH3:43])[CH:41]=O)[CH2:38][CH2:37]1>N1CCCCC1.CC#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:41][C:40]([NH:39][CH:36]3[CH2:38][CH2:37]3)([CH3:44])[CH3:43])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)NC1CC1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC1CC1
Reaction time: 0.33 h
Yield: 27.6 %

Procedure:
A solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (118 mg, 0.25 mmol, 1.0 equiv), 2-(cyclopropylamino)-2-methylpropanal (0.16 g, 1.25 mmol, 5.0 equiv) and one drop of piperidine in MeCN (10 mL) was stirred overnight at 40° C. The solvent was removed and the residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 40 mg (27%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 581 (M+H+). H1-NMR (400 MHz, CDCl3+D2O, ppm): 8.33 (s, 1H), 7.54-7.43 (m, 3H), 7.33 (s, 1H), 7.28-7.25 (m, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.94 (dd, J=8.4, 2.0 Hz, 1H), 6.85 (dd, J=11.6, 2.0 Hz, 1H), 4.89-4.64 (m, 3H), 3.65-3.52 (m, 2H), 2.78 (m, 1H), 2.14-1.79 (m, 4H), 1.57-1.55 (d, 6H), 1.20 (m, 2H), 0.98 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15]O)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][Cl:3])=[CH:8][CH:7]=1
Reactant: OCCCNc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCCCNc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Thionyl chloride (4.4 mL) was added to a solution of 3-(4-chlorophenylamino)propan-1-ol (2.17 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added, followed by extraction with ethyl acetate (200 mL). Heptane (100 mL) was added to the resulting extract to prepare a mixed solution. The solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=2:1) to obtain (4-chlorophenyl)-(3-chloropropyl)amine. (4-Chlorophenyl)-(3-chloropropyl)amine was dissolved in THF (45 mL). Triethylamine (4.9 mL) and phenyl chlorocarbonate (1.8 mL) were added at 0° C., and the reaction solution was stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g). Phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g) was dissolved in ethanol (60 mL). Hydrazine monohydrate (5.65 mL) was added at room temperature, and the reaction solution was heated under reflux for 17 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 2.19 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A solution of 21 g of indole-4-carboxylic-acid-methylester in 100 ml of methylene-chloride, 24.9 ml of triethylamine and 7.34 g of 4-dimethyl-aminopyridine is proportionately mixed at 0° C. with 34.2 g of p-toluene-sulfonic-acid-chloride. After 16 h at 0° C., the mixture is diluted with methylene chloride, washed neutral with saturated sodium bicarbonate solution and NaCl solution, and the solvent is distilled off in vacuum. 35.37 g of 1-tosylindole-4-carboxylic-acid-methylester with a m.p. of 145°-147° C. (diisopropylether) is obtained.
Reaction SMILES: [N:1]1([CH:6]([CH:14]([OH:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:10]([O:9][C:7](=[O:8])[CH:6]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH:14]([O:23][C:24](=[O:27])[CH2:25][CH3:26])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)C(C(O)c1ccc(Cl)cc1Cl)n1cncn1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)OC(c1ccc(Cl)cc1Cl)C(C(=O)OC(C)(C)C)n1cncn1
Yield: 76.3 %

Procedure:
3.15 gms of t-butyl α-(1,2,4-triazol-1-yl)-β-hydroxy-β-(2,4-dichlorophenyl)propionate were added to 50 mls of chloroform along with 1.1 gms of 4-dimethylaminopyridine. 1.25 gms of propionyl chloride were then added to the system. The reaction mixture was then refluxed for 18 hours. The reaction solution was then first washed with aqueous 5 wt. % hydrochloric acid and then with aqueous sodium hydroxide. The organic phase was dried over sodium sulfate and then filtered. The filtrate was evaporated to dryness under vacuum affording 2.78 gms of the title compound as a yellow wax.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[O:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:9]=[C:8]([C:29]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)[N:7]=1>CO>[NH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[C:6]([CH3:5])=[N:7][C:8]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:36][CH:35]=4)[N:30]=3)=[N:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(OCCNC(=O)OC(C)(C)C)c1
Solvent: CC(=O)Cl
Solvent: CO
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(OCCN)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (229 uL, 3.21 mmol) was added dropwise to MeOH (1.1 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 1 hr. Tert-butyl (2-(3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenoxy)ethyl)carbamate (Example 67; 60.0 mg, 0.107 mmol) was the added in one portion, and the reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure; the residue was purified using Prep-HPLC to furnish the title compound; MS (ES+) C2iH19F3N6O3 requires: 460. found 461 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.17 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.17 (m, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 6.67 (s, 1H), 5.32 (s, 2H), 4.06 (m, 2H), 3.21 (m, 2H), 2.47 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][S:28][C:29]1[CH:30]=[C:31]([C:35]([C:37]2[N:38]=[CH:39][N:40]3[CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[S:42][C:41]=23)=[O:36])[CH:32]=[N:33][CH:34]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:43]3[S:42][C:41]4=[C:37]([C:35]([C:31]5[CH:32]=[N:33][CH:34]=[C:29]([S:28][CH3:27])[CH:30]=5)=[O:36])[N:38]=[CH:39][N:40]4[CH:44]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(SC)c3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: CSc1cncc(C(=O)c2ncn3cc(C4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)sc23)c1
Yield: 50.9 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (100 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 169 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 179 mg of 7-(5-methylthiopyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=1.[NH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[N:20]=1
Reactant: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3F)nc12
Reactant: CC(C)(CN)CO
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3F)nc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
To a mixture of 2-(2,4-difluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methyl-imidazo[1,2-a]pyrazine (1.4 g, 3.5 mmol) in ACN (30 mL) was added 3-amino-2,2-dimethyl-propan-1-ol (Lancaster, 0.79 g, 7.7 mmol). The mixture was heated to about 80° C. After about 16 h, the mixture was treated with additional 3-amino-2,2-dimethyl-propan-1-ol (Lancaster, 0.20 g, 1.9 mmol) and heated at about 80° C. for about another 4 h. The mixture was filtered through a pad of silica gel and eluted with EtOAc. The solution was evaporated, triturated with ether, and then filtered. The solid was dissolved in hot methanol (˜10 mL). The solution was cooled and the solvent evaporated. The resulting solid was dried at 100° C. under vacuum to yield the title compound as a white solid (0.88 g, 59%): LC/MS (Table 1, Method g) Rt=2.38 min; MS m/z: 425.2 (M+H)+, mp 173.8-174.5° C.