Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.5 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 3.30 (s, 4H), 3.77 (s, 4H), 4.15 (s, 3H), 6.90-6.97 (m, 3H), 7.28-7.45 (m, 4H), 7.75-7.76 (m, 1H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:21]([N:12]1[C@H:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:6][CH:5]=2)[CH2:9][CH2:10][C:11]1=[O:13])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1

Procedure:
8.6 g (S)-5-Biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (34.22 mmol) is dissolved in 135 ml methylene chloride. 4.2 g DMAP (34.22 mmol) is added. The mixture is further diluted with 10 ml methylene chloride. Then 14.9 g BOC2O (68.44 mmol) is added and further 10 ml methylene chloride is added. This reaction mixture is then stirred at reflux for 7.5 h. Then a further 3.7 g BOC2O is added. After a total reaction time of 24 h at reflux the solvent is evaporated completely. The evaporation residue is then filtered over 460 g of silica gel with an eluent of toluene:ethyl acetate 4:1. The product fractions are concentrated in vacuo to yield the crude product, which is recrystallised from methylene chloride/heptane fraction 1:6, to yield (S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1-a, R1=BOC).
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][C@@H:8]([CH3:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C[C@@H](Cc1ccccc1)N=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-1-phenylpropan-2-amine (626 mg, 4630 μmol) in benzene (10 mL) was added 4-chlorobenzaldehyde (651 mg, 4630 μmol) and MgSO4 (1000 mg, 8308 μmol) and the suspension stirred at RT 4 h. The suspension was filtered and the solid washed with benzene (2×2 mL). The combined filtrates were concentrated to give (S)—N-(4-chlorobenzylidene)-1-phenylpropan-2-amine, which was carried on into the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (1.0 g, 5.0 mmol) in toluene (30 mL) and ethanol (20 mL) was added (4-methoxyphenyl)boronic acid (1.52 g, 10 mmol), 2M Na2CO3 (14 mL), Pd(PPh3)4 (0.057 g, 0.05 mmol), the reaction was purged with argon and heated at 80° C. for about 6 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine solution (20 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 1-(5-(4-methoxyphenyl)-pyridin-2-yl)ethanone as off white solid (1 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.76 (d, 2H), 7.027 (d, 2H), 3.80 (s, 3H), 2.63 (s, 3H). LC-MS m/z calcd for [M+H]+ 228.09. found 228.2.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cnc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
5-Iodo-1H-pyrrolo[2,3-b]pyridine (24, 0.303 g, 1.22 mmol), (trimethylsilyl)acetylene (25, 0.210 mL, 1.46 mmol), bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.055 mmol), and copper(I) iodide (0.0019 g, 0.010 mmol) were dissolved in triethylamine (19 mL, 0.14 mol) under an atmosphere of nitrogen. The resulting mixture was heated to 60° C. and stirred under an atmosphere of nitrogen for 16 hours. The triethylamine was removed under vacuum, 30 mL of water was added to the residue, and it was extracted with 2×20 mL with ether. The combined organic layers were washed with brine and dried over sodium sulfate. Solids were filtered out and the filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography, eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a solid (26, 0.237 g). MS (ESI) [M+H+]+=215.3.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:7]2.F[B-](F)(F)F.[H+].[CH3:31][Si](C=[N+]=[N-])(C)C.O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH3:31])=[N:7]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC(C)(C)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
7-Fluoro-2-(2-hydroxy-1,1-dimethylethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-99) (50 mg, 0.15 mmol) was dissolved in methylene chloride (0.5 ml), aqueous 42% tetrafluoroboric acid solution (32 μl, 0.15 mmol) was added, then with cooling with ice, trimethylsilyldiazomethane (2 M hexane solution, 77 μl, 0.15 mmol) was dropwise added, followed by stirring at 0° C. for 10 minutes, further trimethylsilyldiazomethane (2 M, hexane solution, 77 μl, 0.15 mmol) was dropwise added, followed by stirring at 0° C. for 1 hour. After the reaction, water was added followed by extraction with methylene and washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with n-hexane/ethyl acetate (5:1, v/v) to obtain the entitled compound (41.2 mg, 79%) as a colorless transparent oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>CO.O>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccccc1N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1N1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of o-toluidine (2.0 g; 18.7 mmol) in methanol (62 mL) was added sodium carbonate (4.95 g; 46.75 mmol) followed by 1,4-dibromobutane (4.85 g; 22.4 mmol). The resulting mixture was stirred at 50° C. under a nitrogen atmosphere overnight and then diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to yield the title product as a dark yellow-orange oil (1.24 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:13])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 71 was prepared from 1-(4-chlorophenyl)cyclo propanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.39–7.34 (m, 6H), 7.26 (t, 1H, J=7.2 Hz), 6.96 (d, 1H, J=7.6 Hz), 5.68 (br s, 1H), 3.26 (dd, 2H, J=6.8, 12.8 Hz), 2.88 (d, 2H, J=13.2 Hz), 2.45 (m, 1H), 2.30 (t, 2H, J=7.2 Hz), 2.19 (s, 3H), 1.96 (t, 2H, J=11.6 Hz), 1.78 (d, 2H, J=12.8 Hz), 1.65–1.58 (m, 6H), 1.02 (dd, 2H, J=3.6, 6.8 Hz); ESMS m/e: 454.2 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][NH:13][C:14]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]3[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:17]2[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])=[O:15])[N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[Cl:45][C:39]1[CH:40]=[C:41]([Cl:44])[CH:42]=[CH:43][C:38]=1[CH:17]1[CH:16]([C:14]([NH:13][O:12][CH2:11][C:8]2[N:7]=[C:6]([CH2:5][OH:4])[O:10][N:9]=2)=[O:15])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: CC(=O)OCc1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2noc(CO)n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution of 323 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate in 6.5 ml of methanol was added 66 mg of potassium carbonate, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) and then recrystallized from ethyl acetate to obtain 157 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:6]2.[H-].[Na+].F[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1)=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:6]2
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(CCC(F)(F)F)cc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(CCC(F)(F)F)cc2c1
Yield: 71 %

Procedure:
6-(Methyloxy)-2-phenyl-3-(3,3,3-trifluoropropyl)-1-naphthalenol (125) (0.35 g, 1.00 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.32 g (71%) of the title compound (126) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 2.10-2.25 (m, 2H), 2.80-2.90 (m, 2H), 3.94 (s, 3H), 6.67 (d, J=8.8 Hz, 2H), 7.07-7.14 (m, 3H), 7.18 (d, J=2.4 Hz, 1H), 7.22-7.30 (m, 3H), 7.60-7.64 (m, 3H), 7.70 (d, J=9.2 Hz, 1H), 9.80 (s, 1H). LCMS (ESI): m/z 451 (M+H)+.
Reaction SMILES: O.O.[NH2:3][CH:4]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][S:14][C@H:9]12)=[O:6].[O:31]=[C:32]1[N:36]([C:37](Cl)=[O:38])[C:35]2[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=2[NH:33]1.Cl>C(#N)C>[O:31]=[C:32]1[N:36]([C:37]([NH:3][CH:4]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:7][CH:8]2[C:23](=[O:24])[N:10]3[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][S:14][C@H:9]23)=[O:6])=[O:38])[C:35]2[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=2[NH:33]1
Reactant: O=C(Cl)n1c(=O)[nH]c2ccccc21
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)[nH]c4ccccc43)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 102.6 %

Procedure:
To 15 ml. of dry acetonitrile were added 883 mg. (2 mmoles) of 7-(α-aminophenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid dihydrate. The mixture was cooled, and 3.13 grams (14.4 mmoles) of N,O-bis-trimethylsilylacetamide were added. Solution was complete within two minutes. The resulting mixture then was stirred at room temperature, and 452 mg. (2.3 mmoles) of 2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride were added, the temperature of the mixture rising from 25° C. to 28° C. Analysis of a sample of the reaction mixture after 30 minutes by thin-layer chromatography (TLC) indicated that reaction was complete. After two hours, the reaction mixture was slowly dropped into rapidly stirred ice water, the pH of the resulting suspension being 1.9. The pH was adjusted to 1.7 by addition of hydrochloric acid. The mixture was filtered, and the solid which was collected was washed with dilute hydrochloric acid and air-dried to give 1.16 grams of the title compound as a buff-colored powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3ccncc3)cccc21
Product: CC1c2cccc(-c3ccncc3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:46][C@@H:45]6[C@@H:43]([CH2:44]6)[N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=4)=[CH:32][CH:31]=3)=[CH:18][N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C@@H:10]12[CH2:11][C@@H:12]1[CH2:13][C@@H:14]([C:15]1[NH:19][CH:18]=[C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]3[CH:31]=[CH:32][C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:46][C@@H:45]6[C@@H:43]([CH2:44]6)[NH:42]5)=[N:38][CH:37]=4)=[CH:34][CH:35]=3)[N:16]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3cccc4c(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)cccc34)cc2)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)c2cccc(-c3ccc(-c4cnc([C@@H]5C[C@H]6C[C@H]6N5)[nH]4)cc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 118.1 %

Procedure:
4M HCl (0.757 mL, 3.03 mmol) in dioxane was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (141 mg, 0.202 mmol) in dioxane (3.0 mL) and the reaction was stirred at rt for 6 h. The solids were washed down the sides of the vial with MeOH and the reaction was concentrated under a stream nitrogen to yield an HCl salt of (1R,3S,5R)-3-(5-(4-(5-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (119 mg) as a yellow solid. LC-MS retention time 2.333 min; m/z 499.57 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.15 (d, J=8.3 Hz, 1 H), 8.03-8.08 (m, 2 H), 8.01 (d, J=8.0 Hz, 2 H), 7.95 (s, 1 H), 7.77 (d, J=6.5 Hz, 1 H), 7.68-7.74 (m, 1 H), 7.65 (d, J=8.0 Hz, 2 H), 7.57-7.64 (m, 2 H), 5.03 (t, J=9.4 Hz, 1 H), 4.97 (dd, J=10.8, 8.0 Hz, 1 H), 3.57-3.66 (m, 2 H), 2.76-2.89 (m, 4 H), 2.11-2.21 (m, 2 H), 1.27-1.34 (m, J=7.7, 5.1, 5.1, 2.6 Hz, 2 H), 1.05-1.14 (m, 2 H).
Reaction SMILES: Cl.[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[O:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[C:24]([CH3:26])=[CH2:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:29]([O:28][C:23](=[O:27])[CH:24]([CH3:26])[CH2:25][N:19]1[CH2:20][CH2:21][O:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:16][CH:15]=2)[CH2:18]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCOc1ccc(C2CN(CC(C)C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 140 °C
Yield: 50.7 %

Procedure:
To a suspension of 2-(4-octyloxy-phenyl)-morpholine hydrochloride (0.17 g; 0.5 mmol) in DMF (5.00 mL) was added tert-butyl methacrylate (0.17 mL; 1.0 mmol) and DBU (0.23 mL; 1.5 mmol) The resulting mixture was heated at 140° C. in a sealed flask overnight. After cooling to RT the reaction mixture was partitioned between 5% aqueous NaHCO3 solution and EtOAc. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 2-methyl-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.11 g).
Reaction SMILES: [C:1]1([CH:7]([CH3:17])[CH2:8][C:9]([C:13]([F:16])([F:15])[F:14])([OH:12])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[OH:12][C:9]([C:13]([F:14])([F:15])[F:16])([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17])[CH2:10][O:11][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: CC(CC(O)(CO)C(F)(F)F)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)(CC(C)c2ccccc2)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol in 30 ml of pyridine is mixed at 0° C. with 3.8 g of 4-toluenesulfonic acid chloride. After 16 hours at 0° C., it is concentrated by evaporation in a vacuum, mixed with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation. By crystallization from ethyl acetate/hexane, 4.9 g of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)ester, melting point 95-96° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH:10]=[O:11])[CH:7]=1.[CH:14]([Mg]Br)=[CH:15][CH2:16][CH3:17].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH:10]([OH:11])[CH2:17][CH2:16][CH:15]=[CH2:14])[CH:7]=1
Reactant: CCC=C[Mg]Br
Reactant: COc1ccc(F)cc1CCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)CCc1cc(F)ccc1OC
Yield: 79.6 %

Procedure:
To a solution of 4 (3.0 g, 19.5 mmol) in THF (20 mL) at 0° C. was added a solution 1-butenylmagnesium bromide (0.5 M in THF, 45 mL, 22.5 mmol) dropwise for 15 min. The reaction mixture was poured into a solution of saturated ammonium chloride (80 mL) in a separatory funnel. The organic fraction was extracted with EtOAc (3×60 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The product was purified by flash column chromatography (EtOAc/hexane, 15:85, v:v, Rf=0.2) to give the product as a colorless oil (3.7 g, 94%); 1H NMR (CDCl3, 500 MHz): δ 6.86-6.82 (m, 2 H), 6.76 (dd, J=4.6, 8.6 Hz, 1 H), 5.82 (m, 1 H), 5.04 (d, J=17.3 Hz, 1 H), 4.95 (d, J=10.2 Hz, 1 H), 3.81 (s, 3 H), 3.55 (m, 1 H), 2.75-2.69 (m, 2 H), 2.2 (m, 1 H), 2.1 (m, 1 H), 1.96 (bs, 1 H), 1.73-1.68 (m, 2 H), 1.6-1.53 (m, 3 H).