Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CN(C)CCNC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>O1CCCC1.O>[Cl:23][C:16]1[C:15]([O:14][CH3:13])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: COc1cccc(C=O)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C=O)c1Cl
Temperature: -70 °C
Reaction time: 2 h

Procedure:
At 40° C. n-butyl lithium (6.25 mL, 1.6 M in hexane) was added to a solution of N,N,N′-trimethylethylenediamine (1.27 mL) in 10 mL tetrahydrofuran. After 15 min. the reaction mixture was cooled to −70° C. and a solution of 3-methoxybenzaldehyde (1.22 mL) in 5 mL of tetrahydrofuran was added. The reaction mixture was allowed to warm to 0° C. and was cooled again to −70° C. and n-butyl lithium (6.25 mL, 1.6 M in hexane) was added. The reaction mixture was allowed to warm to 10° C. and was cooled again to −30° C. before it was added to a solution of hexachloroethane (7.10 g) in 10 mL tetrahydrofuran. The reaction mixture was stirred for 2 h. at room temperature, poured into 20 mL 10% HCl in water and extracted several times with ethyl acetate. The combined organic phases were washed with saturated brine, dried on MgSO4 and concentrated. The title product was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (75/25, v/v), Rf=0.38), followed by crystallisation from heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.O=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH2:24][CH2:25][CH3:26])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](C(O)=O)[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(C1NC=CN=1)(C1[NH:24]C=CN=1)=O.[C:33](=[O:36])([O-])O.[Na+]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:33]([NH2:24])=[O:36])[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc3ccc(C(=O)O)cc23)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3ccc(C(N)=O)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-methylpiperazin-1-yl)naphthalene-7-carboxylic acid (0.270 g, 1.00 mmol) in anhydrous tetrahydrofuran (5 mL) at room temperature was added carbonyl diimidazole (0.178 mg, 1.10 mmol, 1.1 eq) directly as a solid. The resulting reaction solution was stirred at room temperature under nitrogen for 3 hours. The appropriate amine (1.1 mmol, 1.1 eq) was then added, and the resulting reaction solution was stirred at room temperature under nitrogen for 16 hours. A saturated solution of sodium hydrogen carbonate was added, and the resulting aqueous mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the residue using silica gel (approximately 50 g) and an appropriate solvent system afforded the corresponding 1-(4-methylpiperazin-1-yl)naphthalene-7-carboxamide.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH3:29])[C:25]2[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=2[N:23]([CH3:34])[CH2:22]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@@H:21]2[C:27](=[O:28])[N:26]([CH3:29])[C:25]3[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=3[N:23]([CH3:34])[CH2:22]2)=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C[C@H](N)C(=O)N(C)c2ccccc21
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1CN(C)c2ccccc2N(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Temperature: 25 °C

Procedure:
208 mg of 32 (852 μmol), 198 mg of 18 (0.712 mmol) and 473 mg of sodium 2-ethylhexanoate (2.848 mmol) in 5 mL of THF are successively introduced into a 25 mL round-bottomed flask, with stirring and under an argon atmosphere. The stirring is maintained at RT for 2 days. The mixture is concentrated under vacuum. The crude product is chromatographed on a silica cartridge [50 g, eluent AcOEt/AcOEt-isopropanol (50/50), in an AcOEt-isopropanol (50/50) gradient: 0 to 30%]). 172 mg of expected product Ex15 are recovered.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=3[CH:35]([CH3:37])[CH3:36])=[O:24])=[N:14][C:13]=2[CH:38]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[C:31]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:29]=[CH:28][C:27]=3[CH:35]([CH3:37])[CH3:36])=[O:24])=[N:14][C:13]=2[CH:38]=1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCSc1nc2cc(OCc3ccccc3)ccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCSc1nc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Under cooling in ice bath, 6-(5-benzyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (514 mg, 2.0 mmol) was dissolved in trifluoroacetic acid (20 ml), followed by addition of thioanisole (1.24 g, 10 mmol), with stirring at ambient temperature for 12 hours. The solvent was distilled off from the reaction solution; the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, and was dried over anhydrous magnesium sulfate, from which the solvents were distilled off. The residue was purified by silica gel column chromatography (30 g of silica gel; elution solvents: hexane:acetone=5:1 to 5:2), to recover the objective compound (459 mg at a yield of 97%) as a pale red amorphous. IR (KBr) cm−1: 3247, 2963, 1649, 1445, 1153. 1H-NMR (d6-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.48-1.91 (6H, m), 2.35 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.31 (2H, t, J=7.1 Hz), 6.70 (1H, dd, J=8.8, 2.4 Hz), 6.92 (1H, d, J=2.4 Hz), 7.09 (1H, d, J=8.3 Hz), 7.10 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.31 (1H, d, J=8.8 Hz), 8.68 (1H, br s), 8.92 (1H, s). EIMS m/z (relative intensity): 440 (M+, 100). Elementary Analysis: C25H32N2O3S Required: C, 68.15; H, 7.32; N, 6.36; S, 7.28. Found: C, 68.16; H, 7.45; N, 6.26; S, 6.86.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([O-])(O)=[O:13].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[NH2:29][C:30]1[S:40][C:33]2[CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH2:37][C:32]=2[C:31]=1[C:41]([NH2:43])=[O:42]>C(Cl)Cl.C1COCC1>[CH2:38]([N:35]1[CH2:36][CH2:37][C:32]2[C:31]([C:41]([NH2:43])=[O:42])=[C:30]([NH:29][C:12](=[O:13])[NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)[S:40][C:33]=2[CH2:34]1)[CH3:39]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1CCc2c(sc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 31 %

Procedure:
A vigorously stirred solution of 4-trifluoromethyl aniline (161 mg, 1.0 mmol) in DCM (3 mL) at room temperature was treated with aq. NaHCO3 (3 mL) and triphosgene (98 mg, 0.33 mmol) and the reaction mixture was vigorously stirred at room temperature for 45 min. 2-Amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (225 mg, 1.0 mmol) was next added followed by THF and the reaction mixture was stirred at room temperature for 8 h. The solvent was then removed under vacuo and the resultant crude product was diluted with methanol and the insoluble solid was filtered off. Upon evaporation of MeOH, the crude oil was taken up in DCM and washed with water (×2), and the aqueous layer was back extracted with DCM. All organics were combined, dried (Na2SO4) and concentrated using a rotary evaporator. The crude product was purified by flash chromatography, Isolera system (SiO2 gel as stationary phase, 12 g HP column, dry loading) using DCM-DCM/MeOH (0%-10% MeOH in DCM) to afford the title compound as a brown solid (128 mg, 31% yield). MS (M+H) 413.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(Cc4ccccc4Cl)C3)cc1-2
Yield: 51 %

Procedure:
Following the procedure for 372, a mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol) and 2-chlorobenzaldehyde gave 373 (123 mg, 51%). LCMS: RT=8.80 min, [M+H]+=492/494. 1H NMR δ (ppm) (CDCl3): 8.34 (1H, d, J=2.34 Hz), 7.90 (1H, s), 7.43 (1H, d, J=7.55 Hz), 7.33 (1H, dd, J=7.76, 1.47 Hz), 7.24-7.13 (3H, m), 7.01 (1H, d, J=8.25 Hz), 5.95-5.82 (1H, m), 4.40-4.34 (2H, m), 3.90-3.83 (2H, m), 3.85-3.76 (3H, m), 3.42-3.36 (2H, m), 3.35-3.28 (2H, m), 1.60 (6H, d, J=6.65 Hz)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:28][C:29]2[C:34]([C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1>CO>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:28][C:29]2[C:34]([C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCN(Cc3ncc(C)cc3C)Cc3ncccc3C(C)(C)c3ccc(F)cc3)c2)cc1
Agent: On1nnc2ccccc21
Solvent: CO
Product: Cc1cnc(CN(CCc2c[nH]cn2)Cc2ncccc2C(C)(C)c2ccc(F)cc2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-{2-[1-{toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine (87.3 mg, 0.143 mmol) in anhydrous MeOH (1.5 mL) was added HOBT (77.1 mg, 0.57 mmol). After stirring overnight the reaction mixture was concentrated. Purification by radial chromatography on silica gel using 5% MeOH/CH2Cl2 afforded COMPOUND 175 (36 mg, 55%) as a clear oil. 1H NMR (CDCl3) δ 1.65 (s, 6H), 1.97 (s, 3H), 2.20 (s, 3H), 2.53 (s, 4H), 3.30 (s, 2H), 3.37 (s, 2H), 6.63 (s, 1H), 6.88 (t, 2H, J=8.52 Hz), 7.04 (m, 3H), 7.30 (m, 1H), 7.61 (s, 1H), 7.93 (d, 1H, J=7.91 Hz), 8.05 (s, 1H), 8.55 (d, 1H, J=3.58 Hz). 13C NMR (CDCl3) δ 18.1, 18.2, 22.8, 31.4, 42.4, 53.3, 57.8, 58.8, 115.5, 115.8, 122.4, 124.1, 127.5, 127.6, 130.2, 132.1, 132.6, 134.5, 134.7, 139.2, 144.0, 145.4, 146.4, 146.5, 153.4, 158.5, 159.8. ES-MS m/z 458 [M+H]+. Anal. Calcd. for C28H32FN5.1.1H2O.0.3 CH2Cl2: C, 73.49; H, 7.05; N, 15.30. Found: C, 70.02; H, 7.02; N, 14.87.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.[OH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.O>CN1CCCC1=O>[OH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:4][CH:3]=2)[CH2:31]1
Reactant: OC1CCNC1
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(N2CCC(O)C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
A mixture of 0.4 g (1.01 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, prepared in step 3.1, and 0.81 ml (10.06 mmol) of 3-hydroxypyrrolidine in 1.2 ml of N-methylpyrrolidinone is heated for 20 minutes in a microwave oven regulated at 200° C. under 300 watts. The reaction mixture is then poured into 50 ml of water. A solid is recovered by filtration and purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. The resulting solid is then recrystallized from a mixture of methanol and dichloromethane. 0.22 g of a solid is recovered by filtration and dried under reduced pressure.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][S:2]1.CO.[C:13]([C:15]1C(=O)C(Cl)=C(Cl)[C:17](=O)[C:16]=1C#N)#N.O>C(Cl)Cl>[CH2:1]1[C:10]2[CH:9]=[C:8]3[C:7](=[CH:6][C:5]=2[CH:4]=[CH:3][S:2]1)[CH:17]=[CH:16][CH:15]=[CH:13]3
Reactant: c1ccc2c(c1)CCSC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C1=Cc2cc3ccccc3cc2CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
The thioisochroman from step 1 (Example 13) (100.0 mg,0.40 mmmol) was dissolved in CH2Cl2 (12 ml) and MeOH (4 ml) followed by the addition of DDQ (109.0 mg,0.48 mmol,1.2 eq [2]) at R.T. The resulting mixture was stirred at room temperature overnight. H2O was added and it was extracted with CH2Cl2. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated in vacuum. The crude obtained was flash chromatographed using toluene:ethylacetate (95:5) to give the trans titled compound (65.0 mg,0.23 mmol) in 58% yield (MP: 84° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[NH2:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([NH:9][C@H:10]([C:18]([NH:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:44])[CH3:45])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:5][CH2:6]1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of N-morpholinocarbonyl-L-phenylalanine (114 mg) and 2(S)-(L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (150 mg) in dry N,N-dimethylformamide (20 ml) which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (125 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (46 mg). The mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (2% methanol in chloroform as eluent) to give 2(S)-(N-morpholinocarbonyl-L-phenylalanyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (174 mg) as an amorphous powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C(OO)=O)[CH:3]=1.C1([CH:18]([O:25][C:26]([C:28]2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SCC=2SC2N(C)N=NN=2)=[O:27])C2C=CC=CC=2)C=CC=CC=1.C1(C(OC(C2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SC=C2SC2N(C)N=NN=2)=O)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[C:26]([O:25][CH3:18])(=[O:27])[CH3:28].[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cn1nnnc1SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cn1nnnc1SC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCC
Product: COC(C)=O
Reaction time: 2 h

Procedure:
10.35 g (51.1 mmols) of m-chloroperbenzoic acid (85% strength) are added to a solution of 20.7 g (33.8 mmols) of a mixture consisting of 7β-phenoxyacetylamino-3-(1-methyl-5-tetrazolylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester and 7β-phenoxyacetylamino-3-(1-methyl-5-tetrazolylthio)-2-cephem-4-carboxylic acid diphenylmethyl ester in 350 ml of chloroform at 0° C. and the mixture is stirred for 2 hours. Excess per acid is then destroyed by adding 85 ml of 0.1 N sodium thiosulphate. The reaction solution is extracted with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and the organic phase is dried over sodium sulphate and concentrated in vacuo. The residue is dried in a high vacuum and gives a mixture of the 1β-oxide and 1α-oxide of 7β-phenoxyacetylamino-3-(1-methyl-5-tetrazolylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester; thin layer chromatogram: silica gel (toluene/ethyl acetate, 1:2), β-sulphoxide: Rf=0.26; α -sulphoxide: Rf=0.13. The two sulphoxides are chromatographed on 1 kg of silica gel with toluene/ethyl acetate, 1:2, and the pure β-sulphoxide of melting point 146° C. (from methyl acetate/hexane; IR spectrum (nujol): characteristic bands at 3.05; 5.58; 5.78; 5.83 and 5.97μ), and the pure α-sulphoxide of melting point 180° C. (decomposition; from methylene chloride/diethyl ether; IR spectrum (nujol): characteristic bands at 2.95; 5.53; 5.77 and 5.92μ) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH:12][S:39]([CH:36]2[CH2:38][CH2:37]2)(=[O:41])=[O:40])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)cn1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)NS(=O)(=O)C2CC2)cn1
Reaction time: 20 h

Procedure:
To a stirred solution of 1-[6-methoxypyridin-3-yl]-1-[1-(pyridin-3-yl)indazol-5-yl]oxypropan-2-amine (45 mg, 120 μmol) in dichloromethane (4.5 mL) was added triethylamine (40 μl), followed by cyclopropane sulfonic acid chloride (25 mg, 180 μmol) and DMAP (1.5 mg, 12 μmol). The stirring was continued for 20 hours at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane, then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 4 mg as a racemic mixture of two diastereomeres (7%).
Reaction SMILES: C([O:9][CH2:10][C:11]1([CH2:14][C:15]#N)[CH2:13][CH2:12]1)(=O)C1C=CC=CC=1.[OH-:17].[K+].[N+](=C)=[N-].CC[O:24][CH2:25]C>C(O)C.CCCCCC>[OH:9][CH2:10][C:11]1([CH2:14][C:15]([O:24][CH3:25])=[O:17])[CH2:12][CH2:13]1
Reactant: N#CCC1(COC(=O)c2ccccc2)CC1
Reactant: [OH-]
Reactant: CCOCC
Agent: C=[N+]=[N-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Product: COC(=O)CC1(CO)CC1
Temperature: 10 °C
Yield: 50 %

Procedure:
The nitrile of Step 3 (0.388 mol) was dissolved in ethanol (400 mL), 8N KOH (800 mL) was added and the reaction mixture was heated to reflux overnight. Most of the ethanol was evaporated and ice was added to the mixture. Concentrated HCl was added (600 mL) dropwise at 0° C. (without warming over 10° C. inside the solution) until obtention of pH approx. 1. The acid was then extracted with EtOAc two times and the organic phases were washed 2 times with brine and dried over Na2SO4. The solvent was evaporated and the solid was dissolved in THF (500 mL). A solution of diazomethane in Et2O (about 1.7 L, 0.85 mol) was added at 0° C. until the yellow color remained and no more acid could be seen by TLC. The solvent was evaporated and the residual oil was purified by flash chromatography using 1:1 to 2:1 EtOAc:hexane to yield 28.2 g, (50% yield) of the title compound. 1H NMR (CDCl3) δ0.55 (4H, m), 2.45 (2H, s), 2.55 (1H, t), 3.5 (2H, d), 3.70 (3H, s).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])CCCC1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:38]=[C:36]([NH:35][CH3:30])[N:37]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nccc(-c2c(-c3ccncc3)nn3c(NC4CCCC4)cccc23)n1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (From example 1, 0.13 g, 0.35 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:20 methanol-ethyl acetate) to give the title compound (100 mg, 75%) as a yellow solid. 1H NMR (CDCl3): δ 8.72 (d, 2H), 8.13 (d, 1H), 7.65 (m, 3H), 7.35 (t, 1H), 6.43 (d, 1H), 6.10 (d, 1H), 6.05 (d, 1H), 5.10 (m, 1H), 4.05 (m, 1H), 3.05 (d, 3H), 1.2–2.2 (m, 8H); MS m/z 386 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](I)[CH3:25]>>[C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][CH2:24][CH3:25])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCI
Reactant: CC(C)(CCCN1CCCC(CO)C1)S(=O)(=O)c1ccccc1
Product: CCOCC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (55 mg of 60% dispersion in oil) was washed with i-hexane and treated with tetrahydrofuran (3 ml). [1-(4-Benzenesulfonyl-4-methyl-pentyl)-piperidin-3-yl]-methanol (95 mg, 0.28 mmol) was added and the mixture was stirred at room temperature for 10 min. Ethyl iodide (0.5 ml) was added to the mixture that was stirred for 5 hours. The reaction mixture was quenched with 25% ammonia and extracted into dichloromethane. The combined organic extract were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give to give the title compound.