Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F:28][C:29]([F:41])([F:40])[CH2:30][O:31][C:32]1[N:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1.C([BH3-])#N.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:38][C:35]4[CH:36]=[N:37][C:32]([O:31][CH2:30][C:29]([F:41])([F:28])[F:40])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=Cc1ccc(OCC(F)(F)F)nc1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)(F)COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)cn1
Yield: 7.6 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (599, 124.1 mg, 0.31 mmol, prepared as described in Example 68, Scheme 185) in ethanol (3.00 mL) and acetic acid (0.2 mL) were added 6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbaldehyde (603, 164.0 mg, 0.80 mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.700 g). The reaction was irradiated with microwave on 300 watts, 100° C. for 150 minutes. To the reaction was added a solution of potassium hydroxide (9.0 M in water, 1.0 mL). The reaction was irradiated with microwave on 300 watts, 100° C. for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0409, 10.6 mg, 7.6%). MS ESI) [M+H+]+448.4.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][OH:11].[CH3:12][C:13]([C:16]1[CH:21]=[C:20]([SH:22])[CH:19]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:27])([CH3:15])[CH3:14].C(OCC)(=O)C>C(Cl)Cl>[CH3:24][C:23]([C:18]1[CH:19]=[C:20]([S:22][CH2:9][CH2:10][OH:11])[CH:21]=[C:16]([C:13]([CH3:12])([CH3:14])[CH3:15])[C:17]=1[OH:27])([CH3:26])[CH3:25]
Reactant: OCCBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O

Procedure:
Triethylamine (0.42 g, 0.0042 mole), 2-bromoethanol (0.52 g, 0.0044 mole) and the title compound of Example 2 (1.0 g, 0.0042 mole) were stirred in methylene chloride (50 ml) for 20 hours. The reaction was condensed and ethyl acetate (25 ml) added to the residue. After filtering the white solid the filtrate was concentrated and the product purified by chromatography on silica, m.p. ca. 66° C.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([C:8]1[N:9]([CH2:22][CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][N:25]2[CH3:29])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1CCCl
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cc3ccccc3)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Yield: 63.9 %

Procedure:
Compound 3 (165 mg, 0.654 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (132.4 mg, 0.719 mmol), and powdered potassium carbonate (271.2 mg, 1.962 mmol) were placed in an argon-purged flask. DMF (5 mL, Aldrich sure seal™) was added and the mixture heated to 65° C. in an oil bath for 20 hours. The solution was cooled to room temperature and diluted with water (10 mL) and ethyl acetate (25 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with brine (2×10 mL) and dried over magnesium sulfate. The sample was filtered, concentrated, and the resultant crude product purified using dry silica gel column chromatography eluting with 15-20 mL portions of solvent system (2M NH3 in methanol:CH2Cl2, 5:95) to afford a yellow solid 4 (152 mg, 63.9%); 1H NMR (CDCl3) δ 8.50 (d, 1H, J=2.2 Hz), 8.07 (dd, 1H, J=2.2, 9.0 Hz), 7.36-7.17 (m, 6H), 6.44 (s, 1H), 4.16 (d, 2H, J=3.0 Hz), 4.10-3.97 (m, 2H), 3.06 (t, 1H, J=7.1 Hz), 2.21 (s, 3H), 2.15-2.00 (2×m, 2H), 1.97-1.55 (m, 5H), 1.53-1.40 (m, 1H); ESI-MS (m/z, %): 364 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH3:25][C:26]1[CH:27]=[C:28]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]3[N:22]=[CH:23][N:24]=[C:4]3[CH:3]=2)[CH:29]=[C:30]([CH3:32])[CH:31]=1
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2cc3ncnn3c(NCCNc3ccc([N+](=O)[O-])c(N)n3)n2)c1

Procedure:
In analogy to the procedure described for Example 94, 39.9 mg (72% of theory) of the product are obtained as a solid starting from 50 mg (0.133 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo-[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 55A) by coupling with 19.9 mg (0.13 mmol) of (3,5-dimethylphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]([O:14][CH3:15])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl-].[SH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl.O>[CH3:15][O:14][C:6]1[C:7]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]=2[C:3]([CH2:2][S:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CO)c2c1OC(C)(C)C2
Reactant: Sc1ccncc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CSc2ccncc2)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Compound 48a (2.0 g) obtained in Step A was dissolved in methylene chloride (100 ml), and then diisopropylethylamine (5.0 ml) and methanesulfonyl.chloride (0.8 ml) were added thereto, followed by stirring at room temperature for one hour. At the same temperature, 4-mercaptopyridine (1.4 g) was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 48 (1.4 g, 48.3%) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(4-Amino-2-phenylbenzoyl)methionine methyl ester hydrochloride (5.0 g, 12.7 mmol), prepared as in Example 192B, and 3-pyridinecarboxaldehyde (1.25 mL, 13.3 mmol) were dissolved in 100 mL 1% acetic acid in methanol. After 10 minutes, sodium cyanoborohydride (0.95 g, 15.9 mmol) was added. After stirring at room temperature 18 hours, the reaction mixture was evaporated and partitioned between 5% NaHCO3 and ethyl acetate. The organic layer was washed with 5% NaHCO3 and brine, dried over Na2SO4, and evaporated to provide [4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester which was used without further purification. MS m/e 450 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.65 (m, 2H), 1.87 (m, 2H), 2.00 (s, 3H), 3.63 (s, 4H), 4.42 (s, 2H), 4.61 (m, 1H), 5.69 (d, J=7 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 6.63 (m, 1H), 7.45 (m, 6H), 7.68 (m, 2H), 8.55 (m, 1H), 8.62 (d, J=3 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]([O:19][CH3:20])=[N:17][C:16]3[C:11]2=[N:12][C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:14][C:15]=3[NH2:21])[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC1N=C2C(N=C(OC)N2CCCCCCl)=C(N)N=1)[CH2:28]CC.N1CCCCC1>>[CH2:23]([O:22][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[C:18]([O:19][CH3:20])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:1]2[CH2:4][CH2:28][CH2:27][CH2:3][CH2:2]2)=[C:15]([NH2:21])[N:14]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Solvent: C1CCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C@H:26]12[CH2:32][C@H:31]1[CH2:30][C@@H:29]([CH2:33][NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1)[NH:28][CH2:27]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:28]2[C@H:29]([CH2:33][NH:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][N:36]=3)[CH2:30][C@H:31]3[C@H:26]([CH2:32]3)[CH2:27]2)=[O:10])[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)nc1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2C[C@H]3C[C@H]3C[C@H]2CNc2ccc(C(F)(F)F)cn2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6-methyl-3-(2-pyrimidinyl)-2-pyridinecarboxylic acid D19 (99 mg), DIPEA (0.066 ml, 0.376 mmol) and N-[(1S,4S,6S)-3-azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyridinamine D12 (34 mg) in DCM (3 ml), stirred under nitrogen at room temperature was added TBTU (60.4 mg, 0.188 mmol) in one charge. The reaction mixture was stirred at room temperature for 5 hours. NaHCO3 aqueous saturated solution was added and the aqueous extracted with DCM, the phases were separated on a hydrophobic frit and the combined organic solvent was removed to give the crude product which was purified by flash chromatography (silica —NH 11 g column, gradient elution from Cy to Cy/EtOAc 2:8 in 30 minutes, flow rate 30 mls/minute). The product so obtained was purified a second time by flash chromatography (silica —NH 11 g column gradient elution from Cy to Cy/EtOAc 1:1 in 20 minutes, flow rate 30 mls/minute) to afford the title compound E3 (21 mg). UPLC (Acid GEN_QC): rt1=0.68 minutes, peak observed: 469 (M+1). C24H23F3N6O requires 460. 1H NMR (500 MHz, CDCl3) δ ppm 0.08-0.16 (m, 1 H), 0.73-0.81 (m, 1 H), 0.82-1.32 (m, 3H), 2.46-2.58 (m, 2 H), 2.66 (s, 3 H), 3.52-3.69 (m, 2 H), 3.70-3.80 (m, 1 H), 4.47-4.66 (m, 1 H), 6.38-6.50 (m, 1 H), 6.74-7.01 (m, 1 H), 7.08 (t, 1 H), 7.35 (d, 1 H), 7.47 (d, 1 H), 8.33 (s, 1 H), 8.54-8.64 (m, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:27][CH2:28][S:29][CH3:30])[NH:5][C:6](=[O:26])[C@H:7]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH:8][C:9](=[O:21])[C@H:10]([CH:18]([CH3:20])[CH3:19])[NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Cl.[OH-].[Na+]>CO>[N:11]1([C@@H:10]([CH:18]([CH3:20])[CH3:19])[C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:31])[CH2:27][CH2:28][S:29][CH3:30])=[O:26])[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:21])[CH2:15][CH2:14][CH2:13][C:12]1=[O:17]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)CCCCl)C(C)C)C(=O)N[C@@H](CCSC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C(C)C)N1CCCC1=O)C(=O)N[C@@H](CCSC)C(=O)O

Procedure:
The product of Step A was suspended in 5 mL of methanol and 0.6 mL of 1N NaOH was added. After 1 h. the methanol was evaporated, the residue was dissolved in water and filtered. The filtrate was acidified and the product was extracted into ethyl acetate. After standard workup, a solid was obtained, which was washed with water and ether. After drying the solid weighed 25 mg. FAB mass spectrum m/z=430 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][N:10]([CH:14]([CH3:16])[CH3:15])[C@@H:9]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][C@@H:12]([CH3:26])[S:11][N:10]([CH:14]([CH3:16])[CH3:15])[C@@H:9]2[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)N1SCC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)N1S[C@H](C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a degassed solution of 239.9 mg (0.602 mmol) of (3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazinan (Example 117, Step D) in THF (2.0 mL) was added iodomethane (60.0 μl, 0.960 mmol), followed by dropwise addition of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (640.0 μl, 0.640 mmol). After stirring at room temperature for 17 hours, the reaction was quenched with MeOH (3 mL), then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 70% DCM in hexanes gradient) provided the title compound as a white solid. The 1H NMR showed 6% of the 6S epimer was also isolated.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[Br-]>>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([OH:21])=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: [Br-]
Agent: [K+]
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Yield: 40.2 %

Procedure:
The procedure described in Example 4 was repeated using p-nitrobenzyl 7-phenylacetamido-3-chloro-3-cephem-4-carboxylate as the starting material. The corresponding acid was obtained in 40.2% yield. M.p. 142°-145° C. IR (KBr) cm-1 : 3260, 1755, 1635, 1515, 680. NMR (DMSO-δ6) δ: 3.2-4.2 (m, 4 H, S--CH2 & Ar--CH2), 5.2 (d, 1 HS--CH), 5.7 (q, 1 H, N--CH), 7.3 (s, 5 H, Ar--H), 9.1 (d, 1 H, NH).
Reaction SMILES: Br[CH2:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][OH:9].[OH-].[Na+].C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[CH2:12]([O:11][CH2:10][C@@H:7]1[NH:6][C:3](=[O:4])[CH2:2][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CBr
Reactant: N[C@H](CO)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1COC[C@H](COCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Bromoacetyl chloride (5.06 mL) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-1-propanol (10 g) in toluene (100 mL) and a 2 N sodium hydroxide solution (100 mL) under ice-cooling. The reaction solution was stirred at 0° C. for 30 minutes and then at 60° C. for one hour. The reaction solution was returned to room temperature. Then, a toluene-THF (1:1) mixed solution was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous 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 1.36 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[S:16][CH:15]=[CH:14][C:10]=2[N:11]([CH3:13])[N:12]=1.C(C1[O:21][CH2:20]1)Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[O:1]1[C:7]2[C:2]1=[C:3]([C:8]1[C:9]3[S:16][CH:15]=[CH:14][C:10]=3[N:11]([CH3:13])[N:12]=1)[CH:4]=[CH:5][C:6]=2[O:21][CH3:20]
Reactant: Cn1nc(-c2ccccc2O)c2sccc21
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(-c2nn(C)c3ccsc23)c2c1O2

Procedure:
A mixture of 14 g of 3-(2-hydroxyphenyl)-1-methyl-1H-thieno[3,2-c]pyrazole, 10 g of epibromohydrin, 5 g of potassium carbonate and 75 ml of acetonitrile was stirred under nitrogen at 70°-80° C. After 16 hours of stirring, thin layer chromatography (1:1 hexane/ethyl acetate) showed residual starting material. Therefore, 2 g of epibromohydrin and 10 ml of dimethylformamide were added and the mixture was stirred overnight at 92° C., and thereafter quenched, extracted with ether/ethyl acetate (1:1), washed and dried (over anhydrous magnesium sulfate). The epoxide was separated from other by-products using HPLC (eluent=DCM).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([N:26]4[CH2:25][CH2:24][CH:23]([N:20]5[CH2:21][CH2:22][O:17][CH2:18][CH2:19]5)[CH2:28][CH2:27]4)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(C(F)(F)F)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Yield: 66.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.77 g) and 4-(4-morpholinopiperidin-1-yl)-3-trifluoromethylaniline (1 g), the title compound (1.1 g) was obtained, melting point: 193–194° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O>[C:9]([O:8][C:7]([NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A solution of tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (10.0 g, 53.7 mmol) in DCM (40 ml) was treated with TEA (14.9ml, 107 mmol) and cooled to 0° C. Benzyl chloroformate (7.6 ml, 53.7 mmol) was added dropwise and the resulting suspension was allowed to warm gradually to room temperature over a period of 18 hours. The reaction mixture was diluted with water (100 ml) and the organic phase separated. The aqueous phase was extracted with further DCM (2×50 ml) and the combined organic extracts dried (sodium sulphate) and concentrated in vacuo to give a pale yellow solid (14.6 g, 85%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].[CH2:13]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:23]1([C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:22])[C:24](=[O:28])[CH2:25][CH2:26][CH2:27]1)[CH3:2]
Reactant: CCOC(=O)CCCCCCBr
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCCC1(C(=O)OCc2ccccc2)CCCC1=O

Procedure:
To a 100 ml. RB flask was added 13 g. to Ethyl-7-bromoheptanoate and 12.8 g. of 2-benzyloxycarbonylcyclopentanone. The reactants were dissolved in 50 ml. of anhydrous acetone and refluxed over 17 g. of anhydrous potassium carbonate under nitrogen for 20 hours. The reaction mixture was then cooled and filtered and the filtrate evaporated to afford 22.1 g. of crude oil, which was not further purified at this stage.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=O)[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-].[NH4+].[Cl-]>CO>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:20])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=O)N(CCCCCC=O)C(C)(C)C
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#CCCCCCN(C(=O)C(=O)OCC)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 850 mg of 16g in 12 ml of methanol was added 850 mg of K2CO3, followed at 0° C. by 850 mg of dimethyl 1-diazo-2-oxopropylphosphonate. The mixture was stirred at 0° C. for 2 hr, followed by stirring at RT for 16 hr. The reaction mixture was poured into 5% aq. NH4Cl solution and extracted with ethyl acetate. The extract was washed with water, dried, concentrated and the crude material was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate as eluent, to give 650 mg of 16h as a colorless oil, as the methyl ester (due to transesterfication in the medium).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].[N:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[C:21](=[O:33])[NH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[C:25]([C:30](O)=[O:31])[CH:24]=4)[N:19]=2)=[CH:11][CH:10]=1>>[CH3:7][N:6]([CH3:8])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:30]([C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[C:20]([C:18]3[N:19]=[C:15]([C:12]4[CH:11]=[CH:10][N:9]=[CH:14][CH:13]=4)[S:16][CH:17]=3)[C:21](=[O:33])[NH:22]2)=[CH:27][CH:26]=1)=[O:31]
Reactant: CCNCCN(C)C
Reactant: O=C(O)c1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CCN(CCN(C)C)C(=O)c1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in Example 8734 employing N′-ethyl-N,N-dimethylethane-1,2-diamine (Aldrich) and 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carboxylic acid. MS m/z: 448.2 (M+1). Anal. Calc'd for C24H25N5O2S.1.7H2O: C, 60.28; H, 5.99; N, 14.65. Found: C, 60.03; H, 5.61; N, 14.39.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14]C)=[O:12])[NH:8][N:7]=1)=[O:5])C.[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.O>CN(C=O)C>[CH3:14][O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH3:1])=[O:5])[N:7]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[N:8]=1)=[O:12]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1 g 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester in 20 ml of DMF and 188 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature 1.32 g of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 3 h. Then 100 ml water were added and the precipitating product was collected by filtration. Yield: 1.7 g.