Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25])[C:6]([O:8][CH3:9])=[O:7].C(N(C(C)C)C(C)C)C.Cl[C:36]1[C:41]([Cl:42])=[CH:40][C:39]([C:43]([F:46])([F:45])[F:44])=[CH:38][N:37]=1>CN(C=O)C.CCOC(C)=O>[Cl:42][C:41]1[C:36]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([O:13][C:12]4[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=4[F:2])[C:15]3=[O:25])[CH2:20][CH2:21]2)=[N:37][CH:38]=[C:39]([C:43]([F:45])([F:44])[F:46])[CH:40]=1
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a solution of (S)-methyl 3-fluoro-4-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)benzoate hydrochloride (0.1 g, 0.29 mmol) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.543 mL, 2.97 mmol) and 2,3-dichloro-5-(trifluoromethyl)pyridine (0.193 g, 0.892 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (50 mL) and washed with water (20 mL), and brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum. The material was purified on silica, using a gradient of DCM to 10% EtOAc/DCM as eluent to yield (S)-methyl 4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoate (0.10 g, 63% yield).
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][CH3:25])[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][CH3:25])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)CC
Reactant: O=Cc1ccccc1Cl
Product: CCOC(=O)C1=C(CC)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketopentanoate in the same manner as in Example 1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.CC([O-])(C)C.[K+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>O1CCOCC1>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[N:14]=1
Reactant: Brc1cccc(Br)n1
Reactant: c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1cccc(-n2cccn2)n1
Yield: 89.7 %

Procedure:
To a solution of 1H-Pyrazole (10.0 mmol, 680 mg) in distilled dioxane (30 mL) were added KOtBu (11.0 mmol, 1.26 g), and followed by addition of 2,6-dibromopyridine (10.0 mmol, 2.37 g). The reaction mixture was refluxed for 48 hour, and then quenched with 5 mL of water. Solvent was removed under reduced pressure and water was added to the residue, then the mixture was extracted with DCM. The combined organic layers were washed with brine and dried over MgSO4. After solvent evaporation, the crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=20:1 as eluent) to afford a white solid (2.01 g, 90%). 1H NMR (400 MHz, CDCl3, ppm): 8.53 (s, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.73 (s, 1H), 7.67 (t, 1H, J=7.8 Hz), 7.35 (d, 1H, 7.6 Hz), 6.46 (s, 1H). 13C NMR (100 MHz, CDCl3, ppm): 162.72, 140.73, 139.91, 127.58, 125.25, 110.89, 108.23.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:15](=[C:16]([CH3:32])[C:17]5[C:22]([CH:23]=4)=[N:21][C:20]([C:28]([F:31])([F:30])[F:29])=[CH:19][CH:18]=5)[N:14]=3)=[CH:11][C:10]([C:33]([F:36])([F:35])[F:34])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:37][NH2:38].CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH3:37][NH:38][C:25]([C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:28]([F:29])([F:30])[F:31])=[N:21]2)=[C:16]([CH3:32])[C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:33]([F:34])([F:36])[F:35])[CH:11]=1)=[O:26])=[O:27]
Reactant: CN
Reactant: Cc1c2ccc(C(F)(F)F)nc2cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)c1cc2nc(C(F)(F)F)ccc2c(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C

Procedure:
2-[2-(3-Chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-methyl-6-trifluoromethyl-3-oxa-1,5-diaza-anthracen-4-one (0.249, 0.456 mmol) in 20 ml of tetrahydrofurane is treated with methylamine (0.11 ml of 8M solution in ethanol, 0.9 mmol) and stirred at room temperature. TLC analysis (hexane:ethyl acetate 4:1) after 12 h shows reaction completion. The mixture is concentrated in vacuo, and then purified by flash column chromatography to give the title compound as white crystals.
Reaction SMILES: [Cl: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][O:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:19]4[CH:20]=[N:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc(-c2cccc3c2CCNC3C)cn1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)cn1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [S:1]1[C:5]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)=[CH:4][C:3]2[CH2:18][CH2:19][CH2:20][C:2]1=2.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:5]4[S:1][C:2]5[CH2:20][CH2:19][CH2:18][C:3]=5[CH:4]=4)=[N:10][C:9]=13)=[O:17])[CH2:25]2
Reactant: O=C(O)c1cccc2oc(-c3cc4c(s3)CCC4)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cc5c(s4)CCC5)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
A mixture of 2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzo[d]oxazole-4-carboxylic acid (90 mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (86 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.27 mL, 1.92 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and semi-preparative HPLC to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide (55 mg, 41%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J=7.5 Hz, 1H), 8.16 (dd, J=8.0, 1.0 Hz, 1H), 7.65 (s, 1H), 7.61 (dd, J=8.0, 1.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 4.60-4.50 (m, 1H), 3.10 (d, J=10.0 Hz, 2H), 3.03-3.00 (m, 2H), 2.86-2.82 (m, 2H), 2.65-2.52 (m, 4H), 2.54 (s, 3H), 2.18-1.96 (m, 3H), 1.62-1.46 (m, 3H), 1.25-1.18 (m, 2H); MS (ESI+) m/z 422 (M+H); HPLC>99% (AUC), tR=13.28 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[CH2:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7])=[CH2:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=Cc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=Cc1cccc(C(=O)Cl)c1

Procedure:
To a mixture of 3-vinylbenzoic acid (1.0 g, 6.75 mmol) in CH2Cl2 (20 mL) is added oxalyl chloride (2.35 mL, 3.42 g, 26.9 mmol) and 1 drop of DMF. After 2 h the solvent is removed under reduced pressure and the residue is redissolved in CH2Cl2 and concentrated again (4×) to afford the title compound which is used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.[CH3:12][CH:13]([NH2:15])[CH3:14]>>[OH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([NH:15][CH:13]([CH3:14])[CH3:12])=[O:11])[CH2:7][CH2:8]1
Reactant: CC(C)N
Reactant: O=C(O)C1CCC(CO)CC1
Product: CC(C)NC(=O)C1CCC(CO)CC1

Procedure:
Prepared as in Example 24a from 4-(hydroxymethyl)cyclohexanecarboxylic acid and propan-2-amine as a colorless oil (57%). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (d, J=7.6 Hz, 6H), 1.22-2.08 (m, 9H), 2.12 (m, 1H), 3.28 (t, J=7.6 Hz, 2H), 3.79 (m, 1H), 4.34 (s, 1H), 7.43 (s, 1H). MS 200 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[O:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)=[CH:24][CH:25]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cnccc1O
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: N#CC(Cl)(Cl)Cl
Product: c1ccc(COc2ccc(-c3nc4cnccc4o3)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of commercially available 4-hydroxy-3-amino-pyridine (14, 19.3 g, 175 mmol) in acetonitril (1500 ml) was added 4-benzyloxy-benzoic acid (24, Ra═Rb═H, 40 g, 175 mmol), triphenylphosphine (142.5 g, 543 mmol, 3.1 eq) and trichloroactonitril (54.5 ml, 543 mmol, 3.1 eq). The reaction mixture was allowed to reach room temperature and the mixture was stirred for 16 hrs at 80° C. The mixture was concentrated in vacuo and the residues was dissolved in DCM and washed with 2N NaOH (3×). The combined water layers were extracted with DCM and the organic layers dried (Na2SO4) to give crude 25 (Ra═Rb═H) as oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19][C:20](O)=O.[OH-].[Na+]>O>[CH3:17][O:18][CH2:19][C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCC(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 200 °C
Reaction time: 0.12 h

Procedure:
3-Amino-4-(2-methylpropylamino)quinoline (5.0 g; 0.023 mol) and methoxyacetic acid (20 mL) were mixed and heated at about 200° C. until all bubbling had stopped. Heating was continued for 5-10 min longer and the dark solution was allowed to cool to room temperature. The solution was diluted with water, made strongly basic with 50% sodium hydroxide and extracted with ether. The combined extracts were dried over magnesium sulfate and evaporated to dryness to yield 5.2 g of crude product. The crude product was used as such for further reactions. A small sample was recrystallized from ether to yield nearly colorless crystals, m.p. 96-99° C. Analysis: Calculated: C, 71.4; H, 7.1; N, 15.6. Found: C, 71.1; H, 7.0; N, 15.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][CH2:18][C:19]([OH:21])=O)[S:16][CH2:15][CH2:14][CH2:13][S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(O)=O.[CH2:33]([NH2:45])[CH2:34][C:35]1[CH:44]=[CH:43][C:40]([O:41][CH3:42])=[C:37]([O:38][CH3:39])[CH:36]=1>O1CCCC1>[CH3:39][O:38][C:37]1[CH:36]=[C:35]([CH:44]=[CH:43][C:40]=1[O:41][CH3:42])[CH2:34][CH2:33][NH:45][C:19](=[O:21])[CH2:18][CH2:17][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[S:12][CH2:13][CH2:14][CH2:15][S:16]1
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(C2(CCC(=O)O)SCCCS2)cc1OC
Agent: O=C(O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)CCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC
Reaction time: 3 h

Procedure:
13.2 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionic acid, 4 g of triethylamine and 180 ml of tetrahydrofuran are cooled to 0° C and treated dropwise within 10 minutes with 5.44 g of chloroformic acid is isobutyl ester in 80 ml of tertrahydrofuran. The mixture is then held at room temperature for 3 hours and treated at 0° C with 7.25 g of homoveratrylamine in 40 ml of tetrahydrofuran. The suspension is left to stand at 3° C for 48 hours, then evaporated, treated with water and extracted with ether/methylene chloride (3:1). The ethereal extracts are washed with water, sodium bicarbonate solution, 1-N tartaric acid and water. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized from methylene chloride/ether at 0° C. There is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionamide of melting point 135°-136° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])(=O)=O.OB(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[C:25]1([C:7]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A mixture of dimethyl 5-(trifluoromethylsulfonyloxy)isophthalate (2.3 g), dihydroxy-phenylborane (1.23 g) and triethylamine (2.0 4 g) in N,N-dimethylformamide (30 ml) was heated at 100° C. and stirred for 3 hours under nitrogen. After evaporating the solvent, the residue was dissolved in a mixture of dichlomethane (100 ml) and water. The organic layer was successively washed with aqueous 10% sodium carbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from hexane to afford dimethyl 5-phenylisophthalate (1.07 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([OH:21])[CH2:19][CH3:20]>>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([O:21][CH2:18][CH2:19][CH3:20])=[N:3][C:4]=3[NH2:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: Nc1nc(Cl)nc2c1ncn2C1C=CCCC1
Reactant: CCCO
Product: CCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of 2.4 g. (9.2 mmoles) of 2-chloro-9-(2-cyclohexenyl)-9H-adenine in 60 ml. of 1 N sodium n-propoxide in n-propanol was heated at reflux overnight under a nitrogen atmosphere. The reaction mixture was poured into ice-water containing sufficient acetic acid to neutralize the excess alkoxide. The mixture was evaporated in vacuo. The residue was dissolved into CHCl3 with stirring. The CHCl3 extracts were washed with water, dried with Na2SO4 and evaporated to give 2.35 g. (90%) of title product; m.p. 157°-159° C. IR(KBr): 3450, 3110, 1630, 1585, 1470, 1390, 1335 cm-1. UV: λmaxMeOH 266 nm (ε13200). NMR(CDCl3): δ1.03 (3H, t, 7 Hz), 1.80(8H, m). 4.15(2H, t, J=7 Hz), 5.03 (2H, m), 5.88(1H, m), 6.56(2H, m), 7.4(1H, s).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[S:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21])([CH3:4])[CH3:3].CC(C1C=C(S[C@@H]2CC[CH2:39][C@H:38]2[OH:42])C=C(C(C)(C)C)C=1)(C)C.CC(C1C=C(C(C)(C)C)C=CC=1S[C@H]1CCC[C@H]1[OH:63])(C)C>C(Cl)(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:8]=[CH:7][C:6]=1[S:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[O:21][CH2:39][C:38]([OH:42])=[O:63])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(S[C@@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1ccc(S[C@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(S[C@@H]2CCC[C@H]2OCC(=O)O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method described in Example 77, except that the title product of Example 91 was substituted for the title product of Example 75, Compound A. The structure was supported by NMR, Ir, optical rotation (CHCl3, 25° C.; 589 nm +1.91°±2.69°; 365 nm -28.2°±18.1°) and elemental analysis.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])=[CH:5][CH:4]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: [K]
Product: Clc1ccc(OCCCCCCBr)cc1

Procedure:
The intermediate 6-(4-chlorophenoxy)hexyl bromide was prepared from the potassium salt of 4-chlorophenol and 1,6-dibromohexane.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[C:7]#[N:8]>N1C=CC=CC=1>[C:13]1([C:10]2[CH:9]=[C:6]3[C:7]([NH2:8])=[N:3][NH:2][C:5]3=[N:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1cc(-c2ccccc2)cnc1Cl
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Nc1n[nH]c2ncc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (1.42 g, 28 mmol) was added to a stirred solution of 2-chloro-5-phenylnicotinonitrile (2.45 g, 11.4 mmol) in pyridine (25 ml). The reaction mixture was stirred at reflux for 6 hours, cooled and the resulting solid was filtered and dried in vacuo, affording the title compound as a solid.
Reaction SMILES: C(OC)(OC)OC.[Br:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([NH:15][NH2:16])=[N:13][CH:14]=1.[C:23](O)(C(F)(F)F)=O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[N:13]([CH:23]=[N:16][N:15]=2)[CH:14]=1
Reactant: NNc1ncc(Br)cc1-c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COC(OC)OC
Product: Brc1cc(-c2ccccc2)c2nncn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Trimethyl orthoformate (564 μL, 5.16 mmol) was added into a solution of 1-(5-bromo-3-phenylpyridin-2-yl)hydrazine (1.29 mmol, crude) in CH2Cl2 (12 mL). TFA (100 μL, 1.29 mmol) was added after 15 mins. The reaction mixture was stirred at room temperature for 30 mins and then concentrated. The residue was purified by a flash column using a gradient of ethyl acetate (50-80%) in heptane as an eluent. The product containing fractions were concentrated to give 6-bromo-8-phenyl-[1,2,4]triazolo[4,3-a]pyridine (328.7 mg, 85% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([SH:16])=[C:13](O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-:20])([O-])=O.[K+].[K+].[CH3:23]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:16][CH3:23])=[C:13]([O:20][CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(OCc2ccccc2)ccc1S
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
Dissolve 5-benzyloxy-2-mercapto-phenol (17.8 g, 76.72 mmol) in DMF (300 mL) and add K2CO3 (31.8 g, 0.23 mol) and MeI (32.7 g, 0.23 mol). Stir the reaction mixture at room temperature overnight. Add water (800 mL) and extract the aqueous layer with EtOAc (3×800 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica, 5-20% of EtOAc/hexane) to give 13.5 g of 4-benzyloxy-2-methoxy-1-methylsulfanyl-benzene (68%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)(=O)=O)=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[ClH:23].[O:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13][CH:12]1[CH2:11][NH:37][CH2:36][CH:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])[CH2:31][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Reactant: NCC1CCN(c2ccccc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cl
Product: Clc1ccccc1N1CCC(CNCC2COc3ccccc3O2)CC1
Reaction time: 24 h

Procedure:
A mixture of 1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate (1.68 g, prepared in a similar manner to that described in Example 1), 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine (1.8 g) and potassium carbonate (10 g) in acetonitrile (150 ml) was heated under reflux with stirring for 24 hours. Potassium iodide (0.2 g) was added to the reaction mixture and heating under reflux continued for a further 24 hours. The cooled mixture was filtered and the solvent removed from the filtrate in vacuo. The residue was passed through a silica column using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluant. The solvent was removed from the eluate in vacuo and the clear oily residue dissolved in ether. An excess of an etheral solution of hydrogen chloride was added, and the solvent removed in vacuo to give N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-chlorophenyl)piperid-4-yl]methylamine hydrochloride (0.37 g), m.p. 275°-278° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C@@H:24]2[CH2:29][O:28][C:27]3=[N:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][N:26]3[CH2:25]2)=[CH:18][CH:17]=1.C([SiH2]OC(C)(C)[C@@H]1OC(=O)N(C2C=CC(C3C=CC(CO[C@@H]4COC5=NC([N+]([O-])=O)=CN5C4)=CC=3)=C(F)C=2)C1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][O:23][C@H:24]2[CH2:29][O:28][C:27]3=[N:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][N:26]3[CH2:25]2)=[CH:20][CH:21]=1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-c2ccc(CO[C@@H]3COc4nc([N+](=O)[O-])cn4C3)cc2)c(F)c1
Agent: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CN(c2ccc(-c3ccc(CO[C@@H]4COc5nc([N+](=O)[O-])cn5C4)cc3)c(F)c2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1O[C@H](CO)CN1c1ccc(-c2ccc(CO[C@H]3COc4nc([N+](=O)[O-])cn4C3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
3-[2-Fluoro-4′-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxymethyl)-biphenyl-4-yl]-5(R)-hydroxymethyl-oxazolidin-2-one. To a solution of 5(R)-(tert-butyl-dimethyl-silanyloxymethyl)-3-[2-fluoro-4′-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxymethyl)-biphenyl-4-yl]-oxazolidin-2-one (70 mg, 0.117 mmol) in THF (8.0 mL) was added TBAF (1.0 mL, 1.0 mmol, 1.0 M in THF). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, purified by flash chromatography to give the title product (36 mg, 64%) as a yellow solid. ESI MS m/z 485.3 (M+H+); 1H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.60 (dd, J=13.6, 2.4 Hz, 1H), 7.56-7.50 (m, 3H), 7.44-7.38 (m, 3H), 5.23 (t, J=5.6 Hz, 1H), 4.74-4.66 (m, 4H), 4.46 (d, J=12.0 Hz, 1H), 4.26-4.20 (m, 2H), 4.10 (t, J=9.2 Hz, 1H), 3.85 (dd, J=8.8, 6.0 Hz, 1H), 3.68-3.64 (m, 1H), 3.58-3.52 (m, 1H).