Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[C:22](=[O:25])([O-])[O-:23].[Na+].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[C:13]([CH3:20])=[C:14]([N:19]3[CH2:20][C:13]4[CH:14]=[C:15]5[O:23][CH2:22][O:25][C:16]5=[CH:4][C:5]=4[CH2:6]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)c(N2Cc3cc4c(cc3C2)OCO4)c(C)c2c1OC(C)(C)C2c1ccccc1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.56 mmol) in tetrahydrofuran (30 ml) were added 5,6-bis(chloromethyl)-1,3-benzodioxazole (604 mg, 2.76 mmol), sodium carbonate (1.17 mg, 11.0 mmol), and tetrabutylammonium iodide (700 mg, 1.90 mmol) and the mixture was refluxed with heating for 15 hours. The reaction mixture was cooled down to room temperature and then poured into ice water. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium chloride, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 8:1) to obtain 853 mg (56% yield) of the title compound. Melting point: 245-248° C. (Ethyl acetate).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Mg].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1.[Br-].[Zn+2].[Br-]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
11.2 g of anhydrous zinc bromide in 25 ml of THF are added dropwise at about 0° to a Grignard solution prepared from 20 g of 4-n-propylbromobenzene and 2.4 g of magnesium turnings in 100 ml of THF. After the mixture has been stirred for 2 hours, a mixture of 22.5 g of 4-bromotrifluorotoluene, 1.5 g of [(diphenylphosphine)ferrocenyl]palladium(II) chloride and 25 ml of THF is added dropwise, and the mixture is stirred for 24 hours at room temperature and poured into 100 ml of saturated ammonium chloride solution. Customary work-up gives 4-(4-n-propylphenyl)trifluorotoluene, M.p. 97° C., Δε=14.2, viscosity η (20° C.)=6 mm2 /s.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O[CH:14](OCC)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:19][CH:18]=1)C>C(Cl)(Cl)Cl>[O:9]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:22]=2)[NH:10]1
Reactant: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Reactant: NC(=O)c1ccccc1O
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C(Cc2ccc(OCC3NC(=O)c4ccccc4O3)cc2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of polyphosphonate ethyl ester (PPE) (3.15 g, 7.29 mmol) in chloroform (4.0 mL) was added salicylamide (0.5 g, 3.65 mmol) followed by addition of a solution of 5-[4-[(2,2-diethoxy)ethoxy]phenyl methyl]thiazolidin-2,4-dione (1.36 g, 4.0 mmol) obtained in example 2, in chloroform (10 mL) dropwise at 25-30° C. The reaction mixture was immersed in a preheated oil bath and refluxed for 3 h. The reaction mixture was cooled to room temperature and CHCl3 was removed under reduced pressure. To the resultant residue aq. sat. NaHCO3 solution (25 mL) was added and stirred for 30 min. at 25-30° C. The precipitated brown coloured solid was filtered and purified by column chromatography using EtOAc:pet. ether (1:1) to yield the title compound (1.15 g, 81%). mp: 134° C.-138° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]1[N:12]=[CH:11][N:10]([C:13](N2C=NC=C2)=[O:14])[CH:9]=1.O>ClCCl>[N:10]1([C:13]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:14])[CH:9]=[CH:8][N:12]=[CH:11]1
Reactant: CCCCCCO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCOC(=O)n1ccnc1
Temperature: 30 °C

Procedure:
A solution of n-hexanol (25.95 g) in dichloromethane (400 ml) was slowly added to solution of N,N-carbonyldiimidazole (48.08 g) in dichloromethane (100 ml) and stirred for 2½ hour at 25-35° C. Water was added to the reaction mixture. Both the dichloromethane layer and aqueous layer were separated and the dichloromethane layer was distilled under reduced pressure to provide the title compound. Yield: 60 g
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][C:34]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[C:34]([C:42]([F:43])([F:45])[F:44])[CH:35]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1ccc(N=C=O)cc1C(F)(F)F
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 46.4 mg (0.21 mmol) of 4-methoxy-3-trifluoromethylphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 15 mg (25.3% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1[CH:6]=CC=C[CH:2]=1.Cl.C([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2SC=1C(Cl)=O)CC.C(S(C1C=CC(N)=CC=1)(=O)=O)CCCCCC>CN(C)C=O>[CH3:11][NH:15][C:16]1[CH:2]=[N:1][CH:6]=[C:18]([NH:19][CH3:14])[CH:17]=1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Reactant: c1ccncc1
Agent: CCCCCCCS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNc1cncc(NC)c1

Procedure:
In the mixture of 50 ml of pyridine and 5 ml of dimethylformamide was suspended 1.04 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonyl-chloridehydrochloride (described in Example 13). To the suspension was added 940 mg of 4-n-heptylsulfonylaniline obtained in Reference Example 7, and 45 mg of 3,5-dimethylaminopyridine, followed by stirring at 70° C. for 17 hours. The reaction mixture was concentrated and to the concentrate was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the mixture was added saturated hydrogenchloride diethylether solution, followed by stirring at room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol (10:1 by volume). To the resulting substance was added saturated hydrogenchloride diethylether solution. The solvent was removed under reduced pressure. The residue was recrystallized from methanol-diethylether to obtain 559 mg of the titled compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:32][CH3:33])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl>[CH2:1]([C:3]1([CH2:32][CH3:33])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:42])=[O:28])=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)O)cc1)c1ccc(C)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)Cl)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.150 g of [S-(R*,S*)] 4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in 5 ml methylene chloride containing a catalytic amount of dimethylformamide is added 0.5 ml of oxalyl chloride. The mixture is stirred at room temperature for 30 minutes and then concentrated in vacuo to yield (S-(R*,S*))-4-((3,3-diethyl-1-((1-(4-methyl-phenyl)-butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoyl chloride.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1)C.C(=O)(O)O.[NH2:32][C:33]([NH2:35])=[NH:34].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:13]2[C:12]([N:7]3[CH2:8][CH2:9][C:10]4[N:34]=[C:33]([NH2:35])[N:32]=[CH:4][C:5]=4[CH2:6]3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(COc2ncccc2N2CCC(=O)C(=CN(C)C)C2)cc1
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ncccc2N2CCc3nc(N)ncc3C2)cc1

Procedure:
A solution of 3-dimethylaminomethylene-2′-(4-methoxybenzyloxy)-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (673 mg, 1.83 mmol) in ethanol (100 ml) was treated with guanidine carbonate (1.32 g, 7.33 mmol), followed by addition of sodium acetate trihydrate (1.99 g, 14.64 mmol) and the reaction mixture was refluxed for 21 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The separated organic layer was dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 6% methanol in EtOAc) gave the title compound as a light yellow, amorphous solid (477 mg, 72%).
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:17]([O-])=O)=[CH:7][C:8]2[O:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[NH2:17][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][C:9]2[C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OC(=O)C2(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(cc1N)OC(=O)C2(C)C

Procedure:
Pd/C (1.50 g) and compound 19 (3.00 g, 1.14 mmol) were suspended in THF (1500 mL) at 25° C. under hydrogen at 30 psi for 4 hours. The mixture was then filtered through a pad of Celite®, and the filtrate was concentrated in vacuo to give compound 20 as a white solid. 1H NMR (DMSO-d6; 400 MHz) δ 7.05 (s), δ 6.49 (s), δ 5.01 (s), δ 1.35 (s), δ 1.33 (s).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:33])=[C:5]1[C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3cccc(C(F)(F)F)c3)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 149.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (55 mg, 0.12 mmol), β-alanine (863 mg, 9.7 mmol) and NaOMe solution (14.5 mL, 7.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 46 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2[N+](=O)[O-])C1
Temperature: 120 °C
Yield: 77.2 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (1.41 g, 10.0 mmol), (R)-3-aminopiperidine-1-carboxylic acid tertbutyl ester (2 g, 10.0 mmol) and potassium carbonate (152 mg, 11.0 mmol) in DMF (18 mL) was heated to 120° C. under microwave irradiation for 30 min. The reaction mixture was partitioned between EtOAc (150 mL) and water. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10% EtOAc in DCM) affording (R)-3-(2-Nitrophenylamino)piperidine-1-carboxylic acid tertbutyl ester as an orange oil (2.48 g, 77%). LCMS: RT 3.95 min [M+H-tBu]+ 266.2.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCOCC1.O.CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([OH:15])[CH2:12][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O)C1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of (3R,5R)-5-(tert-butyldimethylsilyloxy)piperidin-3-ol (1 eq) in 20 mL of 1,4-dioxane and 8 mL of water was added benzyl chloroformate (1.5 eq). The mixture was stirred at room temperature for 4 hours. The crude mixture was diluted with 100 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:3) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (74%). LC/MS (m/z): 366.2 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].I.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Agent: I
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A mixture of 432 mg of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (1 mmol), 63 mg of red phosphorous (2 mmol), 0.4 ml of aqueous 57 wt % HI (3 mmol), and 1 ml of glacial acetic acid was refluxed with stirring for 30 min. Then the reaction mixture was diluted with 25 ml of ethyl acetate, filtered by suction through a pad of celite, washed with a solution of 0.2 g of NaHSO3 in 5 ml of water, and washed two times with 5 ml of concentrated aqueous sodium bicarbonate solution. The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (85:15). 123 mg of the title compound were obtained; 1H NMR (CDCl3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38 to 7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1)=O.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:19]1([CH2:1][C:3]2[S:11][C:10]3[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=3[CH:4]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCC3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 2-formyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (0.3 g, 0.122 mmol) and azetidine (96 mg, 1.683 mmol) were dissolved in 1,2-dichloro-ethane (7 ml) and stirred at room temperature for 10 min. Sodium triacetoxyboro-hydride (0.331 g, 1.571 mmol) was added and the resulting mixture stirred at room temperature for 48 h. Saturated sodium hydrogen carbonate solution was added and the phases were separated. The aqueous phase was extracted with diethylether (3×) and the organics were washed with saturated sodium chloride solution (1×). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/methanol, 10:1). Yield: 0.28 g (81%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:9])=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH2:25]([C:32]1[N:37]=[N:36][C:35]([N:38]2[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]2)=[C:34]([CH3:45])[C:33]=1[CH3:46])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([C:32]1[N:37]=[N:36][C:35]([N:38]2[CH2:39][CH2:40][C:41]([OH:44])([C:2]3[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:9])=[CH:4][N:3]=3)[CH2:42][CH2:43]2)=[C:34]([CH3:45])[C:33]=1[CH3:46])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(=O)CC2)c1C
Reactant: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(O)(c3ccc(C(C)(C)OCOCC[Si](C)(C)C)cn3)CC2)c1C
Temperature: -40 °C

Procedure:
To compound 34 (272 mg, 0.786 mmol) in THF (6 mL) at −78° C. is added t-butyl lithium (1.7 M in pentane, 1.0 mL, 1.7 mmol). The mixture is stirred at −78° C. for 30 min, to which compound 24 (209 mg, 0.707 mmol) in THF (2 mL) is added at −78° C. The mixture is stirred and warmed up slowly to −40° C. in 1 h, then quenched at −40° C. with saturated ammonium chloride. THF is removed and the residue was extracted with ethyl acetate (3×). The organic phase is washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue is purified by silica gel chromatography (40-60% ethyl acetate in heptane) to provide recovered compound 24 (103 mg, 49%) and the title compound 35 (106 mg, 27%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[S:5][C:6]=1[C:7](OCC)=[O:8].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[S:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1sc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a mixed solution of the compound (380 mg, 1.2 mmol) obtained in Example 70a in ethanol/tetrahydrofuran (v/v=1/1, 6 mL) were added calcium chloride (500 mg, 4.5 mmol) and sodium tetrahydroborate (170 mg, 4.5 mmol), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=65/35) to give the title compound (160 mg, 50%) as a colorless solid.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH2:34][CH2:33]1>>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:34][CH2:33]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CN1CCN(CCCCN)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-(4-methyl-piperazin-1-yl)-butylamine by the procedure analogous to Example 1. MS (APCI, m/z): 515 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11]1.C(OB(O)OC(=O)C)(=O)C.[CH:37]1([N:40]2[C:49]3[C:44](=[CH:45][C:46]([F:53])=[C:47](F)[C:48]=3[O:50][CH3:51])[C:43](=[O:54])[C:42]([C:55]([OH:57])=[O:56])=[CH:41]2)[CH2:39][CH2:38]1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:23]([NH:22][CH2:21][C@@H:19]1[O:18][C:17](=[O:26])[N:16]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3([OH:15])[CH2:14][CH2:13][N:12]([C:47]4[C:48]([O:50][CH3:51])=[C:49]5[C:44]([C:43](=[O:54])[C:42]([C:55]([OH:57])=[O:56])=[CH:41][N:40]5[CH:37]5[CH2:39][CH2:38]5)=[CH:45][C:46]=4[F:53])[CH2:11]3)=[C:2]([F:1])[CH:3]=2)[CH2:20]1)(=[O:25])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNC3)c(F)c2)C(=O)O1
Agent: CC(=O)OB(O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1c(N2CCC(O)(COc3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In analogy to example 76 with 143 mg N-{(5S)-3-[3-fluoro-4-(3-hydroxy-pyrrolidin-3-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-yl-methyl}-acetamide (MW: 367.38, 0.39 mmol), 165 mg of 1-cyclo-propyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid diacetylborate (MW: 423.137, 0.39 mmol) and 100 mg of ethyl diisopropylamine (MW: 129.25, 0.78 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 143 mg, 57%. MS: 643.7 (M+H)+, 641.7 (M+H)−, Method ESI+, ESI−.