Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7]([NH:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:8][O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+]>Br>[N:13]1([CH2:12][CH2:11][NH:10][C:7]2[C:6]3[CH:19]=[CH:20][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COc1ccc2c(NCCN3CCOCC3)noc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc2c(NCCN3CCOCC3)noc2c1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
6-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine (2.9 g) was dissolved in 48% hydrobromic acid (50 ml) and heated to reflux under nitrogen for 3 hours. The reaction was cooled to room temperature, neutralized with saturated sodium carbonate (Na2CO3) solution, and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 3:2 acetone/heptane and subsequently titration with DCM/heptane provided the product (1.0 g), m.p. 151°-152° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH3:20])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+].Cl>O1CCCC1.CO.O>[C:1]([C:3]1[C:4]([CH:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH3:20])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(C)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(c1ccc2ccccc2c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
Ethyl 4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylate (13.3 g, 31.6 mmol) in tetrahydrofuran (200 mL) and methanol (150 mL) was stirred until the mixture turned into a clear solution. To the solution was added 1.000 M sodium hydroxide in water (158 mL). The resulting turbid mixture was vigorously stirred at rt for 12 h. The volatiles were removed under reduced pressure, and the resulting aqueous solution was acidified by addition of 12.0 M of hydrochloric acid in water (15.9 mL, 191 mmol) at 0° C., and then extracted with EtOAc (×3). The combined organic layers were washed with 1M HCl soln, dried, and concentrated to provide 4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylic acid as a white solid (12.1 g, 97.5% yield). 250 mg of the racemic mixture was purified on chiral prep HPLC to provide each enantiomer (115 mg each, >95% ee) (OJ column, elution with 85/5/10/0.1% hexane/iPrOH/EtOH/Et2NH). LCMS: (AA) ES+ 393; 1H NMR (400 MHz, MeOD) δ 7.85-7.76 (m, 3H), 7.76-7.71 (d, J=8.6 Hz, 1H), 7.49-7.38 (m, 2H), 7.38-7.29 (dd, J=8.5, 1.7 Hz, 1H), 5.90-5.74 (q, J=7.3 Hz, 1H), 3.82-3.69 (m, 4H), 3.52-3.43 (dd, J=5.8, 4.0 Hz, 4H), 1.91-1.80 (d, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[Cl-].[CH3:25][CH2:26][N:27]1[C:33](=[O:34])[C:31](=[O:32])[N:30]([C:35]([NH:37][C@@H:38]([C:45]([NH:47][C@@H:48]2[C:51](=[O:52])[N:50]3[C@@H:53]([C:58]([O-:60])=[O:59])[C:54]([CH3:57])([CH3:56])[S:55][C@H:49]23)=[O:46])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:29][CH2:28]1.[Na+].C(Cl)(Cl)Cl.CS(C)=O>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[CH3:25][CH2:26][N:27]1[C:33](=[O:34])[C:31](=[O:32])[N:30]([C:35]([NH:37][C@@H:38]([C:45]([NH:47][C@@H:48]2[C:51](=[O:52])[N:50]3[C@@H:53]([C:58]([OH:60])=[O:59])[C:54]([CH3:56])([CH3:57])[S:55][C@H:49]23)=[O:46])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:29][CH2:28]1
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C(=O)[O-])c2ccccc2)C(=O)C1=O
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C(=O)O)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Yield: 26.12 %

Procedure:
Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Sodium piperacillin (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and a cloudy solid was obtained in 26.12% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=30-40° C. Thermal data determined by thermalgravimetric analysis (TGA): Tonset5%=165° C. and Tonset=177° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(F)c2)CC1
Yield: 100.5 %

Procedure:
The solution of 4-(3-fluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 6.4 mmol) in ethyl acetate (20 mL) in the presence of 10% palladium on carbon was shaken under the hydrogen with a pressure of 50 psi at room temperature for 2 hr. The reaction mixture was filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The organic layer was collected, concentrated, and dried to give 4-(4-amino-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.90 g, crude) as a light red solid, which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH:1]1([N:5]([CH3:12])[CH2:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)(C(Cl)=O)=O.[I:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH:29]C(=O)OC(C)(C)C)[N:22]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][CH3:44])[CH:38]=2)[N:21]=1.C(O)(C(F)(F)F)=O>C(#N)C.C(Cl)Cl.CN(C=O)C>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([C:37]3[CH:38]=[C:39]([N:43]([CH3:44])[C:9](=[O:11])/[CH:8]=[CH:7]/[CH2:6][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH3:12])[CH:40]=[CH:41][CH:42]=3)[N:21]=[C:20]([I:19])[C:28]=12
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Reactant: CNc1cccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C(=O)/C=C/CN(C)C1CCC1)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
To a stirred solution of (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid (139 mg, 0.48 mmol) in acetonitrile (4 mL) was added a drop of DMF before introducing (COCl)2 (73 mg, 0.574 mmol). The resulting mixture was stirred at RT for 2 h. Solvent was removed in vacuo. The residue was dissolved in DCM (5 mL) and the resulting solution was slowly introduced to a pre-cooled solution of tert-butyl-3-iodo-1-(3-(methylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (46) (186 mg, 0.4 mmol) in DCM (5 mL) dropwise. Stirring was continued at RT overnight. TFA (8 mL) was added and resulting reaction mixture was stirred at RT for additional 2 h and then concentrated in vacuo. The residue was dissolved in sat. aqueous NaHCO3. The crude product was extracted with 85% DCM/IPA (50 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated to provide (E)-N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide (52) (222 mg, quant. yield) as a white solid. LC-MS (ESI): m/z (M+1) 518.1.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]([NH:13][C:14]3[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[N:9]([CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])[C:8]=2[C:7]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:6][CH:5]=1>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]([NH:13][C:14]3[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:8]=2[C:7]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCn1c(Nc2cccnc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cccnc3OC)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
To a suspension of lithium borohydride (45.6 mg, 2.09 mmol) in tetrahydrofuran (5 mL) was added ethyl 4-{4-chloro-7-(1-ethylpropyl)-2-[(2-methoxypyridin-3-yl)amino]-1H-benzimidazol-1-yl}butanoate (320 mg, 0.697 mmol) at 0° C. The mixture was stirred at room temperature for 6 hr. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (250 mg, 0.60 mmol, 86%) as a white amorphous.
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1.P([O-])([O-])([O-])=O.[OH-].[Na+]>>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Temperature: 23 °C
Reaction time: 17 h
Yield: 24.2 %

Procedure:
NAD+ (34.0 mg, 38.0 μmol) was placed in 2 mL of a 0.1 M phosphate buffer. The pH of this solution was adjusted to 8.1 with NaOH and then placed in an 80 mL Fisher-Porter bottle. The Fisher-Porter bottle was evacuated and refilled with argon three times then [Cl2Ru(TPPTS)2]2 (6.9 mg, 2.6 μmol) was added under a flow of argon. The Fisher-Porter bottle was evacuated and filled with 70 psi of H2 and stirred to 23° C. for 17.0 hr. The volatiles were removed under reduced pressure and a sample dissolved in D2O. To this was added 20 μl of trimethylsilylpropionate standard solution. 1H NMR integration shows that 9.2 μmole of NADH have been produced under these conditions.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=3)[C:9]2=[O:23])=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[CH2:19]([O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:23])[N:8]([C:5]1[CH:6]=[CH:7][C:2]([N:28]3[CH2:29][CH2:30][C@@H:26]([N:25]([CH3:31])[CH3:24])[CH2:27]3)=[CH:3][CH:4]=1)[CH2:17][CH2:16]2)[CH2:20][CH2:21][CH3:22]
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(Br)cc1)C2=O
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C)C3)cc1)C2=O

Procedure:
According to Method R, 2-(4-bromophenyl)-6-butoxy-3,4-dihydro-2H-isoquinolin-1-one was reacted with dimethyl-(R)-pyrrolidin-3-yl-amine. In this way the product was obtained with molecular weight 407.56 (C25H33N3O2); MS (ESI): 408 (M+H+).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=2)[NH:18][CH:17]=1.[CH3:31]I>CN(C)C=O>[O:13]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=2)[NH:18][CH:17]=1
Reactant: CI
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)S(C)(=O)=O
Reaction time: 1 h

Procedure:
Sodium hydride (80% in oil; 0.1 g) was added under nitrogen to a stirred solution of N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]methanesulphonamide (1.2 g) in dry dimethylformamide (16 ml). After 1 h, methyl iodide (0.75 ml) was added.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:12][CH3:13]>>[CH2:12]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: O=C(O)c1cccnc1S
Reactant: CCBr
Product: CCSc1ncccc1C(=O)O
Yield: 80 %

Procedure:
2-Mercapto-nicotinic acid (2 g, 12.8 mmol) and bromoethane were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound (1.9 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(CCO)C.C(Br)(Br)(Br)[Br:21]>CCCCCC.C1COCC1>[Br:21][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(Br)c1

Procedure:
Starting with 2-chloro-4-methylpyridine II, treatment with n-butyllithium in the presence of N,N-dimethylaminoethanol in hexane, followed by addition of carbon tetrabromide in THF affords 2-bromo-6-chloro-4-methylpyridine III. Compound III undergoes a palladium coupling with boronic acid IV in the presence of a base, such as Na2CO3, in a suitable solvent, such as DME, to give chloropyridine V.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1F
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(3-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.34-7.52 (m, 3H), 6.83-6.91 (m, 2H), 5.21 (s, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.368 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H15F6NO3S, 474.1 (M−H). found 474.1.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:45]([O:47][CH2:48][C:49]([Cl:52])([Cl:51])[Cl:50])=[O:46]>C(Cl)Cl>[CH2:2]([O:4][C:5]([C:7]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[C:45]([O:47][CH2:48][C:49]([Cl:52])([Cl:51])[Cl:50])=[O:46])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a 0° C. solution of 3.0 g (5.83 mmol) (R,R)-5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt and 60 mL CH2Cl2 was added 2.54 mL (1.88 g, 14.57 mmol) of i-Pr2NEt followed by 0.84 mL (1.30 g, 6.12 mmol) of 2,2,2-trichloroethyl chloroformate. After stirring at room temperature for 6 h, the reaction mixture was quenched with 10 mL sat. aq. NaHCO3, and extracted with 3×100 mL Et2O. The combined organics were washed with 1×100 1N HCl, 1×100 mL brine, dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (4/1 to 2/1), gives 3.46 g (5.30 mmol, a 91% yield) of the title compound (Rf =0.32; 2/1 hexanes/EtOAc) as an oily, off-white solid; 1H NMR 300 MHz, CDCl3): δ 1.20-1.39 (complex m, 9H), 2.60-2.80 (m, 1H), 2.80-2.91 (m, 1H), 3.01-3.19 (m, 1H), 3.23-3.31 (m, 1H), 3.40-3.53 (m, 1H), 4.10-4.23 (m, 1H), 4.30-4.42 (complex m, 4H), 4.70-4.89 (m, 3H), 6.65-6.88 (complex m, 4H), 7.15-7.39 (complex m, 3H); MS (ES) m/z (relative intensity): 654 (M+ +H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([P:13]1(=[O:12])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 60 °C

Procedure:
52.5 g (0.3 mol) of 2-chlorobenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. During the dropwise addition, the mixture was cooled to 60° C., and the temperature was then kept at 60°-70° C. When the reaction was complete, 40 ml of toluene were added at 45° C. 92 g (89% of theory) of the abovementioned compound of melting point 108° to 110° C. were obtained.
Reaction SMILES: [CH:1]1([C:7]2[S:23][C:10]3[N:11]=[C:12]([CH3:22])[N:13]=[C:14]([CH2:15][NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C(Cl)Cl>[CH:1]1([C:7]2[S:23][C:10]3[N:11]=[C:12]([CH3:22])[N:13]=[C:14]([CH2:15][N:16]4[C:17]([CH3:20])([CH3:21])[CH2:18][O:19][C:29]4=[O:30])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(CNC(C)(C)CO)c2cc(C3CCCCC3)sc2n1
Solvent: ClCCl
Product: Cc1nc(CN2C(=O)OCC2(C)C)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
To a mixture of 2-{[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]amino}-2-methylpropan-1-ol (55 mg) and DCM was added CDI (40 mg), followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 3-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-4,4-dimethyl-1,3-oxazolidin-2-one (54 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: BrCC1CC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC1CC1

Procedure:
The title compound, MS: m/e=272.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromomethyl-cyclopropane.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]1[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]#[N:23])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]1[CH2:11][CH2:12]1)[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]#[N:23])[CH2:18][CH2:17]1)=[O:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: N#CC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
In a round-bottomed flask, Boc-D-cyclopropylglycine (1.80 g, 8.36 mmol) and piperidine-4-carbonitrile (1.2 g, 10.9 mmol) were dissolved in DMF (30 ml). HATU (3.5 g, 9.2 mmol) and N,N-diisopropylethylamine (2.3 ml, 13.2 mmol) were added and the yellow solution was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 2.72 g (95%) of [(R)-2-(4-cyanopiperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a light yellow oil which was used without further purification.
Reaction SMILES: C([Cl:4])(=O)C.CC(O)C.[NH2:9][CH2:10][C:11]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCCC1>[ClH:4].[NH2:9][CH2:10][C:11]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)Cl
Agent: NCC1(O)CCCCCC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cl
Reaction time: 0.83 h

Procedure:
Acetyl chloride (264 ml) and tetrahydrofuran (191 ml) were charged to a vessel containing 2-propanol (1143 ml) maintaining the temperature at 10° C. to 15° C. 1-(aminomethyl)cycloheptanol (381 g) in tetrahydrofuran (1613 ml) and tetrahydrofuran (381 ml) were charged maintaining the temperature at 10° C. to 15° C. The reaction mixture was stirred for 50 minutes and filtered. The filter cake was washed with premixed tetrahydrofuran/2-propanol [tetrahydrofuran (267 ml), 2-propanol (114 ml)], and tetrahydrofuran (1905 ml). The filter cake was dried at 40° C. for 23 hours to provide the title compound as a colourless solid (464 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[N:16]([CH:17]2[CH2:19][CH2:18]2)[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][C:22]=1[F:29])=[O:7].C[C:31]1(C)O[C@@H](CON)C[O:32]1>>[OH:1][C@H:2]([CH2:31][OH:32])[CH2:3][O:4][NH:5][C:6]([C:8]1[N:16]([CH:17]2[CH2:19][CH2:18]2)[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][C:22]=1[F:29])=[O:7]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: CSc1ccc(Nc2c(C(=O)NOCCO)n(C3CC3)c3ccncc23)c(F)c1
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H](O)CO)n(C3CC3)c3ccncc23)c(F)c1

Procedure:
The title compound was prepared in an analogous fashion to 1-cyclopropyl-3-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-hydroxy-ethoxy)-amide, replacing O-(2-vinyloxy-ethyl)-hydroxylamine with O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine. 1H-NMR (500 MHz, DMSO-d6). δ ppm 11.58 (broad s, 1H), 8.51 (d, J=0.83 Hz, 1H), 8.31 (d, J=5.87 Hz, 1H), 7.56 (dd, J=5.88, 1.20 Hz, 1H), 7.36 (s, 1H), 7.18 (dd, J=12.13, 2.50 Hz, 1H), 6.87 (dd, J=8.46, 2.50 Hz, 1H), 6.45 (t, J=8.99 Hz, 1H), 4.94-4.78 (m, 1H), 4.62-4.53 (m, 1H), 3.94 (dd, J=9.91 Hz, 1H), 3.76 (dd, J=9.85, 7.0 Hz, 1H), 3.73-3.66 (m, 1H), 3.56-3.47 (m, 1H), 3.42-3.31 (m, 2H), 2.41 (s, 3H), 1.15-1.08 (m, 2H), 0.87-0.83 (m, 2H); LC-MS (method C): [M+H]+=447.2, RT=0.479 min.