Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:23]([C:22]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:21]=1[O:20][CH:17]([CH3:19])[CH3:18])=[O:24])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1cc2c(cc1OC)C(C)(C)CNC2
Product: COc1cc2c(cc1OC)C(C)(C)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (CA [57553-25-0]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 462.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1N
Product: Brc1ccc2[nH]cnc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4-bromobenzene-1,2-diamine (4.0 g, 21.5 mmol) and formic acid (95%, 100 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to RT and concentrated in vacuo to afford a dark oil. The crude oil was partitioned between EtOAc (500 mL) and NH3/H2O (50 mL). The EtOAc layer was separated and concentrated in vacuo to afford 4.5 g (100%) of 5-bromo-1H-benzo[d]imidazole (78) as brown solid: MS (ESI) m/z=197.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][C:28]([F:29])([F:30])[F:31])[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[C:21]3[CH:36]=[CH:37][CH:38]=[CH:39][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(CC(F)(F)F)c2ccccc2-c2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-(2′,2′,2′-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-M), the title compound was prepared. The reaction was monitored by tlc (Rf=0.15, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 5% MeOH/CHCl3).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
4-Morpholin-4-ylmethyl-benzene-1,2-diamine (1 mol. eq.) and 4-nitro-1H-pyrazole-3-carboxylic acid (1 mol. eq.) were dissolved in dimethylformamide (DMF) (10 vol.). 0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.2 mol. eq.) was added and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated in vacuo until no further solvent was seen to distil. The residue was then dissolved in glacial acetic acid (10 vol.) and heated at 65° C. for 12 hours. The mixture was concentrated in vacuo and then dissolved in water (6 vol.) at 75° C. The black solution was cooled to 0-5° C. over 2 hours during which time a solid was formed. The solid was removed by filtration and the aqueous filtrate was diluted with ethyl acetate (4 vol.) and tetrahydrofuran (2 vol.). Solid NaHCO3 was added slowly to the stirred mixture until no further effervescence was observed and a pH of 6.8 was reached. The mixture was then stirred until a precipitation was observed. After standing the mixture at 0-5° C. for 2 hours, the solid was collected by filtration and washed with water (2 vol.) and ethyl acetate (2 vol.) and dried to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole as a brown solid (40%). (LC/MS (basic method): Rt 1.93, [M−H+]− 327).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:17])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Yield: 52.1 %

Procedure:
A mixture of 5.0 g of 3-methoxy-4-nitrobenzoic acid and 5.0 g of thionyl chloride is heated under argon for 1 hour. The volatiles are removed in vacuo to give 2.85 g of a 3-methoxy-4-nitrobenzoyl chloride as a residue which is dissolved in 50 ml of methylene chloride. To the preceding solution is added with stirring 1.75 g of N,N-diisopropylethylamine followed by 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine. The reaction mixture is stirred under argon for 18 hours and diluted with saturated sodium bicarbonate. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. While boiling, hexane is added to the filtrate to give, upon cooling, 3.39 g of the desired product as a solid, m.p. 191-192° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH2:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[C:24]([CH3:26])[C:23]([C:27](O)=[O:28])=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][C:27]([C:23]2[C:24]([CH3:26])=[N:25][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:21][CH:22]=2)=[O:28])[CH:4]=1)[CH3:2]
Reactant: CCc1cn(N)c2ncccc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2ncccc12
Temperature: 150 °C
Yield: 43.7 %

Procedure:
A mixture of 3-ethyl-pyrrolo[2,3-b]pyridin-1-ylamine (126 mg, 0.78 mmol), 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (180 mg, 0.78 mmol), HATU (356 mg, 0.036 mmol) and DIPEA (302 mg, 2.34 mmol) in DMF (4 mL) is heated at 150° C. for 1 h. The reaction is quenched with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-100% ethyl acetate in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide (128 mg). MS: 376 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.25-8.33 (m, 2H), 8.16 (d, 1H), 8.05 (d, 1H), 7.62 (q, 1H), 7.39-7.48 (m, 2H), 7.16 (dd, 1H), 2.78 (s, 3H), 2.75 (q, 2H), 1.29(t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:33])([F:34])[F:35])[CH:26]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: FC(F)(F)Oc1cccc(CCBr)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2cccc(OC(F)(F)F)c2)c1
Yield: 17 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and. 1-(2-bromo-ethyl)-3-trifluoromethoxy-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-[2-(3-trifluoromethoxy-phenyl)-ethyl]-9H-purin-6-ylamine: Yield 17%, 1H NMR (CD3OD) δ 8.18 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.12-7.10 (m, 2H), 7.04-7.01 (m, 3H), 6.95 (bs, 1H), 4.57 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.24 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 492.1.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[CH2:16]([NH:23][CH2:24][CH2:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:16]([N:23]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8])[CH2:24][CH2:25][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCNCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(OCCN(Cc1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
Triflic anhydride (11.18 g, 6.5 ml, 39 mmol) dissolved in 90 ml of DCM was added drop by drop to a well stirred solution of N-benzyl ethanol amine (2 g, 13.2 mmol) and diisopropylethyl amine (5.1 g, 6.9 ml, 39.7 mmol) in dichloromethane (160 ml) at 0° C. and stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with dichloromethane. Organic layer was washed with water and dried under sodium sulfate. Solvent evaporation under reduced pressure afforded 500 mg of the title compound as a an oil
Reaction SMILES: [CH:1]1([N:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:7](=O)[O:8]C)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH:1]1([N:6]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C:7]2=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N(CCc1cccc(OC)c1)C1CCCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN(C1CCCC1)C2=O

Procedure:
To a solution of methyl cyclopentyl(3-methoxyphenethyl)carbamate (1.39 g, 5 mmol) in POCl3 (20 mL) was added P2O5 (1.4 g, 10 mmol). The reaction mixture was heated at reflux for 2 h. Excess POCl3 was removed under reduced pressure and the residue was quenched with ice water. The mixture was neutralized with Na2CO3 and extracted with ethyl acetate. The organic phase was dried over Na2SO4. Removal of the solvent in vacuo followed by chromato-graphic purification afforded 2-cyclopentyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 1H, J=8.6 Hz), 6.81 (d, 1H, J=8.6 Hz), 6.63 (s, 1H), 5.18-5.14 (m, 1H), 3.85 (t, 1H, J=6.7 Hz), 2.88 (t, 1H, J=6.7 Hz), 1.88-1.70 (m, 2H), 1.64-1.63 (m, 4H), 1.62-1.61 (m, 2H). LC-MS (ESI) Calcd for C15H19NO2 [M+H]+: 246.14. Found: 246.00.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:15][C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:14])=[N:9][C:10]=1[S:12][CH3:13]
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CSc1nc(N)nc(-c2ccco2)c1Cl

Procedure:
From 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine and N-chlorosuccinimide in acetic acid. ES-MS m/e (%): 244 (M{37Cl}+H+, 40), 242 (M{35Cl}+H+, 100).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:28])=[O:27]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a stirring solution of benzyl 4-hydroxy-1-piperidinecarboxylate (3.55 mL, 23.4 mmol, Aldrich) and Et3N (7.18 mL, 51.5 mmol, Aldrich) in CH2Cl2 (25 mL) at room temperature was added a solution of methanesulfonyl chloride (1.99 mL, 25.8 mmol, Acros) in CH2Cl2 (25 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl aqueous solution, H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 7.43 g of the desired product as a yellow oil. MS (ESI) 314 (M+H).
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH2:6]([S:8][C:9]1[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]([CH3:14])[CH3:13])[CH3:7]>C(OCC)C>[BrH:1].[CH3:14][N:12]([CH2:11][C:10]1[C:9]([S:8][CH2:6][CH3:7])=[C:18]([OH:19])[CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCSc1c(CN(C)C)cccc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCSc1c(O)cccc1CN(C)C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
30% Hydrogen bromide in acetic acid (3.6 mL, 18.05 mmol) was added to (2-ethylsulfanyl-3-methoxybenzyl)-dimethylamine (800 mg, 3.55 mmol) and the reaction mixture was heated with stirring at 100° C. After 17 h, the reaction was complete by LC/MS analysis and was then allowed to cool to room temperature. Diethyl ether (100 mL) was added with stirring and after 20 min the orange diethyl ether solution was decanted off. This procedure was repeated until a tan solid precipitated. 3-Dimethylaminomethyl-2-ethylsulfanyl-phenol hydrobromide (770 mg, 100%) was filtered off as a tan solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:40]=[CH:39][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=2)[O:28][CH2:29][C@H:30]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31]2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].C(O)C.O>[Fe].C(Cl)Cl>[NH2:15][C:11]1[C:10]([CH3:18])=[C:9]([N:8]([CH2:19][C:20]2[CH:40]=[CH:39][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=3)[O:28][CH2:29][C@H:30]3[NH:34][C:33](=[O:35])[CH2:32][CH2:31]3)=[CH:22][CH:21]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OC[C@@H]4CCC(=O)N4)c3)cc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@@H]3CCC(=O)N3)c2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the product from Example 278A in a capped test-tube were added iron powder (78.4 mg, 1.4 mmoles), NH4Cl (7.5 mg, 1.4 mmoles), ethyl alcohol (3 mL) and water (1 mL). The reaction mixture was shaken violently at 80° C. overnight. CH2Cl2 (4 mL) was added to extract the product. Then, the reaction mixture was filtered. The CH2Cl2 layer was separated and dried in vaccuo.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:17][CH:16]([O:18][N:20]3[C:24](=[O:25])[C:23]4[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]3=[O:30])[CH2:15]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of N-benzhydrylazetidin-3-ol (1.0 g, 4.18 mmol) in anhydrous THF (66 mL) under nitrogen were added N-hydroxyphthalimide (750 mg, 4.60 mmol) and triphenylphosphine (2.19 g, 8.36 mmol). The reaction mixture was cooled to 0° C. and DEAD (1.52 mL, 8.36 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced. The residue was purified on column chromatography (eluent: pentane/EtOAc 7/3 to 4/6) to give the title compound (600 mg, 37%) as a wax.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(F)c(CN2CCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(CN2CCCC2)c1
Yield: 72.3 %

Procedure:
A mixture of 1-(2-fluoro-5-nitrobenzyl)pyrrolidine (450 mg, 2.007 mmol) in EtOAc (15 mL) was treated with 10% Pd/C (107 mg) and hydrogenated (1 atm) for 3 h. Additional 10% Pd/C (100 mg) was added and the mixture hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 4-fluoro-3-(pyrrolidin-1-ylmethyl)aniline (282 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.75 (dd, J=10.0, 8.7 Hz, 1H), 6.56 (dd, J=6.4, 2.9 Hz, 1H), 6.39 (ddd, J=8.7, 4.3, 2.9 Hz, 1H), 4.85 (s, 2H), 3.44 (d, J=1.5 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H); MS (ESI) m/z: 195.1 [M+H]+.
Reaction SMILES: ClC(OC(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[S:21][CH:20]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:19](=[O:33])[N:18]([CH2:34][C:35]([OH:37])=O)[C:17]=2[CH:38]=1)=[O:12])[CH3:9].CN1CCOCC1.C[Si](C)(C)[O:48][NH2:49].Cl>O1CCCC1>[OH:48][NH:49][C:35](=[O:37])[CH2:34][N:18]1[C:17]2[CH:38]=[C:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH:14]=[CH:15][C:16]=2[S:21][CH:20]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:19]1=[O:33]
Reactant: C[Si](C)(C)ON
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)C(CCCc1ccc(OC)cc1)S2
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)NO)C(=O)C(CCCc1ccc(OC)cc1)S2
Reaction time: 0.42 h

Procedure:
At −15° C., isopropyl chloroformate (2.84 ml) was added dropwise to a solution of {6-(ethoxycarbonyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl}acetic acid (10.64 g) and N-methylmorpholine (3.2 ml) in tetrahydrofuran (200 ml). After the dropwise addition of the whole isopropyl chloroformate, the resulting mixture was stirred for 25 minutes and then O-(trimethylsilyl)hydroxylamine (3.52 ml) was added dropwise thereto. After 3 hours, the reaction mixture was poured into a 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate. The oil layer was washed with a saturated aqueous sodium chloride solution, dehydrated over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel chromatography (hexane/ethyl acetate=2/3 to 1/3). To the resulting yellow oil were added toluene and hexane to effect crystallization. The solid obtained was collected by filtration and concentrated under reduced pressure. Ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (8.24 g) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][CH2:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>O1CCOCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:28]4[CH2:27][CH2:26][NH:25][CH:24]([CH2:23][F:22])[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: FCC1CNCCN1
Solvent: C1COCCO1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNC(CF)C3)c(F)c(F)c2c1=O

Procedure:
In the same manner as described in Example 1, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid, 2-fluoromethylpiperazine, and dioxane was refluxed for 5 hours to give 1-cyclopropyl-5,6,8-trifluoro-7-(3-fluoromethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, which was recrystallized from chloroform, m.p. 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: C1CCNC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCCC2)c2cc[nH]c2n1
Temperature: 70 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.531 mmol), pyrrolidine (0.050 mL, 0.600 mmol) and triethylamine (0.200 mL, 1.43 mmol) in dioxane (4 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give 2-chloro-4-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (116 mg). MS 223.3 and 225.3 (M+H, Cl pattern)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4](Cl)[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4]([O:21][C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[CH:15]=2)[N:3]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: -40 °C
Yield: 90.1 %

Procedure:
To a stirred mixture of 2,4,6-Trichloro-5-isopropyl-pyrimidine (23.68 g, 0.105M), 3,5-dimethylphenol (12.2 g, 0.2M) in anhydrous DMF (200 ml) cooled in a dry ice-acetone bath (−40° C.) under nitrogen atmosphere, was portionwise added 60% sodium hydride (4.2 g, 0.105M). The reaction temperature was then slowly raised to room temperature during 3 hr. The reaction mixture was then diluted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a pale yellow solid. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 28 g (90%) a white solid. m.p. 107-108° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.35 (6H, s), 3.58 (1H, m), 6.72 (2H, s), 6.91 (1H, s).