Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.Cl.NO.[N:18]1C=CC=CC=1.[Se](=O)=O.S([O-])([O-])(=O)=O.[Mg+2]>CN(C)C=O>[C:1]([C:3]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:18]
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
10.15 g (53.4 mmol) of 3-formyl-7-nitro-1H-indole was dissolved in 150 ml of dimethylformamide, and 3.93 g (56.0 mmol) of hydroxylamine hydrochloride and 4.5 ml (55.6 mmol) of pyridine were added thereto. After heating under stirring at 70 to 80° C. for 2 hours, 6.3 g (56.8 mmol) of selenium dioxide and about 5 g of magnesium sulfate were added thereto. After heating at 70 to 80° C. for further 2.5 hours, the insoluble matters were filtered off and the filtrate was concentrated. Water was added thereto, and the resulting crystals were collected by filteration and successively washed with water and ethyl ether. The crystals were dissolved in a mixed solution of tetrahydrofuran and acetone, and the insoluble matters were filtered off. After concentrating the filtrate, ethyl acetate was added to the residue and the crystals were collected by filtration, to give 8.61 g of the title compound.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[Cl:13][C:14]1[C:15]([NH:21][NH2:22])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1>C(OC(O)C)C>[NH2:12][C:11]1[N:21]([C:15]2[C:14]([Cl:13])=[CH:19][C:18]([Cl:20])=[CH:17][N:16]=2)[N:22]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CCOC(C)O
Product: CCOC(=O)c1cnn(-c2ncc(Cl)cc2Cl)c1N
Reaction time: 2 h
Yield: 98.3 %

Procedure:
16.9 g (0.1 mole) of ethyl ethoxymethylenecyanoacetate and 17.8 g (0.1 mole) of 3,5-dichloro-pyrid-2-ylhydrazine in 150 ml of ethoxyethanol are stirred at 80° C. for 5 hours and then at 120° C. for a further 2 hours. For working up, the solvent is removed in vacuo. 29.6 g (98% of theory) of 5-amino-1-(3,5-dichloro-pyrid-2-yl)-4-ethoxycarbonyl-pyrazole of melting point 98°-101° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>CO.[C].[Pd]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([F:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(F)cc(N)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a solution of methyl 5-fluoro-2-methyl-3-nitrobenzoate (3.20 g, 15.0 mmol) in methanol (150 mL) was added palladium-carbon powder (320 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.47 g, yield 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH3:21])=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cnccc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cnccc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-4-pyridinecarboxylic acid as starting materials, MS (LC/MS): 422.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:31]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:25]=3[N:24]([CH3:39])[C:23]=2[N:40]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].[ClH:58]>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:58].[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26][C:25]=4[N:24]([CH3:39])[C:23]=3[N:40]=2)[C:8](=[O:12])[CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5F)cc4=O)nc31)CCNCC2
Temperature: 135 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (83 mg, 0.35 mmol), tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (146 mg, 0.384 mmol), CuI (80 mg, 0.42 mmol), 8-hydroxyquinoline (10 mg, 0.070 mmol) and Cs2CO3 (125 mg, 0.384 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a cream colored solid. 2 N HCl in Et2O (100 mL) was added to a solution of the cream colored solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et2O (9 mL) was added, the resulting suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 40° C. for 12 h to afford 40 mg (24%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 9.04 (br s, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.67 (dd, J=15.5, 8.5 Hz, 1H), 7.35 (ddd, J=10.0, 10.0, 2.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.18 (ddd, J=8.5, 8.5, 2.0 Hz, 1H), 6.14 (dd, J=8.0, 3.0 Hz, 1H), 6.06 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.59-3.32 (m, 4H), 3.31-3.26 (m, 2H), 3.17-3.14 (m, 2H); ESI MS m/z 437 [M+H]+.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:16])[CH:3](OC(=O)C)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[F:11]>C(O)(=O)C.[Zn]>[Cl:16][C:2]([Cl:1])=[CH:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[F:11]
Reactant: CC(=O)OC(c1cc(F)ccc1F)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Fc1ccc(F)c(C=C(Cl)Cl)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
The title compound of Example 36.1 (18.2 g, 59 mmol) was dissolved in acetic acid (95 mL) in a 500 mL two neck flask. Zinc powder (7.6 g, 116 mmol) was added in one portion. The temperature of the mixture reached 60° C. The reaction was complete after 30 min. The mixture was filtered and pentane (200 mL) and water (200 mL) were added. The phases were separated and the water phase washed once again with pentane. The organic phases were combined and washed with sodium hydrogen carbonate solution until pH was neutral, dried (MgSO4), filtered and concentration on reduced-pressure evaporator to give a yellow oil. Yield 82%, 10.2 g.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CCBr)cc1
Product: Cc1ccc(CCN(N=C(c2ccccc2)c2ccccc2)c2ccc(C)cc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 4-methylphenethylbromide (278 mg, 1.4 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[C:4]([Cl:17])[N:3]=1.[CH2:18](Cl)Cl.F[B-](F)(F)F.[H+].C[Si](C=[N+]=[N-])(C)C>CCOC(C)=O.CCCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:18])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[C:4]([Cl:17])[N:3]=1
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CO[C@H](C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Yield: 31 %

Procedure:
To a round bottom flask was added (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (364 mg, 1.31 mmol) followed by the addition of DCM (10.8 mL). The reaction mixture was then cooled to 0° C. in a (ice/water bath) under nitrogen. To this cold solution was added tetrafluoroboric acid (0.20 mL, 1.31 mmol, 50% aqueous solution) followed by the addition of trimethylsilyldiazomethane (1.96 mL, 3.93 mmol, 2 M in hexanes) divided into 3 portions added 20 min apart. A second addition of trimethylsilyldiazomethane in hexanes (1.96 mL, 3.93 mmol, 2 M in hexanes) again divided into 3 portions added 20 min apart was added. Reaction mixture was quenched with water and diluted with DCM. Phases paritioned and the aqueous phase extracted with DCM. Organic phases combined and washed with brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (119 mg, 0.41 mmol, 31% yield) as a colorless oil which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.09 (d, J=6.50 Hz, 3H) 3.44 (s, 3H) 4.09 (qd, J=6.46, 4.16 Hz, 1H) 4.38-4.49 (m, 1H) 4.60 (dd, J=9.49, 2.84 Hz, 1H) 4.99 (ddd, J=8.50, 3.95, 2.96 Hz, 1H) 8.23 (s, 1H). LCMS m/z 292.0 (M+H)+, Rt 0.86 min.
Reaction SMILES: [C:1]([CH2:5][NH:6][NH2:7])([F:4])([F:3])[F:2].C([O:10][C:11]([C:13]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18](=O)[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=O)C.C(O)(=O)C>C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([N:15]1[CH2:16][CH2:17][C:18]2=[N:7][N:6]([CH2:5][C:1]([F:4])([F:3])[F:2])[C:11](=[O:10])[C:13]2([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1(Cc2ccccn2)CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NNCC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2=NN(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Temperature: 70 °C
Yield: 110.6 %

Procedure:
A 70% aqueous solution of CF3CH2NHNH2 (325 mL, 1.986 mol) (obtained from Aldrich) was extracted with toluene (3×1200 mL). To a solution of the product from step A (600 g, 1.655 mol) in toluene (900 mL) was first added the combined toluene extracts containing the anhydrous 2,2,2-trifluoroethyl hydrazine, followed by acetic acid (121.4 g, 1.986 mol). The reaction mixture was heated at about 70° C. for about 2 hours, then another toluene extraction of 70% aqueous 2,2,2-trifluoroethyl hydrazine (50 g) was added. The reaction mixture was heated at about 80° C. for about 3.5 hours, cooled to room temperature and diluted with saturated aqueous NaHCO3 (2 L). The toluene layer was separated and washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give an oil (754.8 g). Crystallization from methanol/water afforded the desired product as a white solid (609.5 g). 1H-NMR (CDCl3) δ 1.50 (s, 9H), 2.53 (d, 1H), 2.70 (br s, 2H), 2.88 (br s, 1H), 3.31 (m, 2H), 3.97 (m, 1H), 4.19 (m, 1H), 4.46 (br s, 1H), 4.63 (br s, 1H), 7.06 (m, 2H), 7.51 (m, 1H), 8.34 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:17]1[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=1)=[O:8]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
5-Chloro-2,4-difluorobenzoic acid (1.17 g, 6.08 mmol) was dissolved in thionyl chloride (5.0 mL) and heated at 60° C. under a nitrogen atmosphere for 5 hours. The reaction mixture was concentrated in vacuo and azeotroped with DCM (2×10 mL) and toluene (10 mL). Then the crude was dissolved in DCM (15 mL) and cooled to 0° C. 4-Methylphenol (0.665 g, 6.15 mmol) and triethylamine (1.05 mL, 7.53 mmol) in DCM (10 mL) were added dropwise and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (10 mL), then washed with saturated aqueous solution of sodium hydrogencarbonate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude solid. The solid was triturated in the minimum amount of heptanes to afford the title compound as a white solid (1.20 g, 69%):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]([O:19]C)=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:21]([CH3:24])(=[O:23])=[O:22])=[N:14]3)=[CH:4][CH:3]=1.[Li+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]([OH:19])=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:21]([CH3:24])(=[O:22])=[O:23])=[N:14]3)=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(Sc3ccc(F)cc3)c(O)ccc2n1

Procedure:
5-(4-Fluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 102 (1 g) was dissolved in 5 mL DMF and treated with 500 mg LiCl and refluxed overnight. This mixture was partitioned between dilute HCl and EtOAc. The product was purified by chromatography (1:1 EtOAc/hexane) to provide 5-(4-fluoro-phenylsulfanyl)-2-methanesulfonyl-quinolin-6-ol; 401 (800 mg); ([M+H]+)=350.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:58]=[CH:57][C:37]3[NH:38][C:39]([C:41]4[C:49]5[C:44](=[CH:45][CH:46]=[C:47]([NH2:50])[CH:48]=5)[N:43]([CH:51]5[CH2:56][CH2:55][CH2:54][CH2:53][O:52]5)[N:42]=4)=[N:40][C:36]=3[CH:35]=2)[CH2:30][CH2:29]1>CN(C=O)C>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:50][C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][O:52]1)[N:42]=[C:41]2[C:39]1[NH:38][C:37]2[CH:57]=[CH:58][C:34]([N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)=[CH:35][C:36]=2[N:40]=1)=[O:6]
Reactant: Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CC1(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
2,2-Difluorocyclopropanecarboxylic acid (6.42 mg, 0.053 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (9.69 mg, 0.072 mmol), EDC (13.74 mg, 0.072 mmol) and sodium bicarbonate (4.01 mg, 0.048 mmol) was added to a solution of 3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.048 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Upon purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (15 mg). 1H NMR: (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.76-7.72 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.05 (m, 2H), 5.86 (dd, 1H, J=2.4 and 9.6 Hz), 3.99 (m, 1H), 3.86 (m, 4H), 3.81 (m, 1H), 3.16 (m, 4H), 2.77-2.69 (m, 1H), 2.61 (m, 1H), 2.18-2.08 (m, 3H), 1.89-1.80 (m, 2H), 1.74-1.68 (m, 2H); ESI-MS [M+H]+: 523.2.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1.[K+].[Br-]>O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH2:33][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-(4-chlorobenzyl)piperazine, yield 86%. White crystals, m.p. 232–234° C.; 1H NMR (DMSO-d6): δ 11.92 (br s, 1H), 3 AB-systems: 7.83–7.62 (t-like, 4H) and 7.62–7.48 (d-like, 2H), and 7.32–7.07 (m, 6H); 4.51–3.95 (br s at 4.37 ppm overlapping with br signal at 4.2 ppm, 4H), 3.95–2.95 (br m, 9H: 6H+water); IR (KBr): ν 1717 (C═O) cm−1.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3=[N:9][C:10]([F:13])=[CH:11][CH:12]=[C:7]3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].[Br:16]N1C(=O)CCC1=O>CN(C=O)C>[Br:16][C:6]1[C:7]2[C:8](=[N:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: Fc1ccc2ccn(C3CC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(Br)cn(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 1-cyclopropyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (2.03 g, 11.52 mmol) in DMF (38 mL) is added sodium hydroxide (0.506 g, 12.67 mmol), followed by N-bromosuccinimide (2.26 g, 12.67 mmol) portionwise over 5 minutes, resulting in an exothermic reaction (28° C.). The mixture is stirred at room temperature for 15 min., and further sodium hydroxide (46.1 mg, 1.15 mmol) and N-bromosuccinimide (0.205 g, 1.15 mmol) are added. Stirring is continued at room temperature for 30 min. Further sodium hydroxide (46.1 mg, 1.15 mmol) and N-bromosuccinimide (0.205 g, 1.15 mmol) are added. The reaction mixture is stirred at room temperature for 16 h and then poured onto brine (ca. 500 mL) and extracted with CHCl3 (ca. 2×300 mL). The organic layers are combined and dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil, which is purified by column chromatography on silica, eluting with 0 to 100% DCM in isohexane, to give the title compound as a white powder (2.32 g, 9.10 mmol). MS (m/z): 255/257 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[N:7][C:6](=O)[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([N:24]([C:6]2[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[N:3]([CH2:14][CH2:15][CH3:16])[C:2](=[O:1])[CH2:8][N:7]=2)[CH3:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CNC1CCCCC1
Reactant: CCCn1c(=O)cnc(=O)c2ccccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCN1C(=O)CN=C(N(C)C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dioxo-1-propyl-1,4-benzodiazepine (see Example 8) (10.0 g, 0.046 mol) in dichloromethane (200 ml) was added phosphorus pentachloride (11.5 g, 0.055 mol) in dichloromethane (400 ml) over 30 minutes. The reaction mixture was stirred at room temperature for 2 h then the solvent was removed under vacuum and the resulting oil was dried under high vacuum. The oil was redissolved in dichloromethane (200 ml) and a solution of N-methylcyclohexylamine (15.6 g, 0.138 mol) in dichloromethane (125 ml) was added dropwise. When the addition was complete, the reaction mixture was allowed to stir for 18 hours. The solution was washed with saturated sodium hydrogen carbonate solution (100 ml), and the aqueous layer was reextracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (100 ml), dried (sodium sulphate), filtered and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and purified by flash column chromatography, eluted with 2% methanol/0.5% 0.88 ammonia solution/dichloromethane (3 litres) then 5% methanol/0.5% 0.88 ammonia solution/dichloromethane. Yield=15.8 g (quantitative), as a brown oil. 1H NMR (DMSO)δ0.68 (3H, t, J=7.3 Hz), 1.84-2.04 (3H, m), 2.72 (3H, s), 3.40 (1H, d, J=12.2 Hz), 3.54 (1H, m), 3.88 (1H, d, J= 12.2 Hz), 4.22 (1H, m), 7.34 (1H, m), 7.50 (1H, d, J=7.43 Hz), 7.60 (2H, m).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:19][CH3:20])(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+]>>[CH3:17][C:16]1[C:15]([C:14]([O:19][CH3:20])=[O:18])=[CH:10][NH:11][CH:12]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1c[nH]cc1C

Procedure:
By a similar operation as in Reference Example 19 and using p-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate (48.5 g) and potassium tert-butoxide (76.7 g), the title compound was obtained as a pale-yellow solid (yield 16.8 g, 25%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.C([Li])CCC.CON(C)[C:28](=[O:30])[CH3:29].[Cl-].[NH4+]>C1COCC1.O>[Si:13]([O:12][CH:7]([C:4]1[S:3][C:2]([C:28](=[O:30])[CH3:29])=[N:6][CH:5]=1)[C:8]([F:11])([F:10])[F:9])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC(c1cnc(Br)s1)C(F)(F)F
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ncc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In THF (5 mL) was dissolved 2-bromo-5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)thiazole (515 mg, 1.37 mmol) obtained in Step 2. n-Butyllithium (1.65 mol/L solution in n-hexane, 1.24 mL, 2.05 mmol) was added dropwise at −78° C. and the mixture was stirred at −78° C. for 30 minutes. A solution of N-methoxy-N-methylacetamide (1.38 mL, 13.7 mmol) in THF (1 mL) was added to the reaction mixture and the mixture was stirred at −78° C. for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-(5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl) thiazol-2-yl)ethanone (437 mg, 94%).
Reaction SMILES: C(OC(=O)C)(=O)C.[S:8]1[C:12]2=[N:13][C:14]([C:20]([OH:22])=[O:21])=[C:15]([C:17]([OH:19])=O)[CH:16]=[C:11]2[CH:10]=[CH:9]1.N#N.N1C=CC=CC=1>C(COC)OC>[S:8]1[C:12]2=[N:13][C:14]3[C:20](=[O:21])[O:22][C:17](=[O:19])[C:15]=3[CH:16]=[C:11]2[CH:10]=[CH:9]1
Reactant: O=C(O)c1cc2ccsc2nc1C(=O)O
Agent: N#N
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3sccc3cc21
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Acetic anhydride (37.4 g, 0.366 mol) is added to a stirred suspension of thieno[2,3-b]pyridine-5,6-dicarboxylic acid (21.52 g, 0.096 mol) in dimethoxyethane (175 mL) in an inert N2 atmosphere. Upon addition of pyridine (16.78 g, 0.21 mol) at room temperature an exotherm to 45° C. is observed and a homogeneous solution results. The reaction mixture is then stirred at room temperature and the resulting solid filtered off, washed with ether and air dried to give 14.8 g (75%) of thieno[2,3-b]pyridine-5,6-dicarboxylic acid anhydride.