Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[CH3:15][C:16]1[N:21]=[C:20]([C:22](O)=O)[CH:19]=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:17]=1>>[CH3:22][C:20]1[N:21]=[C:16]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[CH:17]=[C:18]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[CH:19]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C(=O)O)n1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cccc(S(N)(=O)=O)c3)no2)n1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.115 g, 0.53 mmol) and 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example D.11) (0.10 g, 0.36 mmol) according to the general procedure V. Obtained as an off-white solid (0.080 g, 49%). MS (ISP) 461.0 [(M+H)+]; mp 277° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl.O1CCOCC1>C(O)(=O)C.[Zn]>[NH2:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(N)cc1C(=O)O
Temperature: 30 °C
Reaction time: 2 h
Yield: 204.9 %

Procedure:
Cyclobranyl ester of 2-methoxy-5-nitrobenzoic acid (25.0 g, 0.040 mole) prepared according to the procedure of Example 172 was suspended in acetic acid (1 l), and thereto 6N-HCl-dioxane (21 ml) and zinc powder (25.0 g) were added. The mixture was stirred at 30° C. for 2 hours. After the reaction, zinc powder was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was extracted with chloroform. The extracts were washed successively with water and saturated aqueous NaHCO3 solution, then dried, concentrated, and the residue was recrystallized from chloroform-ethanol (1:2, v/v), giving cyclobranyl ester of 5-amino-2-methoxybenzoic acid (13.7 g) in a 57.5% yield. m.p. 193°-195° C.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:24]([F:27])([F:26])[F:25])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=1[C:24]([F:27])([F:25])[F:26])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-fluoro-2-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ PPM 0.89 (t, 3 H) 1.28-1.37 (m, 2 H) 1.56-1.63 (m, 2 H) 2.18 (s, 3 H) 2.21 (s, 3 H) 3.90-3.97 (m, 2 H) 5.99 (2, 1 H) 7.36-7.44 (m, 2 H) 7.79-7.83 (m, 1 H); MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc(N2C(=O)CCCC2c2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: CC(=O)Nc1ccc(N2C(=O)CCCC2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 2.42 g of 1-(4-aminophenyl)-6-(3,4-dichlorophenyl)-2-piperidone in 20 ml of chloroform were added 5 ml of acetic anhydride and 0.5 ml of pyridine, and the mixture was stirred at room temperature for 30 minutes and then at 80° C. for 30 minutes. The reaction mixture was cooled and diluted with isopropyl ether. The crystals precipitated were filtered and recrystallized from a mixture of ethanol and dimethylformamide to give 2.69 g of 1-(4-acetylaminophenyl)-6-(3,4-dichlorophenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[N:20]=[C:21]([O:22]C)[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Agent: Cl
Solvent: C1COCCO1
Product: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c(=O)[nH]1
Temperature: 105 °C
Reaction time: 23 h
Yield: 82 %

Procedure:
Under argon gas, 7-[4-(4-fluorobenzoyl)benzyl]-4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (6.75 g) was dissolved in dioxane (45 ml) followed by addition of 4,4'-thiobis(6-t-butyl-m-cresol) (75 mg). Then, 0.5N-hydrochloric acid (12 ml) was added and the mixture was stirred at 105° C for 23 hours. Thereafter, 0.5N-hydrochloric acid (12 ml) was further added and the mixture was stirred at the same temperature as above for 22 hours. Then, 1N-hydrochloric acid (3 ml) and dioxane (6 ml) were added and the mixture was further stirred at the same temperature for 24 hours. This reaction mixture was allowed to stand at room temperature and the resulting crystals were collected by filtration, rinsed with methanol, DME, and ether, and finally dried to provide the title compound (5.35 g).
Reaction SMILES: F[CH:2](F)[C:3](O)([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[CH3:10])C(F)(F)F.CC(=O)C(=O)CC>>[F:11][C:9]([F:12])([C:8]([F:14])([F:13])[CH2:3][CH3:2])[CH3:10]
Reactant: CC(F)(F)C(F)(F)C(O)(C(F)F)C(F)(F)F
Agent: CCC(=O)C(C)=O
Product: CCC(F)(F)C(C)(F)F

Procedure:
As another example, 2-difluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol may be prepared by fluorinating commercially available 2,3-pentanedione to form 2,2,3,3-tetrafluoropentane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-pentene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-pentene to form 2-trifluoromethyl-1,3,3,4,4-pentafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoro-1-pentene which may then be reacted with sulfuric acid and then water to form 2-difluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([Cl:15])=[C:5]([C:7]2([NH2:14])[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1.[C:16]([O-:19])([O-])=[O:17].[Na+].[Na+].ClC([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=O>C1(C)C=CC=CC=1>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][NH:14][C:16](=[O:17])[O-:19])=[CH:27][CH:28]=1)([O-:34])=[O:33].[CH:1]1[CH:2]=[CH:3][C:4]([Cl:15])=[C:5]([C:7]2([NH2:14])[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: NC1(c2ccccc2Cl)CCCCC1=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C([O-])NOc1ccc([N+](=O)[O-])cc1
Temperature: 85 °C

Procedure:
To a mixture of norketamine (0.05 g, 0.22 mmol) in anhydrous toluene (2 mL) and Na2CO3 (0.082 g) was added a solution of para-nitrophenyl chloroformate (0.129 g, 0.64 mmol) in anhydrous toluene (2 mL). After heating for 8 hours at 85° C., the reaction mixture was cooled to room temperature and filtered. Toluene was evaporated under vacuum and the reaction mixture was diluted with dichloromethane (DCM). The DCM layer was washed 6 times with 50% aqueous NaHCO3 solution to remove the para-nitrophenol side-product and then with brine. The DCM layer was then dried over anhydrous sodium sulfate, filtered, concentrated under vacuum to afford the para-nitrophenoxycarbamate of norketamine as a pale solid. 1H-NMR (CDCl3): δ 8.17 (2H, dd), 7.87 (1H, d), 7.37 (3H, m) 7.23 (2H, dd), 3.84 (1H, d), 2.55-1.71 (8H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][NH:15][C:12]2=[CH:13][N:14]=1.[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[C:28]([CH2:33][CH3:34])[N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[Cl:25][C:26]1[N:31]=[C:30]([N:15]2[C:12]3=[CH:13][N:14]=[C:9]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:8])[CH:10]=[C:11]3[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16]2)[CH:29]=[C:28]([CH2:33][CH3:34])[N:27]=1
Reactant: CCC(CC)C(=O)c1c[nH]c2cnc(-c3c(C)cccc3C)cc12
Reactant: CCc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(-n2cc(C(=O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-[5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (200 mg, 0.62 mmol), 2,4-dichloro-6-ethyl-pyrimidine (221 mg, 1.25 mmol), Cs2CO3 (305 mg, 0.93 mmol), and DMF (3 mL) is stirred for 4 h at room temperature. The mixture is diluted with EtOAc (10 mL), and the obtained solution is washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one as colorless oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Na].[NH2:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][Cl:15])[N:8]=1>CO>[NH2:6][C:7]1[N:8]=[C:9]([CH2:14][Cl:15])[CH:10]=[C:11]([N:3]([CH3:4])[CH3:2])[N:12]=1
Reactant: CNC
Reactant: Nc1nc(Cl)cc(CCl)n1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN(C)c1cc(CCl)nc(N)n1

Procedure:
8.1 Parts of dimethylamine hydrochloride was added to a solution of 2.3 parts of sodium in 20 parts of methanol. The resulting mixture was added dropwise with stirring over about 10 minutes to a solution of 9.9 parts of 2-amino-4-chloro-6-chloromethylpyrimidine in 50 parts of methanol. The reaction was monitored by TLC and when reaction was complete the solvent was evaporated and the residue stirred with about 20 parts of water. The solid obtained was filtered and dried. The product was purified by chromatography on silica, eluted with ethyl acetate, followed by sublimation at 110° C./0.04 mb to give 2-amino-4-chloromethyl-6-dimethylaminopyrimidine m.p. 127°-129° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH:11](Br)[CH2:12]Br)=[CH:4][N:3]=1.[OH-].[K+]>>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([C:11]#[CH:12])=[CH:4][N:3]=1
Reactant: Cc1ncc(C(Br)CBr)c(CO)c1O
Agent: [K+]
Agent: [OH-]
Product: C#Cc1cnc(C)c(O)c1CO

Procedure:
The oily product from Step A was refluxed in 15 ml. of 10% (w/v) ethanolic potassium hydroxide under nitrogen for 10 minutes. After cooling the solvent was evaporated. The residue was extracted with 2×20 ml. of hot isopropanol which was then filtered and evaporated to give solid 2-methyl-3-hydroxy-4-hydroxymethyl-5-ethynylpyridine, m.p. 170°-171° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])=[O:8])[CH2:3][CH2:2]1.CCN(CC)CC.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:17])([F:18])[F:19])[CH2:3][CH2:2]1)[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccccc1OC(F)(F)F)C1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of piperidin-4-yl-(2-trifluoromethoxy-phenyl)-methanone in 5 mL of acetonitrile was added Et3N (0.3 mL, 2.4 mmol, 2 eq.), followed by ethyl 2-bromoacetate (0.14 mL, 1.3 mmol, 1.1 eq.) added dropwise and heated at 85° C. overnight. After 18 h, the reaction mixture was concentrated in vacuo, diluted with saturated NaHCO3 (100 mL) and extracted with ethyl acetate (3×50 mL). The combine organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a dark oil. This oil was purified by silica gel column chromatography (30-50% ethyl acetate/heptane) to give the title as a light brown oil (0.36 g, 85%). Exact mass calculated for C18H22F3N1O4 360.1. MS (ESI) m/z 360.7 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[CH:13]=[CH:12]2)C1C=CC=CC=1.B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]=1
Reactant: Clc1cccc(Cl)c1-c1ccc2cc(OCc3ccccc3)ccc2n1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 6-(benzyloxy)-2-(2,6-dichlorophenyl)quinoline 19 (2.5 g) in CH2Cl2 (20 ml) are added, at 0° C., 20 ml of BBr3 (1 M in CH2Cl2). The solution is stirred for 1 h at room temperature. Water (20 ml) is added and the resulting solution is alkalinized with 1 N NaOH. The aqueous phase is extracted with AcOEt (3×20 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated. 2-(2,6-dichlorophenyl)-6-quinolinol 20 is obtained as a yellow solid and is used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:19]1([C:25]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]3[CH2:30][NH:31][CH2:32][CH2:33][N:28]3[C:27](=[O:34])[O:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.C(N(C(C)C)CC)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:31]2[CH2:32][CH2:33][N:28]3[C:27](=[O:34])[O:26][C:25]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:29]3[CH2:30]2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 4-fluorocinnamic acid (50 mg, 0.30 mmol) in tetrahydrofuran (1 mL) were sequentially added oxalyl chloride (46 mg, 0.36 mmol) and N,N-dimethylformamide (one drop), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. A solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (60 mg, 0.20 mmol) in tetrahydrofuran (1.5 mL) and diisopropylethylamine (0.3 mL) were sequentially added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from ethyl acetate-diisopropyl ether to obtain the title compound (32 mg, yield 36%).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH:12](Cl)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C.C(OCC)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: COc1ccc(O)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Oc1ccc(OC)cc1)Oc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Sodium (5.4 g) is dissolved in absolute ethanol (160 cc). 4-Methoxyphenol (29.2 g) dissolved in absolute ethanol (20 cc) is added. The mixture is stirred for 1 hour at ambient temperature. Ethyl 2,2-dichloro-acetate (20 g) dissolved in absolute ethanol (20 cc) is then added and the mixture is heated under reflux for 20 hours. The ethanol is driven off under reduced pressure (20 mmHg) at 40° C. and the residue is taken up in diethyl ether (100 cc). The organic phase is washed with 0.1 N sodium hydroxide solution (100 cc) and with water (2×100 cc) and is then dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methoxyphenoxy)-acetate (30 g) is thus obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[C:16]([C:21]#[C:22][Si](C)(C)C)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[OH:27]S(O)(=O)=O.O>CC(C)=O>[C:21]([C:16]1[C:17]([F:20])=[C:18]([F:19])[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:27])[CH3:22]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F

Procedure:
A mixture of methyl 2-(2-fluorophenylamino)-3,4-difluoro-5-((trimethylsilyl)ethynyl)benzoate (9 mmol, 3.5 g), HgSO4 (9 mmol, 2.67 g), and cone. H2SO4 (18 mmol, 0.96 ml) in acetone:H2O (70:12 ml) was refluxed at 65° C. overnight. The mixture was concentrated, diluted with EtOAc, and washed with water and brine. The organic fractions are combined, dried over MgSO4 and concentrated under reduced pressure. The crude material (brown solid) was triturated with MeOH and the precipitate was filtered, washed with additional MeOH and dried to yield the desired product in 60% (1.78 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([N:11]([CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=3[CH:16]=2)[CH:12]=O)=[C:4]([F:26])[CH:3]=1.CC(O)=O>[Fe].CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]2[N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[CH:12]=[N:8][C:6]=2[CH:7]=1
Reactant: CSc1nc2ccc(CN(C=O)c3c(F)cc(Br)cc3[N+](=O)[O-])cc2s1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Temperature: 80 °C
Yield: 0 %

Procedure:
To a stirred mixture of N-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide (4.8 g, 10.55 mmol) from the previous step, HOAc (15 mL) and EtOH (50 mL) at rt was added portionwise iron powder (1.77 g, 31.65 mmol). The mixture was heated at 80° C. for 2.5 h. After cooling to rt, the mixture was partitioned between saturated aq NaHCO3 and a 10:1 mixture of EtOAc and MeOH. The biphasic mixture was filtered through Celite, and the layers of the filtrate were separated. The aqueous layer was extracted with a 10:1 mixture of EtOAc and MeOH. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residual solid was purified by trituration with diethyl ether to afford 6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.39 mg, 39%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.87 (m, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.75 (m, 1H), 7.30-7.34 (m, 2H), 5.66 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 408 and 410 (M+H)+.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:24])[NH:9][CH2:10][CH2:11][N:12]([SH:23])[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-])=O)([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].C(OCC)(=O)C>[Cl-].[Na+].O.C(Cl)Cl.Cl[Ni]Cl>[C:3]([O:7][C:8](=[O:24])[NH:9][CH2:10][CH2:11][N:12]([SH:23])[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[NH2:20])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1ccc([N+](=O)[O-])c(N(S)CCNC(=O)OC(C)(C)C)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N)c(N(S)CCNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 500 mL round bottom flash equipped with a stir bar was charged with MeOH (200 mL), [2-(5-methyl-sulfanyl-2-nitro-phenylamino)-ethyl]-carbamic acid tert-butyl ester (5 g, 0.02 mol) and NiCl2 (19 g, 0.05 mol) and cooled to 0° C. NaBH4 (1.7 g, 0.05 mol) was added (in four equal portions) to the reaction mixture over a 1 h period. Once the addition was complete the reaction mixture was stirred for an additional 2 h. Brine (100 mL) and ethyl acetate (200 mL) were added to the reaction mixture. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×100 mL). The organic phases were combined and washed with H2O (3×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give a black residue. The crude product was dissolved in 100 mL of CH2Cl2 and separated into two 100 mL round (50 mL in each) and both were concentrated under reduced pressure and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45](O)=[O:46])=[CH:41][CH:40]=2)[S:33]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:43][CH2:44][C:45]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:46])=[CH:48][CH:49]=2)[S:33]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 72.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate (1.66 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.99 g).
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:18]1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:18]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1cncc(C2CCNC2)c1
Product: CCCC[C@@H](C(=O)N1CCC(c2cccnc2)C1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 3-pyrrolidin-3-yl-pyridine A-5 according to General Procedure B.