Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].FC(F)(F)S(O)(=O)=O.ClC(Cl)(Cl)C(=N)O[CH:67]([CH3:69])[CH3:68]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:67]([CH3:69])[CH3:68])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (792 mg in 18 ml 33% methylene chloride in cyclohexane) isopropyl trichloroacetimidate (320 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (75 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 48 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×10 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (158 mg).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:12]([NH:14][C@@H:15]([C:20]([N:22]([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21])[CH2:16][CH2:17][S:18][CH3:19])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[OH:33]O>C(O)(=O)C>[OH2:11].[ClH:1].[NH2:2][C@H:3]([C:12]([NH:14][C@@H:15]([C:20]([N:22]([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:21])[CH2:16][CH2:17][S:18](=[O:33])[CH3:19])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N(C)CCCc1ccccc1
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Product: CN(CCCc1ccccc1)C(=O)[C@@H](CCS(C)=O)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: O

Procedure:
A solution of L-tyrosyl-N-methyl-N-(3-phenylpropyl)-D-methioninamide monohydrochloride (1.3 g.) and aqueous hydrogen peroxide (3%, 2.7 ml.) in acetic acid (10 ml.) was stirred at room temperature for two hours, the concentrated. The residue was evaporated twice from ethyl acetate then purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel (350 g.) using ammonium acetate (0.15%) in methanol-water (3:2) as the eluant (200 ml./min.). A solution of the product (1.0 g.), which appeared in fraction 2 (k'=1.4-3.0), in hydrochloric acid (0.0936N, 30 ml.) and water (30 ml.) was lyophilized, affording L-tyrosyl-N-methyl-N-(3-phenylpropyl)-D-methioninamide S-oxide monohydrochloride monohydrate ([α]D25 +61.4°, c=1, methanol), whose free base is the compound of Formula II wherein Q is Met(O), R1 and R2 are each hydrogen, R4 is (CH2)nY wherein n is 3 and Y is phenyl and R5 is methyl.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([O:26][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: OC1CCCCC1
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Product: CC(C(=O)NC(=O)OC1CCCCC1)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=126° C. and MS: m/e=351.4 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and cyclohexanol.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH3:8].[C:23]([O:22][C:20](=[O:21])[CH2:19][N:15]1[CH2:16][CH2:17][CH:12]([C:7]2[C:6]3[C:10](=[CH:11][C:3]([Br:2])=[CH:4][CH:5]=3)[NH:9][N:8]=2)[CH2:13][CH2:14]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Brc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Product: N
Reaction time: 18 h
Yield: 98.9 %

Procedure:
A mixture of 6-bromo-3-piperidin-4-yl-1H-indazole hydrochloride (500 mg, 1.78 mmol), tert-butyl bromoacetate (0.29 ml, 1.78 mmol), sodium bicarbonate (150 mg, 1.87 mmol), and DMF (10 ml) was stirred at +23° under nitrogen for 18 h The mixture was evaporated in vacuo, treated with aqueous saturated sodium bicarbonate (25 ml), and extracted with ethyl acetate (50 ml). The dried (Na2SO4) organic layer was evaporated in vacuo onto silica gel (Merck 7734). Purification by flash chromatography over silica gel (Merck 9385), eluting with dichloromethane--ethanol--880 ammonia (gradient 967:30:3 to 945:50:5) afforded the title compound as fine white crystals (347 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][CH2:19][CH2:20][CH2:21]Cl)[CH:13]=[CH:14][CH:15]=1.O.C(OCC)(=O)C>C(#N)C>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][CH2:19][CH2:20][CH2:21][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1cccc(CO)c1)OCCCCl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CN1CCN(CCCOC(=O)Nc2cccc(CO)c2)CC1
Temperature: 65 °C

Procedure:
10 g (100 mmol) of N-methylpiperazine are added to a solution of 2.4 g (10 mmol) of 3-chloropropyl (3-hydroxymethylphenyl)carbamate in 10 ml of acetonitrile. The solution is refluxed for 4 h. The mixture is then hydrolysed by addition of water and cooled to about 65° C., and ethyl acetate is added. The mixture is then cooled to room temperature, during which the product is obtained as a solid between the organic and aqueous phases. The product is filtered off and rinsed with water, acetonitrile and ethyl acetate. The product is subsequently dried at 50° C. for several hours; ESI: 308 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1.C[O:13][C:14]#[N:15].Cl[CH2:17]Cl>>[CH3:17][NH:15][C:14]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: NC1CCC(=O)c2sccc21
Reactant: ClCCl
Reactant: COC#N
Product: CNC(=O)NC1CCC(=O)c2sccc21

Procedure:
In 50 ml of dichloromethane, 8.1 g of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is stirred under a nitrogen atmosphere and 2.9 g of methyl cyanate in 50 ml of dichloromethane is added dropwise at below 30° C. After stirring for an hour, the title compound is collected, m.p. 212° C. to 215° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[C:34]([NH2:35])=[C:33]([CH:36]([CH3:38])[CH3:37])[C:25]2[S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1)([CH3:21])[CH3:20]>C1(C)C=CC=C(C)C=1>[CH:19]([C:22]1[C:34]([N:35]2[CH2:2][CH2:3][N:4]=[C:5]2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:33]([CH:36]([CH3:38])[CH3:37])[C:25]2[S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc2c(sc3ccccc32)c(C(C)C)c1N
Reactant: O=C(NCCCl)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)c1cc2c(sc3ccccc32)c(C(C)C)c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
N-(2-chloroethyl)benzamide (4.3 g, 23.42 mmol), was dissolved in 50 mL anhydrous m-xylene under nitrogen. Phosphorus pentachloride (7.31 g, 35.1 mmol) was then carefully added and the mixture heated to reflux under nitrogen for 2 h. The solution was allowed to cooled to room temperature and 2,4-diisopropyldibenzo[b,d]thiophen-3-amine (7.30 g, 25.8 mmol) was added. The reaction mixture was heated to reflux for 20 h. After cooling, the precipitate was filtered and the solid imidazoline product was collected and washed with toluene followed by hexanes. The resultant crude product was dissolved in methylene chloride and washed twice with 50% NaOH. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford title product (4.8 g, 50%).
Reaction SMILES: C(CN)O.[Cl:5][C:6]1[O:10][C:9]([CH:11]2[C:16]3=[C:17]4[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:18]4=[C:19]([C:20]4[S:21][CH:22]=[C:23]([CH3:25])[N:24]=4)[N:15]3[CH2:14][CH:13]([CH2:34][N:35]3C(=O)C4C(=CC=CC=4)C3=O)[O:12]2)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O>[NH2:35][CH2:34][CH:13]1[O:12][CH:11]([C:9]2[O:10][C:6]([Cl:5])=[CH:7][CH:8]=2)[C:16]2=[C:17]3[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:18]3=[C:19]([C:20]3[S:21][CH:22]=[C:23]([CH3:25])[N:24]=3)[N:15]2[CH2:14]1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2C(=O)c4ccccc4C2=O)OC3c2ccc(Cl)o2)n1
Solvent: O
Solvent: NCCO
Solvent: Cc1ccccc1
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN)OC3c2ccc(Cl)o2)n1
Temperature: 70 °C
Reaction time: 6.5 h

Procedure:
Ethanolamine (108 μl, 1.790 mmol) was added to a solution of 10-(5-chlorofuran-2-yl)-8-((1,3-dioxoisoindolin-2-yl)methyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (106 mg, 0.179 mmol) in toluene (3087 μl). The mixture was stirred at 70° C. for 6.5 hours then at room temperature for 16 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with 1M NaOH(aq) (20 ml) passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a mixture of diastereomers.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:32][C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:25]=5[N:24]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([N:29]1[CH2:30][CH2:31][C:25]2[N:24]=[C:23]([C:18]3[C:17]4[C:21](=[CH:22][C:14]([C:7]5[C:6]([CH2:4][CH3:5])=[CH:11][C:10]([OH:12])=[C:9]([F:13])[CH:8]=5)=[CH:15][CH:16]=4)[NH:20][N:19]=3)[NH:32][C:26]=2[CH2:27][CH2:28]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccccc3)CC4)n[nH]c2c1
Temperature: 50 °C
Yield: 10.4 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) in DMF (1 mL), was added benzyl bromide (14.4 mg, 10 μL, 85 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to furnish a brown oil. The crude material was purified by reverse phase chromatography (Method C) to afford 4 mg of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH:22][C:32](=[O:34])[CH3:33])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)c1ccc(-c2nnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of Example 24G (0.044 g, 0.122 mmol) in CH2Cl2 (2 mL) was treated with triethyl amine (0.051 mL, 0.366 mmol) followed by acetyl chloride (0.0173 mL, 0.244 mmol). The reaction was stirred at 25° C. for 1 hour and was concentrated under reduced pressure on a rotary evaporator. The residual white solids (0.075 g) were purified by flash chromatography on silica gel eluting with a solvent gradient of 30% to 50% ethyl acetate in hexanes to provide 0.035 g (71%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (d, J=8.09 Hz, 1H) 7.49 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.99 (dd, J=3.68, 0.74 Hz, 1H) 5.09-5.20 (m, 1 H) 4.63 (heptet, J=5.88 Hz, 1H) 1.85 (s, 3H) 1.45 (d, J=6.99 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10]C)=O.[CH:12]1([C:15]#[N:16])[CH2:14][CH2:13]1.[NH4+].[OH-]>O1CCOCC1.O>[CH:12]1([C:15]2[N:16]=[C:8]([OH:10])[C:4]3[S:5][CH:6]=[CH:7][C:3]=3[N:2]=2)[CH2:14][CH2:13]1
Reactant: N#CC1CC1
Reactant: COC(=O)c1sccc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Oc1nc(C2CC2)nc2ccsc12
Yield: 72 %

Procedure:
Dry HCl gas was bubbled through a solution of methyl 3-aminothiophene-2-carboxylate (1.64 g, 10.4 mmol) and cyclopropanecarbonitrile (27 mL) in dioxane (40 mL) for 1 h then the reaction mixture was diluted with cold water (2 volumes), basified with NH4OH (50 mL) and the resulting solid filtered and air dried to give the title compound (1.44 g, 72%) as a white solid: IR νmax (Nujol)/cm−1 2925, 1664, 1597, 788; NMR δH (400 MHz, DMSO) 1.04 (4H, m), 2.00 (1H, m), 7.20 (1H, d J 5.0 Hz), 8.10 (1H, d, J 5.0 Hz) and 12.60 (1H,br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([Br:26])([CH3:25])C.[C:27]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH2:27][CH2:25][CH2:23][Br:26])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Reactant: CC(C)(Br)Br
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(CCCBr)c(C(=O)OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (200 mg, 0.689 mmol) in DMF (3 mL) under an atmosphere of nitrogen at 0° C. was added dibromopropane (211 μL, 2.067 mmol) and Cs2CO3 (269 mg, 0.827 mmol). The ice bath was removed, and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo, and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted into EtOAc once, and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. the residue was purified by flash column chromatography on silica gel using a 0-50% EtOAc/hexanes gradient elution. Collection and concentration of the appropriate fractions afforded the compound. 1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.40-7.34 (m, 3M), 5.13 (s, 2H), 4.71-4.67 (t, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.39-3.36 (t, 2H), 2.45-2.38 (dt, 2H); ES MS (M+1)=412.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[C@H:4]([CH2:20][OH:21])[CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:21][CH2:20][C@@H:4]1[CH2:3][C:2]([F:1])([F:22])[CH2:6][N:5]1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:18])([F:19])[F:17])[CH:8]=1)(=[O:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CO)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol (275 mg, 0.84 mmol) in anhydrous DCM was added triethylamine (171 mg, 235 μL, 1.7 mmol) followed by methane sulfonyl chloride (106 mg, 72 μL, 0.93 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with DCM and quenched with 3 mL saturated NaHCO3. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated to obtain (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methyl methanesulfonate as a yellow solid (330 mg, 96%). LC/MS: m/z 405 (M+H)+ at 1.71 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:10][C@@H:9]2[CH2:11][C@H:6]1[CH2:7][N:8]2C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:10][C@@H:9]2[CH2:11][C@H:6]1[CH2:7][NH:8]2)=[O:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(N1C[C@@H]2C[C@H]1CN2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
204 mg of the (t-butyl(1S,4S)-5-(trifluoroacetyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [151-1] was dissolved in 3 mL of chloroform, then 3 mL of trifluoroacetic acid was added thereto, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in methanol, and the trifluoroacetic acid was removed through a weak anion-exchange resin. The solvent was distilled off under reduced pressure, and 156 mg of (1S,4S)-2-(trifluoroacetyl)-2,5-diazabicyclo[2.2.1]heptane [151-2] was obtained as a brown oily product.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:21]1([N:27]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccnc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2cccnc2)nc1-c1ccnn1-c1ccccc1
Yield: 19 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-pyridin-3-ylpyridazin-4(1H)-one (crude 260 mg, 0.98 mmol) in 20 mL of methanol was added phenylhydrazine (423 mg, 3.92 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-3-ylpyridazin-4(1H)-one (60 mg, 19% for two steps) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CN(C)CCN(C)C.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>CCOCC.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:24]([OH:29])[OH:25])=[CH:7][C:6]=2[CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc2occc2c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc2cc(Cl)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.8 g (57.7 mmol) 5-chlorobenzofuran in 250 ml dry ether were added 7.32 g (63.0 mmol) tetramethylethylenediamine (TMEDA). The solution was kept below −60° C. under argon, while 37.5 ml of a 1.6M solution of butyllithium in hexane was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of 35.7 g (190 mmol) triisopropyl borate. After warming to room temperature the mixture was quenched with 70 ml 2N hydrochloric acid and stirred for 1 h. The organic layer was washed three times with 30 ml 2N hydrochloric acid, twice with water, and extracted with 2N sodium hydroxide solution, successively. The alkaline aqueous layer was brought to pH5 and extracted with tert.-butylmethylether. All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the pale yellow crystalline boronic acid which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N.[NH:6]=C=O.N[C:10]([NH:12][C:13](N)=[O:14])=[O:11]>>[NH:1]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[NH:4][C:2]1=[O:3].[NH3:6]
Reactant: N=C=O
Reactant: NC(=O)NC(N)=O
Reactant: NC(N)=O
Agent: N
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1

Procedure:
The selective control over pH may be accomplished using any of a variety of well-known buffering systems known in the art. One such buffering system utilizes urea thermal decomposition (i.e., pyrolysis) to increase pH to the desired value. The pyrolysis of urea is well known, and has been described in, for instance, Study of the Urea Decomposition (Pyrolysis) Reaction and Importance to Cyanuric Acid Production, Peter M. Shaber, et al., American Laboratory (August 1999), which is incorporated herein in its entirety by reference thereto for all purposes. For instance, to initiate the pyrolysis reaction, urea is first heated to its melting point of approximately 135° C. With continued heating to approximately 150° C., the urea is vaporized (Eq. 1) and is then decomposed into ammonia and isocyanic acid (Eq. 2). The urea also reacts with the isocyanic acid byproduct to form biuret (Eq. 3). H2N—CO—NH2(m)+heat=H2N—CO—NH2(g)  (1) H2N—CO—NH2(g)+heat NH3(g)+HNCO(g)  (2) H2N—CO—NH2(m)+HNCO(g)H2N—CO—NH—CO—NH2(s)  (3) Upon further heating, e.g., to about 175° C., the biuret referenced above reacts with isocyanic acid to form cyanuric acid and ammonia (Eq. 4), as well as ammelide and water (Eq. 5). H2N—CO—NH—CO—NH2(m)+HNCO(g)CYA(s)+NH3(g)  (4) H2N—CO—NH—CO—NH2(m)+HNCO(g)ammelide(s)+H2O(g)  (5) As the temperature is further increased, other reactions begin to occur. For instance, biuret may decompose back into urea and isocyanic acid. The urea produced is unstable at higher temperatures, and thus, will further decompose into ammonia and isocyanic acid. Urea and the byproducts of the pyrolysis reaction will continue to react and further decompose as the reaction mixture is heated.