Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (1 g, 5 mmol), in anhydrous CH2Cl2 (10 mL) under argon were added ethane sulfonyl chloride (0.57 mL, 5.99 mmol) and Pyridine (0.60 mL, 7.5 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (3×10 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid. 1H NMR (CDCl3) δ: 1.23 (t, J=7.5 Hz, 3 H), 1.52 (d, J=6.8 Hz, 3 H), 2.77 (q, J=14, 7.5 Hz, 2 H), 4.61–4.72 (m, 2 H), 7.24 (d, J=8.3 Hz, 2 H), 7.51 (d, J=8.3 Hz, 2 H). ESIMS (MH+): 293.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@@:8]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)([CH2:7][CH2:6][N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCn2ccnc2)(c2ccc(F)cc2)OC1=O
Yield: 1.2 %

Procedure:
A mixture of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 0.43 mmol), imidazole (44 mg, 0.65 mmol), K2CO3 (178.7 mg, 1.29 mmol) in acetonitrile (4 mL) was heated to reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-[(S)-1-(2′,4′-difluoro-biphenyl-4-yl)-ethyl]-6-(4-fluoro-phenyl)-6-(2-imidazol-1-yl-ethyl)-[1,3]oxazinan-2-one (2.5 mg, 1.2%). LC-MS Method 2 tR=2.14, min, m/z=506; 1H NMR (CDCl3): 1.51 (d, 3H), 2.16-2.63 (m, 7H), 2.94 (m, 2H), 3.91 (m, 1H), 4.32 (m, 1H), 5.66 (m, 1H), 6.25 (m, 1H), 6.81-6.90 (m, 2H), 6.94-7.08 (m, 5H), 7.14-7.26 (m, 6H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16]CC2C=CC=CC=2)[C:10]=1[C:24](=[O:26])[CH3:25])C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([CH:39]=O)[CH:33]=[CH:32]2>>[OH:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[C:10]=1[C:24](=[O:26])[CH2:25][CH2:39][C:34]1[CH:33]=[CH:32][C:31]2[CH2:30][CH:29]([O:28][CH3:27])[CH2:38][CH2:37][C:36]=2[CH:35]=1
Reactant: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Reactant: COc1ccc2cc(C=O)ccc2c1
Product: COC1CCc2cc(CCC(=O)c3c(O)cc(C)cc3O)ccc2C1

Procedure:
Intermediate 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treated with 6-methoxynaphthalene-2-carbaldehyde as described in Example 1, Part B. Subsequent catalytic hydrogenation as described in Example 1, Part C, provided 1-(2,6-dihydroxy-4-methyl-phenyl)-3-(6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one as a by-product. Further treatment of this by-product as described in Example 1, Part D and E, afforded the title compound. 1HNMR (300 MHz, CD3COCD3) δ 7.2-7.0(m, 2H), 6.95-6.85(m 3H), 6.6(s, 1H), 5.6(s, 1H), 5.27(d, J=7 Hz, 1H), 3.95-3.85(m, 1H), 3.75-3.55(m, 6H), 3.37(s, 3H), 3.3-3.2(m, 1H), 3.1-2.6(m, 8H), 2.05(s, 3H). MS: m/z (MH+) 499.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12](Cl)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:32][OH:33]>>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12]([O:33][CH3:32])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCCCCCCCCCc1nc(Cl)nc(C)c1OCc1ccccc1
Reactant: CO
Agent: [Na]
Product: COCOCCCCCCCCCCc1nc(OC)nc(C)c1OCc1ccccc1

Procedure:
To a stirred solution containing 41.0 mg (0.09 mmol) of 5-(benzyloxy)-2-chloro-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidine in 5 mL of anhydrous methanol were added 22 mg (0.94 mmol) of sodium. The mixture was then stirred at reflux for 16 h. The reaction was quenched with water and poured into 50 mL of water. The mixture was extracted with two 50-mL portions of ethyl acetate. The combined organic solution was washed with one 50-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (2×6 cm). Elution with 1:1 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 30 mg (74%); silica gel TLC Rf 0.65 (1:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.24 (br m, 12H), 1.55 (quint, 2H, J=6.8 Hz), 1.68 (quint, 2H, J=7.6 Hz), 2.37 (s, 3H), 2.65 (dd, 2H, J=7.6, 7.6 Hz), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.93 (s, 3H), 4.59 (s, 2H), 4.83 (s, 2H) and 7.37 (m, 5H); 13C NMR (CDCl3) δ 19.21, 26.16, 27.85, 29.36, 29.40, 29.51, 29.53, 29.71, 31.71, 54.69, 55.02, 67.85, 75.80, 96.36, 127.49, 128.38, 128.38, 128.63, 128.63, 136.50, 145.14, 160.61, 162.38 and 165.87; mass spectrum (APCI), m/z (M+H)+431.2910 (C25H39N2O4 requires 431.2910).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9][C:10](=[O:12])[CH3:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(=O)NCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)NCC(=NNC(N)=S)c1ccccc1
Yield: 78 %

Procedure:
Thiosemicarbazide (1.98 g, 20 mmol) was added to a solution of N-(2-oxo-2-phenyl-ethyl)-acetamide (3.84 g, 20 mmol, prepared in the previous step, in 70 ml of methanol plus 5.4 ml of 1N HCl plus 5.0 ml of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration and dried to give 3.9 g (78%) of the title compound as a white solid, mp 208-211° C.
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn:6]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:6].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:6].[Zn+2:6]
Reactant: [Zn]
Agent: O=P([O-])([O-])[O-]
Product: [Zn+2]
Reaction time: 1 h

Procedure:
For example, when the phosphor is coated with Zn3 (PO4)2, the following method can be employed. To a prescribed amount of phosphor, an aqueous phosphate solution necessary for the surface treatment previously determined is added and the resulting suspended mixture is warmed to about 30° to about 60° C. with stirring for several tens minutes. Subsequently an aqueous solution of a zinc salt containing zinc ions in stoichiometrically equivalent amount or 2 to 3 times in excess comparing with the amount of the phosphate group in the mixture is added to the mixture and the pH of the system is adjusted to about 4 to 9 with stirring for several minutes and thereafter the resulting mixture is allowed to stand for about 1 hour. Thus the phosphor substantially coated with zinc phosphate can be obtained. The thus coated phosphor is taken out of the water, washed with water and dried to give a surface treated phosphor. As the aqueous solution of phosphate salt, it is preferable to use an about 10% aqueous solution of phosphoric acid, or water soluble sodium or potassium phosphate, either monobasic, dibasic or tribasic. As the aqueous solution of a zinc salt, it is preferable to use an about 10% aqueous solution of zinc sulfate, zinc nitrate, and the like.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH:27]1([C:32](O)=O)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:32]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)C1CCCC1
Product: CON=C1C[C@@H](c2noc(C3CCCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and cyclopentanecarboxylic acid, the title compound was obtained in 62% purity by HPLC. MS(ESI+): m/z=431.1.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]([CH:53]([CH3:55])[CH3:54])[CH2:41][C@H:42]([C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([C@H:42]([C:43](=[O:44])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)[CH2:41][N:40]([CH:53]([CH3:54])[CH3:55])[C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:47][CH:48]=1
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.111 mL, 0.636 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.070 g, 0.159 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0543 g, 0.159 mmol, see Example B) and O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluronium tetrafluoroborate (“TBTU”) (0.0613 g, 0.191 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was then directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.044 g, 48%). MS ESI (+) m/z 503.4 detected.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[Cl:10][C:4]1[N:3]=[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: C1COCCN1
Reactant: COc1cc(Cl)nc(Cl)c1
Product: COc1cc(Cl)nc(N2CCOCC2)c1
Temperature: 130 °C
Yield: 43 %

Procedure:
A mixture of 2,6-dichloro-4-methoxypyridine (1.0 equiv.) and morpholine (20 equiv.) were heated to 130° C. for 40 min in the microwave. The reaction mixture was centrifuged and the soluble portion was removed from solids. Water was added to the soluble portion which resulted in precipitation of product. This mixture was centrifuged and the soluble portion was discarded. The remaining solids were partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give 4-(6-chloro-4-methoxypyridin-2-yl)morpholine in 43% yield. LCMS (m/z) (M+H)=229.1, Rt=0.76 min.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[C:16]#[CH:15]
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: C#CCBr
Product: C#CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with propargyl bromide to give 5.0 g of product, mp 144° C after recrystallization from methylene chloride-ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
6-hydroxy-2-naphthoic acid (3.0 g) and triethylamine (2.4 g) were dissolved in 30 ml of dichloromethane. Nonanoyl chloride (4.0 g) and dimethylaminopyridine (0.2 g) were added to the solution, and the mixture was stirred at room temperature for about 20 hours. Dilute hydrochloric acid was added, and the organic layer was separated in a separating funnel. The solvent was removed by evaporation, and the residue was dried after washing with n-hexane to give 4.5 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:48]=[N+:49]=[N-:50].[Na+].Cl>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:27][CH2:28][C:29]([F:33])([F:32])[CH2:30][CH2:31]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]4[NH:50][N:49]=[N:48][N:21]=4)=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C#N)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a solution of 0.16 g (0.29 mmol) 4-[2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-ethoxy]-3,5-dimethyl-benzonitrile in 4 ml o-xylene were added 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide and heated for 21 h at 150° C. (oil bath temperature). Another 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide were added and the reaction mixture was heated for another 4 h and after cooling down to room temperature stirred 3 days. The reaction was then poured onto 1M aqueous hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The solid was suspended in acetonitrile, filtered, washed with acetonitrile and dried under high vacuum. White solid (77%). MS (Turbo Spray): m/z=599.194 [M+H].
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].CO>[NH2:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1
Reactant: COC(=O)c1cc(F)c(NCc2ccccc2)cc1Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)c(N)cc1Br
Yield: 73.8 %

Procedure:
A suspension of the methyl 4-(benzylamino)-2-bromo-5-fluorobenzoate (2.4 g, 7.10 mmol) in acetic acid was treated with 10% palladium on charcoal (250 mg) and stirred at room temperature under 2 bar hydrogen for 18 hours. The reaction mixture was then diluted with methanol, filtered through celite and evaporated to low volume. The residue was suspended in water (50 mL) and basified with 5% sodium carbonate solution then was extracted with ethyl acetate (2×). The combined organic phases were dried (sodium sulfate) and evaporated to a sandy solid. This crude solid was dissolved in the methanol and passed down an SCX cartridge. Evaporation of the methanol eluents gave the title compound (1.3 g).
Reaction SMILES: OC[CH:3]([S:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1(C)C=CC=CC=1>>[C:9]1([CH:4]2[CH2:3][S:10][C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=3[O:18]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:19]=1
Reactant: Cc1ccccc1
Reactant: OCC(Sc1cc(O)ccc1O)c1ccccc1
Product: Oc1ccc2c(c1)SCC(c1ccccc1)O2

Procedure:
A solution of 2-(2-hydroxy-1-phenylethylsulfanyl)benzene-1,4-diol (0.83 g) in dry toluene (60 ml) was stirred with Amberlyst 15 (0.5 g) at 60° C. until disappearance of the starting material. After the mixture was filtered and solvent evaporated the crude product was purified by column chromatography using heptane-ethyl acetate (1:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 7.41 (m, 4H), 7.33-7.40 (m, 1H), 6.81 (d, 1H, J 8.7 Hz), 6.61 (d, 1H, J 3.0 Hz), 6.51 (dd, 1H, J 8.7, 3.0 Hz), 5.10 (dd, 1H, J 9.6, 1.9 Hz), 3.28 (dd, 1H, J 13.0, 9.6 Hz), 3.06 (dd, 1H, J 13.0, 1.9 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.C([N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([CH:19]2[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:30])=[CH:24][CH:25]=1
Reactant: Brc1ccccn1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(F)cc1)(c1ccccn1)C1CCNCC1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 36.3 g (0.23 mole) of 2-bromopyridine in 500 ml of anhydrous tetrahydrofuran (THF) at -65° C. was added 88 ml (0.22 mole) of a commercial solution of 2.5M n-butyllithium in hexane at such a rate that the temperature did not exceed -60° C. The dark solution was stirred at -65° C. for 1 hr and then treated dropwise with a solution of 24.9 g (0.1 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 250 ml of THF at such a rate that the temperature did not exceed -60° C. The mixture was stirred for 1 hr at -65° C. and overnight at ambient temperature. The dark mixture was poured into 2 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted once with a 500-ml portion of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 500 ml of a 4% sodium hydroxide solution, 250 ml of water, and 250 ml brine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:45])[CH3:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:45][CH2:43][CH3:44])=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCN
Product: CCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethylamine (2.0 mol/L THF solution, 60.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-ethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.6 mg).
Reaction SMILES: [Sn](Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[CH3:16])[CH:10]=[CH:11][CH:12]=1)([O-])=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:13]([NH:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)[CH3:16])[C:9]2[CH:8]=[C:7]([NH2:4])[CH:12]=[CH:11][CH:10]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C(NC(C)c2ccc(OC(C)=O)cc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(NC(C)c2ccc(OC(C)=O)cc2)c2cccc(N)c2)cc1
Yield: 91.5 %

Procedure:
Tin (II) chloride (451 mg) was added to a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[1-(4-acetoxyphenyl)ethyl]amine (200 mg) [prepared as described in step (a) above] in ethanol (10 ml). The mixture was heated under reflux for 1 hour. At the end of this time, ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture. The insoluble material was removed by filtration. The filtrate was separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer and extract were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. It was then concentrated by evaporation under reduced pressure, to afford the title compound (170 mg) as a yellow oil.
Reaction SMILES: ClCC(Cl)=[O:4].[S:6]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:8]2=[CH:7]1)=[O:12]>>[S:6]1[CH:10]=[C:9]([C:11]([OH:4])=[O:12])[C:8]([C:14]([OH:13])=[O:15])=[CH:7]1
Reactant: O=C1OC(=O)c2cscc21
Reactant: O=C(Cl)CCl
Product: O=C(O)c1cscc1C(=O)O

Procedure:
A 25.5 g. portion of 3,4-thiophenedicarboxylic acid {prepared by the method of Kornfeld and Jones [J. Org. Chem., 19, 1671 (1954)]} is suspended in 50 ml. of chloroacetyl chloride and is heated at reflux for 5.5 hours. Excess chloroacetyl chloride is distilled under reduced pressure. The residue is poured into 100 ml. of water and the resulting crystals are collected to yield 16.1 g. of 3,4-thiophenedicarboxylic anhydride.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: CC(C)(CN)c1nc(-c2ccccc2)n[nH]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccccc2)n[nH]1
Yield: 25 %

Procedure:
This compound was synthesized from 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 25%). 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.29-8.27 (d, J=7.8 Hz, 1H), 8.06-7.97 (m, 3H), 7.71-7.67 (t, J=8.7 Hz, 1H), 7.50-7.41 (m, 3H), 3.75 (s, 2H), 1.54-1.51 (m, 6H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.2 (M+H)+.