Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[C:9](=[NH:32])([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:16][CH:15]=1)[NH2:10].[OH:33]/[CH:34]=[C:35](/[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1)\[C:36](OC)=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]3[NH:10][CH:36]=[C:35]([CH2:40][C:41]4[CH:46]=[N:45][CH:44]=[N:43][CH:42]=4)[C:34](=[O:33])[N:32]=3)=[CH:19][CH:18]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 21.1 %

Procedure:
An alternative synthesis was provided to prepare the compound of Example 20. A suspension of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (17.29 g, 34.0 mmol), methyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (5.5 g, 28.3 mmol) and potassium acetate (5.56 g, 56.6 mmol) in toluene (200 mL) was stirred at room temperature for 2 min. and then heated to reflux for 3 h. The mixture was filtered off and concentrated to dryness, which was then dissolved in DMF and purified by MDAP with TFA. The purified fractions were combined and neutrallized with ammonia. The organic solvent was removed under vacuo and the water layer was extracted with EA. The organic layer was combined and dried over Na2SO4 which was concentrated to give the white solid. The solid was recrystallized in MeCN to afford the title compound (3.0 g, 21.06% yield) LCMS: rt=3.43 min, [M+H+]=503.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:26]=[O:27])=[CH:9][N:8]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)OCn1ccc2cc(Br)cnc21
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)OCn1cc(C=O)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-pyrrolo[2,3-b]pyridin-1-ylmethyl ester (4.09 g, 13.14 mmol) was dissolved in N,N-dimethylformamide (4 ml), and phosphorus oxy-chloride (1.33 ml) was added. The reaction mixture was stirred for 18 hours at 50° C. The reaction was quenched with saturated, aqueous sodium bicarbonate, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography (0-100% (ethyl acetate in hexanes) to give 3.65 g (82%) of 2,2-dimethyl-propionic acid 5-bromo-3-formyl-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 338.0+340.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[CH2:26]([NH2:29])[C:27]#[CH:28].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH2:26][C:27]#[CH:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: C#CCN
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Preparation 19, 8 -chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-chloro-1-[[(2-propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 24 8 -Nitro-1-[[(2-propynyl)amino]methyl]-6(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15]C4(CCN(C)CC4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@H:32]2CNC[CH2:36][N:31]2[C:30](=[O:37])[O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH2:36][N:31]4[C:30](=[O:37])[O:29][CH2:28][C@H:32]4[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1OC[C@H]2CNCCN12
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: O=C1OC[C@H]2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CCN12

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using (R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (71 mg, 50%).
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)[CH3:8].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:7]([CH3:8])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:1]1
Reactant: COC(=O)CCCC(C)=O
Reactant: OCC(S)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCCC1(C)OCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-dimercaptopropanol (2.8 g, 0.022 mol), methyl 4-acetylbutyrate (3.2 g, 0.022 mol) and boron trifluoride etherate (0.62 ml) in methylene chloride (70 ml). The crude product was chromatographed on silica gel using 10% ethyl acetate/hexane as eluent to give 0.91 g (16.5%) of product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:34]1([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:39])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-5-isobutylamino-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M125) (0.43 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (260 mg, 76%).
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([NH2:33])[CH:27]=4)[C:15](=[O:25])[N:16]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][N:10]=2)=CC=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH2:33][C:28]1[CH:27]=[C:26]([C:14]2[C:15](=[O:25])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2ccc(F)c(N)c2)c(=O)n3-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1ccc(F)c(N)c1)c(=O)n2-c1ccccc1
Yield: 46.2 %

Procedure:
A suspension of Example A35 (2.5 g, 7 mmol) in 4-methoxybenzylmethylamine (5 mL) was heated at 160° C. for 3 h. The reaction mixture was cooled to RT and diluted with ether. The resultant white precipitate was collected by filtration and dried to obtained 7-((4-methoxybenzyl)(methyl)amino)3-(3-amino-4-fluorophenyl)-1-phenyl-1,6-naphthyridin-2(1H)-one (3 g, 77%), which was used in the next step without further purification. A suspension of 7-((4-methoxybenzyl)(methyl)amino)-3-(3-amino-4-fluorophenyl)-1-phenyl-1,6-naphthyridin-2(1H)-one (3.0 g, 6 mmol) in mixture of CF3CO2H and CH2Cl2 (3:7, 30 mL) was heated at reflux overnight. Then the solvent was removed under reduced pressure and the residue was recrystallized (EtOAc-petroleum ether) to give 3-(3-amino-4-fluorophenyl)-7-(methylamino)-1-phenyl-1,6-naphthyridin-2(1H)-one (1 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1 H), 7.88 (s, 1 h), 7.60-7.50 (m, 3 H), 7.31-7.29 (m, 2 H), 7.10-6.75 (m, 4H), 5.26 (s, 1 H), 5.08 (s, 2 H), 2.63 (br s, 3 H); MS (ESI) m/z: 361.3 [M+H]+.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[CH:6][C:5]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28](C(=O)C(F)(F)F)[CH2:27][CH2:26]2)(=[O:22])=[O:21]>C(O)C.O>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[CH:6][C:5]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27][CH2:26]2)(=[O:22])=[O:21]
Reactant: O=C(N1CCc2cc(S(=O)(=O)Nc3ccc(OCCc4ccccn4)cc3F)ccc2C1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(Nc1ccc(OCCc2ccccn2)cc1F)c1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Powdered potassium hydroxide (2 mg, 36.2 μmol) was added to a solution of N-{2-fluoro-4-[2-(pyridin-2-yl)ethoxy]phenyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (10 mg) in an ethanol-water mixture (9:1) (2 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure and water was added thereto. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Thereafter, the desiccant was filtered off, followed by concentration under reduced pressure to afford the title compound as a colorless solid (10 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[Br:25]Br>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:9][CH2:10][C:11]2[CH:19]=[C:18]([Br:25])[CH:17]=[CH:16][C:12]=2[NH:13][C:14]1=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A round-bottom flask containing ((R)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-carbamic acid tert-butyl ester (0.338 g, 1.20 mmol) was fitted with a stirbar and septa. Acetic acid (glacial, 5 mL) and bromine (0.37 g, 2.3 mmol) were added, in that order, giving a solution that was stirred at room temperature for 1.5 hours. The reaction was then poured into ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 solution (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (10% to 50% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:13]([C:16]1[CH:21]=[C:20]([Sn](C)(C)C)[N:19]=[C:18]([C:26]#[N:27])[N:17]=1)[CH2:14][CH3:15]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:6]2[CH:7]=[C:8]([C:20]3[CH:21]=[C:16]([CH2:13][CH2:14][CH3:15])[N:17]=[C:18]([C:26]#[N:27])[N:19]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Reactant: Ic1cccc(C2CCCC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(-c2cccc(C3CCCC3)c2)nc(C#N)n1
Temperature: 80 °C
Yield: 36 %

Procedure:
A mixture of 1-cyclopentyl-3-iodo-benzene (158 mg, 0.58 mmol), 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (150 mg, 0.48 mmol) and PdCl2(PPh3)2 (34 mg, 0.05 mmol) in dry DMF (3 ml) was heated to 80° C. for 6 h under a nitrogen atmosphere. More catalyst (40 mg, 0.06 mmol) was added and the mixture was heated for 12 h at 80° C. The solvent was removed under reduced pressure and the residue was partitioned between water (5 ml) and AcOEt (5 ml). The aqueous layer was extracted twice with AcOEt (2×5 ml). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 272 mg of crude product which was purified by silica gel chromatography (eluent:cyclohexane/AcOEt 95/5) to give the above titled compound: 51 mg, yield: 36%, HPLC: 98%.
Reaction SMILES: [S:1]1(=[O:18])(=[O:17])[N:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH:4]2[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:1]1(=[O:17])(=[O:18])[N:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(CCS2(=O)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCC2CNCCN21
Yield: 83.9 %

Procedure:
tert-butyl tetrahydro-2H-isothiazolo[2,3-a]pyrazine-5(3H)-carboxylate 1,1-dioxide (200 mg, 0.724 mmol) in DCM (3 mL) was treated with TFA (1.059 mL, 13.75 mmol) at room temperature for 1 h. Solvent was evaporated and the residue was redissolved in DCM and concentrated again. The crude was purified by SCX cartridge, loading with MeOH, washed with additional MeOH. Product was recovered eluting with 2M NH3 in MeOH. Solvent evaporation give hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (107 mg)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH2:8][CH2:9][CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=1.[C-:23]#[N:24].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH2:8][CH2:9][CH2:10][C:23]#[N:24])[CH:7]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cc(Br)ccc2F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCc1cc(Br)ccc1F
Temperature: 80 °C
Yield: 101.9 %

Procedure:
A solution of Toluene-4-sulfonic acid 3-(5-bromo-2-fluoro-phenyl)-propyl ester (0.59 g, 1.5 mmol) in anhydrous DMSO (3.0 mL) was added sodium cyanide (0.112 g, 2.3 mmol) and heated to 80° C. for 12 h. The mixture was cooled and partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine (1×15 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (10-20% Ethyl acetate/petroleum ether) gave the title compound as a clear oil (0.37 g, 99%), and was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([Cl:37])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][CH:9]=1>CCO>[Cl:1][C:2]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([Cl:37])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@@H:15]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Solvent: CCO
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1

Procedure:
Racemic trans-1-tert-butyl 3-ethyl 4-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}-piperidine-1,3-dicarboxylate was resolved by a Chiral Pak AD preparative column (15% EtOH in Hex) to afford two enantiomers. 1-tert-Butyl 3-ethyl (3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1,3-dicarboxylate was eluted as the slower enantiomer (retention time=26.5 min).
Reaction SMILES: [P:1]([O:19][C:20]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49])([CH:27]([C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].Br[Si](C)(C)C.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[P:1]([OH:11])([OH:3])([O:19][C:20]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49])([CH:27]([C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[O:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(Cn1cncn1)(OP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(F)cc1F
Agent: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(Cn1cncn1)(OP(=O)(O)O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
A solution of the compound of step (a) (310 mg, 0.44 mmol) in methylene chloride (5 ml) was cooled to 0° C. and then treated with bromotrimethylsilane (303 mg, 1.98 mmol) and pyridine (215 mg, 3.70 mmol). The resulting mixture was stirred at 0° C. for 3 hours and then quenched with water (1 ml) containing sodium hydroxide (115 mg, 2.87 mmol). A yellow precipitate was formed, which was isolated by filtration and then partitioned between dilute sulphuric acid and methylene chloride. The organic phase was washed with brine, dried (MgSO4) and the solvent evaporated to give the title compound as a pale yellow solid (80 mg, 35%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].[CH3:11]I>CO>[CH3:11][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
2-Mercaptophenol (0.80 mL, 7.9 mmol) was added to a solution of sodium hydroxide (0.290 g, 7.2 mmol) in methanol (5.0 mL). The resulting light green solution was stirred for 30 minutes before methyl iodide (0.45 mL, 7.2 mmol) was added carefully over 1 minute. The reaction was stirred at ambient temperature for 2 hours, and was evaporated to dryness. The residue was partitioned between ether and water. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to yield an oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.49 (dd, J=7.6 Hz, J′=1.6 Hz, 1H), 7.25 (m, 1H), 6.98 (dd, J=8.2 Hz, J′=1.4 Hz, 1H), 6.88 (td, J=7.4 Hz, J′=1.3 Hz, 1H), 6.65 (bs, 1H), 2.33 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23](O)=[C:22]([Cl:25])[C:21]([Cl:26])=[C:20]([Cl:27])[C:19]=1[Cl:28].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:17][C:18]1[C:23]([O:15][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[C:22]([Cl:25])[C:21]([Cl:26])=[C:20]([Cl:27])[C:19]=1[Cl:28]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Yield: 81.4 %

Procedure:
t-Butoxycarbonyl-D-methionine (20 g, 80.22 mmol) is added to a solution of pentachlorophenol (21.37 g) and dicyclohexylcarbodiimide (16.55 g, 80.3 mmol) in ethyl acetate (200 ml). After 2.5 h the solution is filtered after 2.5 h and the filtrate evaporated to dryness. The residue is recrystallised from hot methanol to give t-butoxycarbonyl-D-methionine pentachlorophenyl ester (32.5 g, 81.4%). A sample of this material (1.03 g, 2.14 mmol) is dissolved in DMF (10 ml) and to this solution is added hydroxylamine hydrochloride (0.149 g, 2.16 mmol) and diisopropylethylamine (0.91 ml, 5.2 mmol). After 16 h at room temperature the solvent is removed by evaporation and the residue partitioned between diethyl ether and 5% aqueous sodium carbonate. The aqueous phase (together with an insoluble oil which forms at the interface) is acidified by addition of citric acid to pH 6 and the product extracted twice with ethyl acetate. The combined ethyl acetate phases are washed successively with water and brine then dried over sodium sulfate. After the solvent is removed by evaporation the product is obtained as a crystalline solid by addition of a small amount of diethyl ether. A sample is recrystallised from ethyl acetate/hexane. mp 133°-134° C. 1H NMR δ (CDCl3) 8.50 (1H, broad s, --NH--), 5.58 (1H, m, urethane NH), 4.23 (1H, m, α--CH), 2.56 (H, m, γCH2), 2.09 (3H, s, S--CH3), 2.03 (1H, m, CH--CHAHB), 1.91 (1H, m, CH--CHAHB), 1.43 (9H, s, C(CH3)3); m/e (EI+) 265 (M+1), (CI-) 2.63 (M-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:29]=[C:12]3[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(O)[CH2:14][CH2:15][CH2:16][CH2:17][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:29]=[C:12]3[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])=[CH:14][CH2:15][CH2:16][CH2:17][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1
Reactant: COc1nc(-c2nc3n(n2)CCCCC3(O)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1nc(-c2nc3n(n2)CCCC=C3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Yield: 7.3 %

Procedure:
A mixture of 2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-9-(2-trifluoromethylphenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-9-ol obtained in Example 181 (49 mg), p-toluenesulfonic acid (76 mg) and toluene (7 mL) was heated under reflux for two hours. Ethyl acetate and saturated sodium bicarbonate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The solid was removed by filtration. The mother liquor was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-methanol system) to obtain 3.46 mg of the title compound as an oil. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:20][NH:21][O:22][CH3:23]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:17])[N:21]([O:22][CH3:23])[CH3:20])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(CCOc2ccc(N=C=O)cc2)cc1
Reactant: CNOC
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
Into a solution of 5.5 g of 4-(4-methylphenethyloxy)phenyl isocyanate in 100 ml of benzene, a solution of 2 g of N,O-dimethylhydroxylamine in 50 ml of benzene is added dropwise at 20° to 30° C. After the addition is finished, the reaction mixture is continuously stirred at the same temperature for an additional 30 minutes. Thereafter, the solvent is removed under reduced pressure, and the residue is recrystallized from ethanol to obtain 7.4 g of N'-[4-(4-methylphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 82°-83° C.
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1B(O)O>>[CH:1]([N:14]1[CH:19]=[C:18]([C:25]2[CH:24]=[CH:23][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccc2ccccc2c1
Yield: 82.4 %

Procedure:
The title compound: was obtained according to the procedure described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.11 g, 0.27 mmol) and 2-naphthylboronic acid (0.07 g, 0.41 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.09 g, 80%) as an off-white solid. 1H NMR (400 MHz, CDCl3): 7.17 (s, 1H), 7.24-7.27 (m, 2H), 7.36 (s, 1H), 7.38-7.47 (m, 10H), 7.76-7.88 (m, 5H), 8.28 for s, 1H). MS (ESI) m/z: 405 [M-H]+.