Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:17])([F:16])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[C:18](OCC)(=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=C>>[F:16][C:5]([F:17])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3][CH2:2][CH:19]([CH2:18][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=[CH2:30])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCCCCBr
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Product: C=CCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the 1-iodo-4,4,5,5,6,6,7,7,7-nonafluoroheptane prepared in Example 1, diethyl malonate and 8-bromooct-1-ene, a procedure analogous to that as shown in Example 3, 4 or 5 was repeated to give ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[F:31])=[O:29]
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1F
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2ccccc2F)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-fluorobenzylamine
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=1)(=[O:3])[NH2:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:49][C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][C@@H:56]1[CH2:60][CH2:59][CH2:58][NH:57]1>CN(C=O)C.C(Cl)Cl>[CH3:49][C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][C@@H:56]1[CH2:60][CH2:59][CH2:58][N:57]1[C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[S:8][CH:7]=2)=[CH:17][CH:16]=1)=[O:15]
Reactant: NC(=O)c1cc(-c2ccc(C(=O)O)cc2)cs1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2csc(C(N)=O)c2)cc1
Yield: 14.4 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 30% DMF/CH2Cl2 using 4-(5-Carbamoyl-thiophen-3-yl)-benzoic acid (360 mg, 1.6 mmol), EDC-HCl (439 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol), DIEA (0.70 mL, 4.0 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (236 mg, 1.4 mmol) to give the title compound (80 mg, 14% yield). MS (ES+) 398.3 (M+H)+
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36]>O1CCCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3n2)cc(OC)c1OC
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 7-iodo-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (6.7 g, 16.29 mmol) in anhydrous tetrahydrofuran (150 ml) was cooled to 0° C. and treated with potassium bis(trimethylsilyl)amide (0.5M in toluene, 35.85 ml, 17.9 mmol) dropwise. After complete addition, the reaction mixture was stirred at room temperature for 1 hour, treated dropwise with chloro-triisopropyl-silane (3.9 ml, 18.4 mmol), and allowed to stir at room temperature for 16 hours. Chloro-triisopropyl-silane (1.0 ml, 4.7 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours, and then at 60° C. for 16 hours. The reaction mixture was partitioned between EtOAc/saturated aqueous NH4Cl. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark solid. The residue was purified by silica gel chromatography using 3-100% EtOAc in hexanes as eluant to provide 7.4 g (80%) of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine as a white solid. MP 156.5-157.2, M+H=568.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].[C:19](O)([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)O
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Temperature: 0 °C

Procedure:
(±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid 3.32 g (13.12 mmol), is dissolved in 15 mL of dichloromethane, cooled to 0° C. and 0.1 g of 4-dimethylaminopyridine (DMAP) added, followed by t-butyl alcohol, and followed by 3.25 g of dicyclohexylcarbodiimide (DCC). This solution is stirred and allowed to slowly warm to room temperature over a 16.5-hour period. TLC shows mainly product, and some slightly lower Rf by-product. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continued four hours. One hundred mL of diethyl ether is added and then filtered. The filtrate is concentrated at reduced pressure. This crude concentrate is chromatographed on silica gel and eluted with 4:1 hexane:ethyl acetate to yield (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5 ]undecane-2-acetate.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: OB(O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Yield: 69.1 %

Procedure:
Ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (1 g, 1.3 eq, 4 mmol) is added to a mixture of 2-chloro-5-pyridine boronic acid (0.48 g, 1 eq, 3.07 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.05 eq, 0.15 mmol) and an aqueous solution of 2 M potassium carbonate (3 ml, 2 eq, 6.14 mmol) in toluene/ethanol (18 ml, 2:1 v/v). The mixture is refluxed overnight and the solvent is evaporated, then taken up in ethyl acetate, and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane 100%) affords 0.6 g of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i97.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][SH:18].CS(O[C@@H:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]1)(=O)=O>CN(C)C=O>[C:32]([O:31][C:30]([NH:29][C@H:26]1[CH2:27][CH2:28][C@H:24]([S:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[O:6][C:2]=2[CH3:1])[CH2:25]1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c(C)o2)cc1
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
To a solution of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (920 mg, 3.49 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) maintained under an inert atmosphere of nitrogen was added cescium camonate (2.3 g). The mixture was stirred for 20 min then tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (1.0 g, 3.58 mmol, 1.02 equiv) was added. The resulting solution was stirred at 35° C. for 50 min then the product was precipitated by the addition of 50 mL water. The precipitate was collected by filtration, washed with water and then dried under vacuum to give 1.37 g (88%) of methyl 4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 447 [M+H]+, 391, 271, 230, 115.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:24]4[CH2:27][CH:26]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:25]4)[N:14]3C3CCCCO3)=[C:10]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[CH:43][C:5]=2[N:4]=1)[CH3:2]>Cl>[NH3:4].[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:24]4[CH2:27][CH:26]([CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH2:25]4)[NH:14]3)=[C:10]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[CH:43][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)n(C3CCCCO3)c2n1
Agent: Cl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)[nH]c2n1
Product: N
Temperature: 25 °C
Reaction time: 48 h
Yield: 116.1 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine (0.28 g, 0.48 mmol) in 1.25 M HCl (10 mL) was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo. The residue was loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, then the desired product was eluted with DCM, 20-80% MeOH in DCM and 10-40% 2 M NH3 in MeOH in DCM. The residue was purified by flash chromatography (Si—PPC, 2 M NH3 in MEOH:DCM, gradient 0:100 to 4:96) followed by (Si—PPC, 2M NH3 in MeOH:EtOAc, gradient 2.5:97.5 to 10:90 then 2 M NH3 in MEOH:DCM, gradient 2:98 to 10:90) to give 422 as a white solid (0.14 g, 59%). LCMS (Method I): RT=2.50 min, [M+H]+ 503.4. 1H NMR (400 MHz, DMSO-d): δ 7.96-7.92 (m, 1 H); 7.64-7.60 (m, 1 H); 7.25-7.20 (m, 2 H); 4.28-4.19 (m, 4 H); 3.83 (dd, J=11.3, 4.3 Hz, 2 H); 3.77 (t, J=4.6 Hz, 2 H); 3.72 (s, 2 H); 3.43-3.38 (m, 7 H); 3.27-3.19 (q, J=7.4 Hz, 2 H); 2.96 (t, J=6.9 Hz, 2 H); 2.19-2.11 (m, 1 H); 1.69-1.57 (m, 1 H); 1.50 (d, J=13.0 Hz, 2 H); 1.31 (t, J=7.4 Hz, 3 H); 1.06 (td, J=12.2, 4.3 Hz, 2 H)
Reaction SMILES: CS(C)(=O)=[O:3].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12](OC(OC)C)=[CH:11][CH:10]=1.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:9]1([CH2:23][CH2:22][C:21]([O:20][CH3:24])=[O:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: COC(C)Oc1ccc(Br)cc1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of dimethylsulfone (42 g, 0.45 mole) in dimethylsulfoxide (225 ml), 60% sodium hydride (17.9 g, 0.45 mole) was added in a small portion at 18°-20° C., stirring was continued at 65°-70° C. for 30 minutes, and then diluted with tetrahydrofuran (225 ml). Then to this mixture, a solution of methyl 3-phenylpropionate (36.6 g, 0.22 mole) obtained in above (1) in tetrahydro-furan (110 ml) was added dropwise at 33°-41° C., and reacted with stirring for 1 hour. After cooling, the reaction mixture was poured into diluted hydrochloric acid, and extracted 5 times with chloroform (100 ml). The organic layer was washed thrice with H2O (200 ml), saturated aqueous sodium bicarbonate (200 ml), then H2O (200 ml), dried over anhydrous MgSO4 and evaporated. The crude solid (60.8 g) was recrystallized from ethyl acetate to afford 24.7 g of 1-methylsulfonyl-4-phenylbutan-2-one as white needles having a melting point of 97.6-°98.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C1C=C([Cl:18])C=C(C(OO)=[O:20])C=1>CC(C)=O>[ClH:18].[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N+:7]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccc(N)n1
Solvent: CC(C)=O
Product: COC(=O)c1cccc(N)[n+]1[O-]
Product: Cl
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Methyl 6-aminopyridine-2-carboxylate (Intermediate 121, 3.3 g, 22 mmol) was dissolved in acetone and to this was added a solution of mCPBA (5.9 g, 23.5 mmol) in acetone. After stirring overnight, the acetone was removed and the residue was suspended in 3 N HCl. The precipitate was filtered off to give the HCl salt (3.57 g, 87%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:16][CH3:17])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[K+].S(=O)(=O)(O)O.O.[C:25]([O-])(O)=O.[Na+]>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:16][CH3:17])[C:13]([O:15][CH3:25])=[O:14])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(C(=O)[O-])c1ccc(-n2cccn2)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(OC)c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a stirred solution of potassium 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate (˜7.55 mmol) in dry MeOH under argon was added sulfuric acid (2.0 mL) dropwise. The mixture was heated at 80° C. for 17 hours. After cooling to room temperature, water was added then the mixture made basic with saturated aqueous NaHCO3 addition. The aqueous phase was extracted with EtOAc and the combined organics were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (20-35% EtOAc-hexanes) provided methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate as a colorless oil (0.88 g, 47% yield for two steps).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1(CC#N)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1cccc(O)c1
Solvent: N#CCc1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(OS(N)(=O)=O)c1
Yield: 85 %

Procedure:
Using the procedure described in Example 56, the title compound was prepared in 85% yield from 10.3 g (0.086 mole) of 3-cyanophenol and 8.3 ml (0.086 mole) of chlorosulfonyl isocyanate in 75 ml of toluene as a white solid, mp 101°-104° C. (benzene-acetonitrile).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.ClC(Cl)(O[C:10](=[O:16])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH:25]([C:27]1[C:32]([I:33])=[C:31]([CH3:34])[CH:30]=[CH:29][N:28]=1)[NH2:26]>ClCCl>[CH:1]1([CH2:4][NH:5][C:10]([NH:26][NH:25][C:27]2[C:32]([I:33])=[C:31]([CH3:34])[CH:30]=[CH:29][N:28]=2)=[O:16])[CH2:3][CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccnc(NN)c1I
Reactant: NCC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(NNC(=O)NCC2CC2)c1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 188.9 %

Procedure:
A solution of cyclopropylmethanamine (0.33 mL, 3.7 mmol) in dichloromethane (2 mL) was added dropwise to a solution of triphosgene (0.39 g, 1.3 mmol) in dichloromethane (15 mL) kept at 0° C. under an argon atmosphere. After 5 minutes, a solution of triethylamine (1.0 mL, 7.2 mmol) in dichloromethane was added dropwise and the mixture was warmed to ambient tempertaure. After stirring two hours, the mixture was cooled to 0° C. and 2-hydrazinyl-3-iodo-4-methylpyridine (preparation 28b, 0.91 g, 3.6 mmol) in dichloromethane (8 mL) was added dropwise. The mixture was warmed to ambient temperature and stirred overnight. The solid precipitate was filtered, washed with diethyl ether and dried to yield the title compound (0.85 g, 68%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[F:24][C:25]([F:36])([F:35])[C:26]1[N:30]2[CH2:31][CH2:32][NH:33][CH2:34][C:29]2=[N:28][N:27]=1>>[CH3:23][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([N:33]1[CH2:32][CH2:31][N:30]2[C:26]([C:25]([F:36])([F:24])[F:35])=[N:27][N:28]=[C:29]2[CH2:34]1)=[O:12])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1nnc2n1CCNC2
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Yield: 38.1 %

Procedure:
The title compound was prepared from (3R)-3-[(1,1-dimethylethoxy-carbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 50.1 mg, 0.15 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (39.2 mg, 0.20 mmol) using a procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate) to afford the title compound (29 mg) as a solid. 1H NMR (500 MHz, CDCl3) δ 1.37 (s, 9H), 2.61˜3.00 (m, 4H), 3.92˜4.30 (m, 5H), 4.93 (s, 1H), 4.95˜5.12 (m, 1H), 5.22˜5.35 (br, 1H), 6.83˜6.95 (m, 1H), 7.02˜7.12 (m, 1H). LC/MS (M+1-t-Bu) 452.
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=[C:6]=[O:7])=O.[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C:14]([OH:16])=[O:15]>O1CCOCC1>[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:6](=[O:7])[NH2:5])[CH:18]=1)[C:14]([OH:16])=[O:15]
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CON=C(C(=O)O)c1cccc(OC(N)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trichloroacetyl isocyanate (70 ml) was dropwise added over 6 minutes at ambient temperature to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40 g) in dry dioxane (200 ml), and the resulting mixture was stirred for 5 hours at ambient temperature. Dioxane was distilled off and to the residue were added ethyl acetate (200 ml) and by small portions water (200 ml) under ice-cooling. The mixture containing trichloroacetylcarbamoyl 2-methoxyimino-2-(3-trichloroacetylcarbamoyloxyphenyl)acetate was stirred for 5 hours at ambient temperature keeping the pH value of the mixture at 6.0 to 6.4 by adding an aqueous solution of sodium bicarbonate. The resulting mixture was washed twice with ethyl acetate. The aqueous layer was adjusted to pH 2 with a 10% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and precipitating crystals were collected by filtration to give colorless crystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl)acetic acid (syn isomer) (15 g), mp 163° C. (dec.). The same compound (5.4 g) was obtained from the mother liquor.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][C@H:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][C@@H:2]([F:1])[C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1F
Yield: 99 %

Procedure:
Following method 2, tert-butyl(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding tert-butyl(3R,4R)-1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 311.2 (MH+); LC Rt=2.14 min.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].C(Cl)Cl.[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)#[N:11]>CCOCC>[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)#[N:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccc(C#N)cc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(C#N)cc21
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of oxalyl chloride in CH2Cl2 (2 M, 1.6 mL, 3.2 mmol) was added dropwise to a solution of 6-cyano-1-methyl-1H-indole (360 mg, 2.3 mmol) in ether (5 mL). Stirring was continued for 30 min at 0° C. and the cooling bath was removed. After 2 h, more of the 2 M solution of oxalyl chloride (0.2 mL, 0.4 mmol.) was added. Stirring was continued at room temperature for additional 2 h. The solid was filtered and washed with ether to give (6-cyano-1-methyl-1H-indol-3-yl)glyoxylyl chloride (450 mg, 79%). Ref:: Troxler, F.; Hamisch, A.; Bormann, G.; Seemann, F.; Szabo, L.; Helv. Chim Acta, 1968, 51(1), 1616.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:42][C:43]1[CH:48]=[C:47]([CH:49]([CH3:52])[CH2:50][NH2:51])[CH:46]=[CH:45][C:44]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:51][CH2:50][CH:49]([C:47]1[CH:46]=[CH:45][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:43]([F:42])[CH:48]=1)[CH3:52])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(CN)c1ccc(-c2ccccc2)c(F)c1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Agent: Cl
Product: CC(CNC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(-c2ccccc2)c(F)c1
Yield: 42.4 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (79 mg, 0.14 mmol) and 2-fluoro-β-methyl-4-biphenylethylamine hydrochloride (45 mg, 0.17 mmol) according to Method C to give the title compound (44 mg). 1H-NMR (400 MHz, CD3OD) d 7.75 (s, 1H), 4.78 (s, 1H), 4.57 (s, 1H), 4.51 (m, 1H), 4.22 (m, 1H), 3.52 (m, 1H), 3.41 (m, 1H), 3.22 (m, 1H), 3.06-2.85 (m, 4H), 2.72 (m, 1H), 1.35 (s, 9H), 1.20 (dd, J=7.0 Hz, J=15.7 Hz, 4H); HRMS m/z 741.3094 (calc. of monoisotopic mass for C41H44FN3O9 gives 741.3062).