Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: Cc1ccc(CCl)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(C)c(C)c3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (250 mg), 4-(chloromethyl)-1,2-dimethylbenzene (89.0 mg), and DMF (5.8 mL) was added K2CO3 (278 mg). After stirring for 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (263 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:43])=[C:19]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[C:33]4[CH2:35][NH:36][CH2:37][CH2:38][C:32]4=[N:31][C:30]=3[NH:39][CH:40]([CH3:42])[CH3:41])[CH2:25][CH2:24]2)=[O:22])[CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:43])=[C:19]([CH:20]=1)[C:21]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]3[CH2:35][N:36]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:37][CH2:38][C:32]3=[N:31][C:30]=2[NH:39][CH:40]([CH3:41])[CH3:42])[CH2:25][CH2:24]1)=[O:22].[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CNCC2
Reactant: CN(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CN(C(=O)N(C)C)CC2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (3.8 mg, 0.036 mmol) was added to a solution of (5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone TFA salt (9.7 mg, 0.018 mmol) and triethylamine (7 μL, 0.053 mmol) in DCM (180 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (3.6 mg, 32.8%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.31-1.34 (m, 6H), 1.89-2.06 (m, 4H), 2.85-2.89 (m, 2H), 2.90-2.92 (m, 6H), 2.93-3.02 (m, 2H), 3.35-3.41 (m, 1H), 3.50-3.58 (m, 4H), 4.08-4.16 (m, 1H), 4.27 (s, 2H), 7.29 (dd, J=10.6, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.0, 2.8 Hz, 1H), 7.76 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH:7]1[CH3:16].[ClH:17].Cl.[C:19]1([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[ClH:17].[ClH:17].[C:19]1([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([N:34]3[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:11])[C:9]5([CH2:15][CH2:14][CH2:13][CH2:12]5)[S:8][CH:7]4[CH3:16])[CH2:36][CH2:35]3)=[CH:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1SC2(CCCC2)C(=O)N1CCCCBr
Reactant: c1ccc(-n2cc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1SC2(CCCC2)C(=O)N1CCCCN1CCN(c2cn(-c3ccccc3)c3ccccc23)CC1
Temperature: 80 °C
Yield: 122.7 %

Procedure:
A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one (6.80 g), 1-(1-phenyl-1H-indol-3-yl) piperazine dihydrochloride (4.80 g), diisopropylethyl amine (8.16 g), K2CO3 (9.50 g), NaI (400 mg) and CH3CN (200 ml) was heated at 80° C. under nitrogen for 24 hours. The mixture was cooled and filtered, the inorganics were washed with dichloromethane, and the filtrate was concentrated under reduced pressure to a residue. The residue was diluted with 0.5N NaOH (150 ml) and the aqueous mixture extracted with ether (3×100 ml). The combined ether extracts were washed successively with H2O (150 ml) and brine (150 ml), dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed on silica gel, eluting with a gradient of 5-10% methanol in dichloromethane. The fractions containing the desired product (Rf =0.42, 10% methanol in dichloromethane) were concentrated to afford 4.84 g of a viscous liquid. The salt of this amine was precipitated from ether by the addition of ethereal HCl. A 4.74 g portion of the salt was recrystallized from ethanol yielding 2.15 g of solid, m.p. 214°-217° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30](O)=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]([NH2:40])=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(=O)O)(c2ccccc2)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Yield: 46.8 %

Procedure:
A mixture of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, 1.12 mmol), HOBT (302 mg, 2.24 mmol), EDCl (440 mg, 2.24 mmol) and DIEA (1 mL) in anhydrous CH2Cl2 (10 mL) were stirred at 0□ under NH3. Then the solution was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (234 mg, yield 48%). 1H NMR (CDCl3): 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H). LC-MS Method 3 tR=1.3, min, m/z=447, 469; 1H NMR (CDCl3) 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H).
Reaction SMILES: C([O:5][C:6]([C@@H:8]([N:10]1[C@@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:12]([N:20]=[N+]=[N-])[C:11]1=[O:23])[CH3:9])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[NH2:20][C@@H:12]([C:11]([NH:10][C@H:8]([C:6]([OH:7])=[O:5])[CH3:9])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@H](N=[N+]=[N-])[C@@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@H](N)Cc1ccccc1)C(=O)O
Yield: 140.8 %

Procedure:
According to the same procedure as in Example 15 except that 1-(1(S)-t-butoxycarbonylethyl)-3(R)-azido-4(S)-phenylazetidin-2-one (300 mg., 0.95 mmol) was used as a starting material, trifluoroacetic acid salt of D-phenylalanyl-L-alanine (316 mg., yield: 95%) was obtained.
Reaction SMILES: CC(C)([O-])C.[Na+].F[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[N+:15]([O-:17])=[O:16].[C:18]1([NH2:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>CN(C=O)C>[F:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cccc1Nc1ccccc1
Reaction time: 20 h
Yield: 72.6 %

Procedure:
Sodium tertbutoxide (1.2 g, 12.58 mmol) was added portionwise to a stirred solution of 1,3-difluoro-2-nitrobenzene (1 g, 6.29 mmol) and phenylamine (1.15 mL, 12.58 mmol) in a hydrous DMF (5 mL) under a nitrogen atmosphere at RT and stirring was continued for 20 h. The mixture was poured into an aqueous solution of NH4Cl and extracted with EtOAc (150 mL). The organic layer was washed with brine, then dried and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% EtOAc in cyclohexane) affording (3-Fluoro-2-nitrophenyl)phenylamine as a red solid (1.06 g, 73%). LCMS: RT 3.80 min.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.CON(C)[C:33]([C:35]1[C:40]2=[N:41][S:42][N:43]=[C:39]2[CH:38]=[CH:37][CH:36]=1)=[O:34]>ClCCl>[N:43]1[S:42][N:41]=[C:40]2[C:35]([C:33]([C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=3)=[O:34])=[CH:36][CH:37]=[CH:38][C:39]=12
Reactant: CON(C)C(=O)c1cccc2nsnc12
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2nsnc12

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available from Synchem) (6.3 g, 14.4 mmol) in dichloromethane (100 mL) at rt was treated with ethyl magnesium bromide (4.8 mL, 14.4 mmol, 3M in THF) and allowed to react for 1 h. A solution of benzo[1,2,5]thiadiazole-4-carboxylic acid methoxy-methyl-amide (Intermediate L2) (2.0 g, 9.0 mmol) in dichloromethane (50 mL) was added via syringe at rt and stirred for 40 m. The residue was isolated in a typical aqueous workup and purified by chromatography on silica gel with 30% EtOAc:hexane to give benzo[1,2,5]thiadiazol-4-yl-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate L3), 1 g (25%).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1C=CC=CC=1.[OH-].[Na+]>CCOCC>[CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)COc1ccc(C=CC(=O)O)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A 500 mL, 1 neck, round-bottomed flask equipped with a magnetic stirrer and reflux condenser is charged with 4-(2-methylpropoxy)benzaldehyde (17.84 g, 0.100 mol, as from Example 2a), malonic acid (10.42 g, 0.100 mol), and 19 mL of pyridine. The mixture is heated with stirring in a 130° C. oil bath for 24 hours, then stirred at room temperature for 16 hours. The reaction mixture is then poured into a separatory funnel containing 300 mL of pH 12 aqueous sodium hydroxide and 300 mL of ether. The layers are separated and the aqueous phase washed with 150 mL of ether. The aqueous phase is then acidified with concentrated hydrochloric acid to bring the pH to 1 whereupon the powdery white acid precipitates out. The mixture is chilled in an ice/salt bath and the solid collected giving 5.89 g (0.027 mol, 27%) of product, m.p. 161°-164° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:23])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[S:10][C:9]1=[S:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:31][O:32][CH2:33][CH2:34]Br>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:23])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][CH2:33][O:32][CH3:31])=[CH:20][CH:21]=2)[S:10][C:9]1=[S:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C=C1SC(=S)N(Cc2ccccc2)C1=O)c1ccc(O)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1ccc(N(C)C=C2SC(=S)N(Cc3ccccc3)C2=O)cc1
Temperature: 50 °C
Yield: 72.4 %

Procedure:
To a solution of 3-benzyl-5-{[N-(4-hydroxyphenyl)-methylamino]-methylene}-2-thioxothiazolidin-4-one (71 mg, 0.20 mmol) in DMF (1.0 mL, anhyd) was added anhyd K2CO3 (29 mg, 0.21 mmol) and 2-bromoethyl methyl ether (20 μL, 0.21 mmol). The reaction mixture was heated at 50° C. After 20 h the reaction mixture was cooled, diluted with CHCl3 (50 mL), washed with H2O (3×25 mL) and brine, dried over anhyd Na2SO4, concentrated and then chromatographed (silica gel, 0:100 to 20:80 EtOAc-DCM) to give the title product (60 mg, 73%) as a yellow solid. 1H-NMR (CDCl3): δ 7.73 (1H, s), 7.44 (2H, d), 7.21-7.30 (3H, m), 7.11 (2H, d), 6.97 (2H, d), 5.23 (2H, s), 4.15 (2H, m), 3.79 (2H, m), 3.48 (3H, s), 3.47 (3H, s).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([O:22][C@H:23]3[CH2:27][CH2:26][NH:25][C:24]3=[O:28])=[C:16]2[CH:15]=[N:14]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([O:22][C@H:23]3[CH2:27][CH2:26][N:25]([S:30]([CH3:29])(=[O:32])=[O:31])[C:24]3=[O:28])=[C:16]2[CH:15]=[N:14]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCC[C@@H]1Oc1ncnc2c1cnn2-c1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC[C@H](Oc2ncnc3c2cnn3-c2ccccc2Cl)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
Butyllithium (1.6M in hexane, 1.668 mL, 2.67 mmol) was added dropwise to (3S)-3-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pyrrolidin-2-one (Intermediate AC2) (800 mg, 2.43 mmol) in THF (15 mL) cooled to −78° C. under nitrogen. The resulting solution was allowed to warm to r.t., then recooled to −78° C. methanesulfonyl chloride (0.207 mL, 2.67 mmol) was added dropwise and the resulting solution was stirred at r.t. for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4) and evaporated (995 mg). The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (368 mg, 37.2%). 1H NMR (400 MHz, CDCl3) δ 2.35-2.47 (1H, m), 2.83-2.92 (1H, m), 3.37 (3H, s), 3.85-3.94 (1H, m), 4.06-4.16 (1H, m), 6.13 (1H, t), 7.44-7.56 (3H, m), 7.59-7.66 (1H, m), 8.32 (1H, s), 8.57 (1H, s); m/z (ES+) (M+H)+=408.29; HPLC tR=2.10 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(=O)([O-])O.[Na+]>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: C1COCCN1
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (110 mg), morpholine (52 μl) and diisopropylethylamine (140 μl) were dissolved in DMF (8 ml), BOP reagent (265 mg) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9) to ethyl acetate was concentrated under reduced pressure to give the object compound (105 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)[C:23]#[N:24].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CCOC(C)=O.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])=[C:20]([F:19])[CH:21]=1)#[N:24]
Reactant: COC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3F)c2OC)nc1
Yield: 88.7 %

Procedure:
Combined methyl 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)nicotinate (1.0 g, 3.20 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.583 g, 6.41 mmol), dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.209 g, 0.320 mmol) and sodium bicarbonate (1.346 g, 16.02 mmol) in dioxane (10 mL) and water (2.5 mL) and heated at 110° C. for 30 min in the microwave. The reaction was diluted with EtOAc, concentrated on Celite® and purified on a 100 g NH column (Moritex) eluted with 10 to 80% EtOAc in hexanes to give the title compound (1.0 g) which was used without further purification. MS m/z 353 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 3.92 (s, 3 H) 7.81 (dd, J=8.1, 1.8 Hz, 1 H) 7.89-7.98 (m, 2 H) 8.00 (dd, J=10.7, 1.6 Hz, 1 H) 8.09 (d, J=3.0 Hz, 1 H) 8.51 (dd, J=8.6, 2.3 Hz, 1 H) 9.08 (dd, J=2.3, 0.5 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[CH2:10][NH:9][C@H:8]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:7]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:24]([O:31][C:32]([CH2:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH:46]([CH3:48])[CH3:47])[C:38](Cl)=[O:39])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:45]([O:44][C:43]1[CH:42]=[CH:41][C:37]([C:38]([N:9]2[CH2:10][C@H:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:7][C@H:8]2[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:39])=[CH:36][C:35]=1[CH2:34][C:32]([O:31][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:33])[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)CCC[C@@H]1C[C@@H](OCC(C)C)CN1
Reactant: CC(C)COc1ccc(C(=O)Cl)cc1CC(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H]1C[C@@H](OCC(C)C)CN1C(=O)c1ccc(OCC(C)C)c(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In 4.8 ml of tetrahydrofuran are dissolved 0.16 g of (2R,4R)-4-isobutoxy-2-(4-methylpentyl)pyrrolidine and 0.78 ml of triethylamine, to which is dropwise added a solution of 3-(benzyloxycarbonylmethyl)-4-isobutoxybenzoyl chloride in tetrahydrofuran (prepared from 0.48 g of 3-(benzyloxycarbonylmethyl)-4-isobutoxybenzoic acid, 0.09 ml of oxalyl chloride and 4.8 ml of tetrahydrofuran) at 5-10° C. The mixture thus obtained is stirred at ambient temperature for 15 hours. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 3.0 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography [eluent; n-hexane:ethyl acetate=3:1] to obtain 0.18 g of benzyl 2-(2-isobutoxy-5-{[(2R,4R)-4-isobutoxy-2-(4-methylpentyl)pyrrolidinyl]carbonyl}phenyl)acetate as a yellow-colored oily product.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:33][C@@H:34]([CH3:38])[C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[OH:33][C@H:34]([CH3:38])[C:35]([N:30]1[CH2:31][CH2:32][CH:27]([C:24]2[N:23]=[C:22]([NH:21][C:9]3[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][C:12]([S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][N:10]=3)[S:26][N:25]=2)[CH2:28][CH2:29]1)=[O:36]
Reactant: C[C@H](O)C(=O)O
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](O)C(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (Example 34, Step C, 0.075 g, 0.16 mmol), (S)-2-hydroxypropanoic acid (0.018 g, 0.19 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.047 g, 0.24 mmol), and N,N-dimethylpyridin-4-amine (0.002 g, 0.016 mmol) were dissolved in CH2Cl2 (5 mL). Triethylamine (0.033 g, 0.32 mmol) was added and the solution was stirred at ambient temperature for 3 hours. Water was added and extracted with CH2Cl2, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in CH2Cl2) to give (R)-2-hydroxy-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)propan-1-one (0.023 g, 27% yield). 1H NMR (d6-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.82 (t, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.25-3.04 (m, 2H), 2.84 (m, 1H), 2.02 (d, 2H), 1.81-1.55 (m, 2H), 1.18 (d, 3H).