Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccc(C(C)C)cc1
Product: COc1ccc(COc2c(C)c(C)c3oc(C)c(-c4ccc(C(C)C)cc4)c3c2C)cc1
Yield: 64 %

Procedure:
Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethylbenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=423.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-ethyl-4,6-bis-trifluoromethyl-benzoic acid (intermediate AO).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:18][C:19](=[O:20])[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C=Nc1ccccc1
Product: COC(=O)c1ccc(NC(=O)Nc2ccccc2)nc1
Temperature: 100 °C
Yield: 104 %

Procedure:
To a solution of methyl 6-aminonicotinate (500 mg, 3.29 mmol) in N,N-diemthylformamide (5 mL) was added phenyl isocyanate (358 μL, 3.29 mmol). The mixture was heated to 100° C. for 2 hours and was then concentrated under vacuum to give the title compound (928 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[C:2]([Cl:1])=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:20])[C:6]=3[CH:14]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Clc1cccc(Cl)c1CN1CCNc2ncc(I)cc21
Product: Clc1cc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)CCN3)ccn1
Yield: 31 %

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (511 mg) was reacted with 2-chloropyridine-4-boronic acid as in General Procedure 4B to give the title compound as a yellow solid (31% yield). M.p.=194° C., LCMS: m/z=405.56 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.17 (2H, t, J=4.8 Hz), 3.53 (2H, m), 4.62 (2H, s), 5.12 (1H, bs), 7.06 (1H, s), 7.42 (4H, m), 7.68 (1H, m), 7.81 (1H, d, J=1.8 Hz), 8.35 (1H, d, J=5.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([O-:12])([OH:11])=[O:10].[N:13]#[C:14][NH2:15]>CCO>[N+:9]([O-:12])([OH:11])=[O:10].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[NH:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
A solution of 4-chloroaniline (70 mmol, 8.88 g) in EtOH (5 mL) on an ice bath was treated with nitric acid (69% aq soln.; 5 mL). To this mixture cyanamide (50% aq. soln.; 5.4 mL) was added. The reaction mixture was stirred at r.t. for 10 min and then refluxed under N2 for a further 22 h. The solvent was evaporated. The dark brown solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a white powder (7.16 g, 44%). 1H-NMR (300 MHz, d6-DMSO) δ7.27-7.54 (m, 4H, Ph-H), 9.65 (br. s, 2H, NH).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)([O:3][CH2:4][CH3:5])=[O:2].[IH:32].C(OCC)C>C(O)C>[IH:32].[C:1]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine (1-(3-carboethoxypropyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.59 g, 1.37 mmol) and aqueous hydriodic acid (2 mL, 57%) in ethanol (25 mL). Heat to reflux. After 2 hours, cool to ambient temperature, pour the reaction mixture into diethyl ether (450 mL), and cool to about −30° C. to give a solid. Collect the solid by filtration and dry to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(OCC)C.[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([NH:34][C:35]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:2][CH2:3]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(N3CCNCC3)ccc2C1
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)NC(=O)N1CCN(c2ccc3c(n2)OCCN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of the compound (0.10 g) obtained in Example 33, step 1 in THF (3 mL)/diethyl ether (3 mL) was added tert-butyl isocyanate (41 μL), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether/hexane to give tert-butyl 8-{4-[(tert-butylamino)carbonyl]piperazin-1-yl}-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.11 g, 85%) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Br:17][C:18]1[N:19]=[C:20]([C:24](O)=[O:25])[NH:21][C:22]=1[Br:23].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Br:17][C:18]1[N:19]=[C:20]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:21][C:22]=1[Br:23]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)c1nc(Br)c(Br)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Br)c(Br)[nH]1
Yield: 72 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (300 mg, 1.30 mmol), 4,5-dibromoimidazole-2-carboxylic acid obtained in Example (2a) (300 mg, 1.11 mmol), WSC hydrochloride (460 mg, 2.40 mmol) and DMAP (50 mg, 0.41 mmol), to obtain 384 mg of the title compound as a white solid (72%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ncccc2O)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Nc2ncccc2O)cc1

Procedure:
The 2-[(4-nitrophenyl)amino]pyrid-3-ol (3) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([NH:22][C:23]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)=[O:24])([CH3:21])[CH3:20])=[CH:17][CH:18]=1
Reactant: Nc1cccc2cnccc12
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(NC(=O)Nc1cccc2cnccc12)c1ccc(Cl)cc1
Yield: 34 %

Procedure:
The title compound was prepared using 5-aminoisoquinoline, the product of Example 76B and the procedure described in Example 73B except that THF was used as solvent. The product was recrystallized from ethyl acetate to provide the title compound as a white solid (840 mg, 34%). MS (ESI+) m/z 355 (M+H)+; MS (ESI−) m/z 353 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 1.63 (s, 6H), 7.23 (s, 1H), 7.37 (d, J 8.8, 2H), 7.47 (d, J 8.8, 2H), 7.73 (t, J 9.2, 1H), 7.93 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.39 (d, J 8.1, 1H), 8.67 (d, J 6.4, 1H), 8.87 (s, 1H), 9.58 (s, 1H); Anal. Calcd for C19H18CIN3O HCl 0.25 EtOH: C, 60.40; H, 5.33; N, 10.54. Found: C, 60.82; H, 5.23; N, 1045.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1>CN(C=O)C.[Cu]I>[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[N:36](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=3)\[CH3:4])[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1cccc(S(C)(=O)=O)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(S(C)(=O)=O)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-(1-Bromoprop-1-en-2-yl)-3-(methylsulfonyl)benzene (189 mg, 0.7 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica (100-200 mesh) using 0-6% MeOH:DCM as eluent. Yield: 158 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.19 (s, 1H), 8.0 (m, 2H), 7.72 (t, 1H), 7.32 (s, 1H), 7.16 (m, 2H), 7.10 (d, 1H), 4.58 (m, 2H), 3.70 (m, 2H), 3.19 (s, 3H), 3.16 (m, 2H), 3.10 (s, 3H), 2.44 (s, 3H), 2.04 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1CCC(=O)O
Yield: 56.9 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (220 mg), 147 mg 5-chloro-2-oxindole, and 2 drops of piperidine in 2 mL of ethanol were heated to 90° C. for 3 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 172 mg of the title compound (50%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C(Cl)Cl.ClC(OC(C)C)=O>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (75.4 g, 0.3 mol) in CH2Cl2 (900 mL) at 1° C. was treated with triethylamine (60.7 g, 0.6 mol). Isopropyl chloroformate (300 mL, 0.3 mol, 1M in toluene) was added while maintaining the temperature less than 12° C. The resulting solution was stirred 16 h at ambient temperature. After 16 h, additional isopropyl chloroformate (15 mL, 0.015 mol, 1.0M in toluene) was added, and the reaction was stirred for 1 h. The reaction mixture was washed with 1N HCl (2×200 mL) and saturated NaHCO3 solution (2×200 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by filtration through Merck silica gel 62 (750 grams, CH2Cl2/MeOH 100/0 to 96/4) to give the title compound (95.48 g, 94.3%). 1H NMR (300 MHz, CDCl3): δ 1.20-1.24 (d, 6H), 1.40 (s, 9H), 2.46-2.52 (t, 2H), 2.81-2.86 (t, 2H), 4.294.32 (d, 2H), 4.86-4.97 (m, 1H), 5.19-5.28 (m, 1H), 6.67-6.72 (dd, 2H), 6.76 (s, 1H), 6.97-7.00 (d, 1H). MS (ES−) m/z 336.1 [M−H]−.
Reaction SMILES: [CH:1]([C@@H:3]1[N:6]([C:7](=[O:9])[CH3:8])[C:5](=[O:10])[C@H:4]1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[N:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:2].CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([C@@H:3]1[N:6]([C:7](=[O:9])[CH3:8])[C:5](=[O:10])[C@H:4]1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])=[N:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])([OH:40])=[O:2]
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Yield: 66 %

Procedure:
To an acetone solution of compound 28 (3.5 g, 6.8 mmol) was added freshly prepared Jones reagent dropwise until TLC indicated the disappearance of the starting material. The acetone layer was separated, and the residue was washed with a fresh portion of acetone. Two acetone portions were combined and concentrated. The residue was purified by silica gel chromatography (EtOAc:MeOH/99:1) to afford 2.4 g (66%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1
Reactant: CCOC(=O)CCCc1nc(Cl)cc(N2CCOCC2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCc1nc(Cl)cc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a solution of 4-chloro-2-(4-ethoxy-4-oxo-butyl)-6-morpholinopyrimidine (1.108 g, 3.54 mmol) in 50 mL THF at −78° C., a diisobutylaluminum hydride (DIBAL) solution (4.72 mL 1.5 M in Toluene, 7.08 mmol) was slowly added. After addition, the obtained reaction mixture was warmed up slowly to 0° C. and kept at 0° C. for 10 min. After routine workup, flash chromatography was performed to obtain 4-chloro-2-(4-hydroxybutyl)-6-morpholinopyrimidine (0.76 g, 2.80 mmol, 79%) as light yellow solid.
Reaction SMILES: [F:1][C:2](I)([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[NH:12]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:13]([C:17]([N:19]1[CH2:34][CH2:33][CH2:32][C@H:20]1[C:21]([NH:23][C@H:24]([C:28](OC)=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15]>C(OCC)C>[NH:12]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C@H:13]([C:17]([N:19]1[CH2:34][CH2:33][CH2:32][C@H:20]1[C:21]([NH:23][C@H:24]([C:28]([C:2]([C:3]([C:4]([F:7])([F:6])[F:5])([F:9])[F:8])([F:10])[F:1])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)C
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Add perfluoropropyl iodide (6.6 mL, 48.0 mmol, from Aldrich, stabilized with Cu) dropwise, under N2, to a -78° C. solution of Boc-Val-Pro-Val-OCH3 ] (3.89, 9.0 mmol) in anhydrous diethyl ether (100 mL). Add methyllithium-lithium bromide complex (28.5 mL, 42.0 mmol) at a rate which maintains an internal reaction temperature below -70° C. Stir the reaction mixture at -78° C. for 1 hour, then remove the cold bath and continue stirring for 5 minutes. Pour the reaction mixture into H2O (100 mL) and acidify the aqueous phase with 1N HCl. Extract the aqueous phase with additional diethyl ether (100 mL) and dry (MgSO4) the combined ethereal extracts. Remove the solvent in vacuo and purify the resultant yellow foam by flash chromatography (4.0×25 cm column eluted with 3:1 Et2O-hexane) to yield the title compound as a white foam. (Yield: 654 mg, 13%). FT-IR (KBr) 3423, 3292, 2972, 2937, 2879, 2823, 2771, 2739, 2253, 1755, 1687, 1635, 1525, 1444, 1392, 1367, 1348, 1313, 1232, 1178, 1126, 1041, 1018, 966, 922, 910, 877, 837, 798, 756, 736, 667, 650, 632, 596 cm-1 ; 1H NMR (300 MHz, CDCl3)δ 7.63 (d, 1H, J=8.2 Hz, NH), 5.44 (d, 1H, J=9.2 Hz, NH), 5.02 (dd, 1H, J=7.8, 4.5 Hz, CH of Val), 4.64 (dd, 1H, J=8.0, 3.0 Hz, CH of Pro), 4.30 (dd, 1H, J=9.2, 6.8 Hz, α-CH of Val), 3.80-3.74 and 3.66-3.60 (pr m, 2H, CH2N), 2.31-1.92 (series of m, 6H, β-CH of Val, CH2CH2), 1.44 (s, 9H, t-Bu), 1.02 (d, 3H, J=7.0 Hz, CH3), 0.98,(d, 3H, J=6.9 Hz, CH3), 0.94 (d, 3H, J=6.7 Hz, CH3), 0.88 (d, 3H, J=6.9 Hz, CH3); 13C NMRδ 193.3, 193.0, 192.7, 172.9, 171.1, 155.7, 118.7, 115.8, 111.3, 108.9, 108.6, 108.2, 105.9, 79.6, 77.3, 77.2, 76.9, 76.6, 59.7, 59.3, 56.8, 47.8, 31.4, 29.0, 28.3, 26.9, 25.1, 19.9, 19.8, 19.7, 19.5, 19.4, 17.5, 17.4, 16.3, 16.1; 19F NMR (376.3 MHz, CDCl3)δ -80.91 (t, CF3), -119.03 and -120.43 (AB quartet, J=297 Hz, CF2), -126.62 (s, CF2), MS (CI/CH4) m/z (rel. intensity) 566 (MH+, 100). HRMS (C23H34F7N3O5) (M+) calcd 566.2492, obsd 566.2475.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@@H:13]1Br)(=[O:10])[CH3:9]>C1(C)C=CC=CC=1.C(#N)C.[Cl-].[Zn+2].[Cl-].[N-]1C=CN=C1.[Ag+]>[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@H:13]1[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Oc1cccnc1
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
2.15 g (15.8 mmol) of anhydrous zinc chloride, 1 g (10.5 mmol) of 3-hydroxy-pyridine and 3 g of 13X molecular sieve are mixed in 10 ml of toluene and 10 ml of acetonitrile. The mixture is stirred for 15 min and then heated to 60° C. and placed in the dark. 2.2 g (12.6 mmol) of silver imidazolate and 4.5 g (12.6 mmol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are added. The mixture is stirred for 18 hours at 60° C. and then filtered. 50 ml of ethyl acetate are added to the filtrate and the organic phase is washed with 1 N sodium hydroxide solution. (A flocculation is observed, which is removed by filtration on a bed of filter aid.) The organic phase is separated off, washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The residue is crystallized by adding ethyl ether; the crystals obtained are filtered off and dried to give 1.45 g of the expected product in the form of white crystals (yield=37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13](C(O)=O)[C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.CS(C)=O.CC(OC)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(C(=O)O)C(=O)O)C1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](CC(=O)O)C1
Yield: 92 %

Procedure:
A suspension of (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)malonic acid (15 g, 55 mmol) in toluene (150 mL) and dimethylsulfoxide (2 mL) was heated to reflux for a period of 2 h. The mixture was allowed to reach ambient and diluted with MTBE (150 mL). The organic solution was washed with 10% aqueous citric acid (2×200 mL), and the solvent was removed under vacuum to afford 11.6 g of (R)-2-(1-(tert-butoxycarbonyl)-pyrrolidin-3-yl)acetic acid as an off-white solid (92% yield). 1H NMR (DMSO-d6, 400 MHz): δ 12.1 (s, 1H); 3.36-3.48 (m, 1H); 3.20-3.34 (m, 1H); 3.05-3.19 (m, 1H, 2.72-2.84 (m, 1H); 2.30-2.42 (m, 1H), 2.22-2.30 (m, 2H); 1.85-2.00 (m, 1H); 1.38-1.54 (m, 1H), 1.35 (2, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:43])([F:44])[F:29])[CH:32]=3)[CH2:42][CH2:41]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 62.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a white solid required compound (501 mg, 1.15 mmol, 63%) was obtained.