Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 5-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′;3′,1″]terphenyl-2′-yloxy]-pentanoic acid, ethyl ester (0.409 g, 0.573 mmol) and 1N KOH (1.15 ml) in THF (6 ml) and methanol (3 ml) was stirred under nitrogen. After ˜18 h, the reaction mixture was concentrated. in vac. The residue was suspended in water (25 ml) and acidified with 2 N HCl (1.15 ml) then extracted with EtOAc (3×25 ml). The combined organics were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by preparatory plate chromatography (50% EtOAc/Hex) to give the title compound as a light yellow foam (0.249 g, 63%); dec.>50° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.12-1.32 (m, 12H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 1.87 (t, J=7.0 Hz, 2H), 3.16-3.27 (m, 4H), 4.12 (t, J=7.0 Hz, 2H), 6.37-6.38 (m, 1H), 6.94-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.59 (m, 2H), 7.66-7.69 (m, 2H), 7.87 (s, 2H), 8.52 (t, J=5.7 Hz, 1H), 11.85 (s, 1H); IR (KBr) 3400, 2940, 1710, 1630, 1550, 1220 cm−; mass spectrum [(+)APCI], m/z 685 (M+H)+; Anal. Calcd. for C40H42Cl2N2O4: C, 70.07; H, 6.17; N, 4.09, Found: C, 69.66; H, 6.17; N, 3.85.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:26])[NH:17][C@H:18]([C:20]2C=CC=CC=2)C)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@@H:14]([O:15][C:16](=[O:26])[NH:17][CH2:18][CH3:20])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCNC(=O)O[C@@H](c1ccccc1)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using ((S)-1-phenyl-ethyl)-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6](=[O:28])[C:7](=[CH:13][C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[NH4+].[OH-]>C1COCC1.[Cu]I>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([CH:13]([C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[CH:18][CH:19]=1)[CH3:2])[C:6]([O:5][CH2:3][CH3:4])=[O:28])[CH3:12]
Reactant: [Li]C
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
MeLi (6.5 mL, 10.4 mmol, 1.6 M in diethyl ether) was added dropwise to a slurry of CuI (0.9 g, 4.73 mmol) in THF (28 mL) at −78° C. under argon. The reaction mixture was stirred for 30 min. A solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (0.84 g, 2.3 mmol) in THF (7 mL) was added dropwise and the reaction was stirred for 180 min at −78° C. Saturated aqueous NH4OH was added dropwise and the mixture was extracted with EtOAc. The organic phase was washed with saturated aqueous NH4OH and NaCl, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 3:1→1:6) gave 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid diethyl ester (0.723 g, 82.4%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[C:9](=[O:16])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:3][CH2:2]1.[CH2:26]([NH2:28])[CH3:27].Cl.CCN(C(C)C)C(C)C>>[CH2:26]([NH:28][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([CH:8]([C:9](=[O:16])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:18][CH:19]=1)[CH3:27]
Reactant: CCN
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1

Procedure:
4-[2-(Tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzoic acid (Preparation 62, 150 mg, 420 μmol) was condensed with EtNH2.HCl in the presence of DIPEA, utilising the general procedure described in EXAMPLE 65, to give the title compound: RTA=2.97 min; m/z (ES+)=388.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.C(O[C:33](=[O:35])[CH3:34])(=O)C>>[C:7]([NH:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:17][O:18][C:33](=[O:35])[CH3:34])([CH2:19][O:20][C:17](=[O:18])[CH3:16])[CH2:21][O:22][C:13](=[O:14])[CH3:4])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:8])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(CO)(CO)CO)c1I
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(COC(C)=O)(COC(C)=O)COC(C)=O)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Amino-2,4,6-triiodo-N-[tris(hydroxymethyl)methyl]isophthalamic acid (50.0 g., 0.076 mol.) was added in one portion to a stirred solution of sulfuric acid (0.36 ml.) in acetic anhydride (136.0 ml.). The temperature of the reaction mixture rose briefly to 82° and dissolution was effected. As the reaction mixture cooled to room temperature, the product began to precipitate at 47° and the mixture was diluted with toluene (100 ml.). The mixture was stirred at room temperature for 1 hr., and filtered. The filter cake was washed with toluene (50 ml.), dried, dissolved in hot methanol (300 ml.), and treated with charcoal (6 g.). After removal of the charcoal, the product precipitated from the cold solution and was collected and dried (70°) to give white crystalline 5-acetamido-2,4,6-triiodo-N-[tris(acetoxymethyl)methyl]-isophthalamic acid (38.8 g.) m.p. 248-251 (dec., uncorr.). (Yield, 62%). This material was pure by TLC analysis (benzene, 2-butanone, 88% formic acid; 60:25:20) and its structure was confirmed by IR and NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37].[OH-].[Na+]>CN1C(=O)CCC1>[CH:23]([NH:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH:36]([CH3:38])[CH3:37])[N:7]=2)=[N:18][N:19]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nccc(-c2c[nH]c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(2-chloropyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (100 mg, 0.196 mmol) and isopropylamine (16.88 μl, 0.196 mmol) in NMP (2.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 135° C. for 1 h. aq. NaOH (0.5 mL, 5 M) was added to the mixture and the reaction was heated in the microwave at 100° C. for 20 min. The mixture was purified with preparative HPLC (eluting with 10-50% MeCN in water with 0.1% TFA in each solvent) and the fractions containing the product were combined and concentrated in vacuo to remove MeCN. The resulting mixture was extracted with CHCl3/iPrOH (4:1) and the combined organic layers were dried (MgSO4), filtered and concentrated to give N-isopropyl-5-(3-(2-(isopropylamino)pyrimidin-4-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (29 mg, 0.077 mmol, 39.1% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 378.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, s), 8.99 (1H, br. s.), 8.30 (1H, s), 8.17 (1H, d, J=5.1 Hz), 7.64 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.6 Hz), 7.45 (1H, d, J=7.2 Hz), 7.00 (1H, d, J=5.3 Hz), 6.70 (1H, br. s.), 4.17-4.29 (1H, m), 3.71-3.83 (1H, m), 1.20-1.30 (12H, m).
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:20][OH:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C)C=O>[NH2:18][C@@H:19]([CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H](CO)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC([C@H](N)CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-((1S)-1-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2-hydroxyethyl)piperdine-1-carboxylate (0.95 g, 2.03 mmol) was added 20% piperidine in dimethylformamide (20 mL) all at once. The reaction was stirred overnight at 25° C. The dimethylformamide was evaporated off and the crude residue was subjected to flash chromatography using methylene chloride-methanol-ammonium hydroxide, 95-5-0.1% as eluent. This yielded the amine product as an oil that crystallized upon standing (0.392 g, 80%). MS (+ESI) 245.2 ([M+H]+); 189.2; 150.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([O:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:11][CH2:12][CH3:13]>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([NH2:30])[N:16]=[C:15]([O:14][C@@H:10]([CH3:9])[CH2:11][CH2:12][CH3:13])[N:23]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Product: CCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 5 h
Yield: 98.7 %

Procedure:
N-Bromosuccinimide (12.16 g, 68.3 mmol) was added portionwise over 5 mins. to a stirred solution of 2-{[(1S)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (14.9 g, 48.8 mmol) in chloroform (80 ml) at <5° C. under an atmosphere of nitrogen. The reaction mixture was stirred at <5° C. for 5 hours then washed with saturated sodium hydrogen carbonate solution (80 ml) then water (80 ml). The foam was dissolved in DCM (50 ml) and washed with water (50 ml) then brine (50 ml). The combined aqueous phases were washed with DCM (50 ml). The combined organic layers were dried through a hydrophobic frit, and the solvent removed in vacuo to yield the title compound as an orange foam (18.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[C:11]([N+:20]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Zn].O>[NH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Yield: 86 %

Procedure:
A mixture of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (11.94 g 39.6 mmol), ammonium chloride (13.48 g, 250 mmol), zinc powder (65.39 g, 1000 mmol), ethyl alcohol (720 ml) and water (70 ml) was refluxed until completion (5 hours). The mixture was filtered through celite and washed with hot ethyl alcohol. The filtrate was evaporated in vacuum. The residue was taken up in the mixture of chloroform (200 ml), water (200 ml) and the pH of this mixture was set to 8 by adding sodium hydroxide solution. The two layers were separated, the aqueous layer was extracted with chloroform (2×50 ml). The organic layers were combined, washed with water and over Na2SO4, and concentrated to give 9.25 product [C]. Yield 86%.
Reaction SMILES: [C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20](O)[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]([Cl:25])[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Solvent: ClCCl
Product: CC(Cl)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(N-carbobenzoxy indol-3-yl)ethanol (1.02 g, 3.45 mmol) in CH2Cl2 (20 ml) at -78° C. under nitrogen was added thionyl chloride (0.63 ml, 8.62 mmol). After warming to room temperature and stirring for 2 hrs, the mixture was evaporated to a brown oil. This was dissolved in CHCl3, treated with activated carbon and filtered through a pad of Super Cel; the filtrate was evaporated to give 1.03 g (95%) of light brown oil: NMR (CDCl3) δ1.90 (3, d, CH3), 5.26 (1, q, CHCl), 5.33 (2, s, PhCH2), 7.20-7.85 (9, m, aromatic H's) 8.04 ppm (1, m, H-7). This material was relatively unstable, and therefore was used immediately without further purification (e.g. as in Example 13).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([Cl:24])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)CNC(=O)OCc1ccccc1

Procedure:
To a mixture of N-[(benzyloxy)carbonyl]glycine (0.78 g, 3.8 mmol), N,N-dimethylformamide (0.1 ml) and tetrahydrofuran (20 ml) was added dropwise oxalyl chloride (0.33 ml, 3.7 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 1 hr. to give a crude product of N-[(benzyloxy)carbonyl]glycyl chloride. To a mixture of tert-butyl N-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (0.40 g, 0.75 mmol), pyridine (0.3 ml, 3.7 mmol) and tetrahydrofuran (100 ml) was added dropwise the crude product. The obtained mixture was stirred for 1 hr. and 4-dimethylaminopyridine (0.01 g, 0.82 mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl N-[(benzyloxy)carbonyl]glycyl-N-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (0.47 g, yield 87%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][C:9]2[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=[N:14][C:8]=2[CH:7]1[C:21](OCC)=[O:22])=[O:5].[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[C:29]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][C:9]2[N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[N:14][C:8]=2[CH:7]1[CH2:21][OH:22])=[O:5]
Reactant: CCOC(=O)C1c2ncn(-c3ccccc3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncn2-c2ccccc2)C1CO
Yield: 76.5 %

Procedure:
To a solution of Example 26 (0.10 g, 0.21 mmol) in THF (10 mL) at −78° C. was added lithium borohydride (0.02 g, 1.08 mmol). After 14 h the reaction was quenched with 1 N NaOH and extracted with DCM (3×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.07 g, 76%). MS (ESI): mass calculated for C21H17ClF3N3O2, 435.1. m/z found 436.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH2:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(=O)(O)[O-].[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CCNc2cc(Cl)nc(SC)n2)cc1OC
Temperature: 85 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine [1 g, 5.1 mmol, Intermediate (29)], 3,4-dimethoxy-phenylethylamine [0.98 g, 5.4 mmol, Intermediate (30)], and sodium bicarbonate (0.86 g, 10 mmol) in EtOH (5 mL) is heated to reflux. After stirring at 85° C. for 4 hours the mixture is diluted with water and filtered. The solid is washed with water, and dried to afford (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine [1.8 g, Intermediate (31)]. LCMS: RT=3.25 minutes, MS: 340 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[Si:26]([O:1][CH2:2][C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A solution of 11.052 g of (1S,5R,6S,7R)-6-hydroxymethyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (DOS No. 2,610,718) in 54.0 ml of absolute dimethylformamide is combined with 3.03 g of imidazole and 6.63 g of tert-butyldimethylsilyl chloride, and the mixture is stirred for 3 hours at room temperature. The solution is subsequently precipitated into 500 ml of ice water, the precipitate is suctioned off, and the residue is dissolved in methylene chloride. The organic solution is dried over magnesium sulfate and concentrated. The crude product is recrystallized from hexane, thus obtaining 15.30 g of the title compound, mp 75.8° C.
Reaction SMILES: CO[C:3]1[C:4]2[N:11]=[C:10]([C:12]3[N:16]([CH3:17])[C:15]([C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)=[N:14][C:13]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH3:29]>O1CCOCC1>[CH3:17][N:16]1[C:12]([C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([NH2:29])[C:4]=3[N:11]=2)=[C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:14]=[C:15]1[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1
Reactant: N
Reactant: COc1ncnc2sc(-c3c(-c4ccccc4)nc(-c4ccsc4)n3C)nc12
Solvent: C1COCCO1
Product: Cn1c(-c2ccsc2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 150 °C
Yield: 68 %

Procedure:
7-Methoxy-2-[1-methyl-4-phenyl-2-(3-thienyl)-1H-imidazol-5-yl][1,3]thiazolo[5,4-d]pyrimidine (Intermediate 44) (26 mg) was dissolved in 0.5M NH3 in 1,4-dioxane (3 mL)/concentrated aqueous NH3 (0.6 mL), sealed and heated under microwave conditions (CEM explorer, 150° C., 150 W) for 1 hour. After which the reaction mixture was concentrated in vacuo, dissolved in EtOAc (20 mL), washed: with 2M NaOH (2×10 mL) then brine (1×15 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 4% MeOH/DCM gave the title compound as an off-white solid (17 mg, 68%);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[CH:14][N:15]=[C:9]2[CH:8]=1.C1C(=O)N([I:23])C(=O)C1>C(O)C.C(OCC)(=O)C>[I:23][C:13]1[N:10]2[CH:11]=[CH:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][C:9]2=[N:15][CH:14]=1
Reactant: c1ccc(-c2ccn3ccnc3c2)nc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCO
Solvent: CCOC(C)=O
Product: Ic1cnc2cc(-c3ccccn3)ccn12
Yield: 83 %

Procedure:
Dissolve 7-pyridin-2-yl-imidazo[1,2-a]pyridine (0.3 g, 1.5 mmol) in absolute ethanol (10 mL) and add NIS (0.35 g, 1 equiv.). Heat the reaction to 50° C. for 30 minutes under N2 then dilute with ethyl acetate. Wash the organic layer with 1 N NaOH followed by sat NaCl. Dry the organic layer over magnesium sulfate, filter and concentrate to give a light tan solid (0.4 g, 82%). MS (ES), m/z 322 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([N:25](C(OCC(Cl)(Cl)Cl)=O)[C@H:26]([C:31]([O:33]C)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][O:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:24]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:23][O:22][N:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of methyl N-(3-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoxazol-4-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (1.0 g, 1.55 mmol) in THF (20 mL) was added acetic acid (10 mL) and zinc dust (2.8 g, 42.8 mmol). The mixture was sonicated for 1 min, then stirred 1.5 h at room temperature. The solids were filtered through celite and the filtrate was co-evaporated with heptane. The residue was dissolved in ethyl acetate and washed with aqueous NaHCO3 and brine and concentrated. The residue was dissolved in methanol (25 mL) and 2 M LiOH (5 mL) was added. The mixture was stirred overnight at room temperature, then diluted with ethyl acetate and washed with pH 3 phosphate buffer. The organic phase was washed with brine and dried over MgSO4, and concentrated to give 710 mg of N-(3-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoxazol-4-yl)leucine.