Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[N:29]=4)[CH:20]=3)[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[N:29]=4)[CH:20]=3)[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxy-methyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.32 mmol) (from Example 27 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.15 g, 94%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[N:13]([C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[C:22]1([C@@H:20]([N:13]2[C@@H:8]3[C@H:7]([CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:6][C@H:14]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]2CCCC[C@@H]2N1[C@@H](C)c1ccccc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
Tetrahydrofuran (210 mL) was charged to 1 L flask containing ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate (14, 30.1 g), sodium t-butoxide (9.6 g) was added at ambient temperature between 19-24° C. under nitrogen. The mixture was then heated to 65° C. and stirred for NLT 1 hour and cooled to 5° C. It was then quenched with a solution of ammonium chloride (10.69 g) in water (34 mL) and concentrated to about 100 mL volume. The mixture was diluted with heptanes (210 mL) and water (105 mL) and the aqueous layer is further extracted with heptanes (2×105 mL). The combined organic layers were washed with water (105 mL), followed by 3.5 M aqueous sodium chloride solution (105 mL). The heptane layer was dried with anhydrous sodium sulfate and concentrated under vacuum to afford 20.65 g of crude compound (15), which was purified on silica gel (700 g) chromatography using 3-4% ethyl acetate in hexanes to afford 8.24 g of (2S,3aR,7aS)-ethyl 1-((S)-1-phenylethyl)octahydro-1H-indole-2-carboxylate (15) as a viscous oil.
Reaction SMILES: [P:1]([O-:16])([O-:15])([O:3][C@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6])=[O:2].[K+].[K+].O.C([NH+](CCCCCCCC)CCCCCCCC)CCCCCCC.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC.C1CCC(NC(N2CCOCC2)=NC2CCCCC2)CC1.C1N([P:97]([O:100][CH2:101][C@H:102]2[O:106][C@@H:105]([N:107]3[C:113](=[O:114])[NH:112][C:110](=[O:111])[CH:109]=[CH:108]3)[C@H:104]([OH:115])[C@@H:103]2[OH:116])([OH:99])=[O:98])CCOC1.N1C=NN=N1>N1C=CC=CC=1>[CH:109]1[C:110](=[O:111])[NH:112][C:113](=[O:114])[N:107]([C@@H:105]2[O:106][C@H:102]([CH2:101][O:100][P:97]([O:2][P:1]([O:3][C@H:4]3[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]3[OH:6])([OH:16])=[O:15])([OH:99])=[O:98])[C@@H:103]([OH:116])[C@H:104]2[OH:115])[CH:108]=1
Reactant: O=P([O-])([O-])O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)N3CCOCC3)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: CCCCCCCC[NH+](CCCCCCCC)CCCCCCCC
Solvent: O
Solvent: c1ccncc1
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Yield: 91 %

Procedure:
Dipotassium α-D-galactosyl phosphate (1.0 equivalents, Sigma), containing 5.5 mol H2O, (110 mg, 253 μmol) was converted into the trioctylammonium salt using 110 μL (253 μmol) trioctylamine and reacted with uridine 5'-monophospho morpholidate 4-morpholine-N,N'-dicyclohexylcarboxamidine salt (296 mg, 404 μmol) and 1H-tetrazole (57 mg, 808 μmol) in dry pyridine (1.25 mL) as described for 32. Purification on a Bio-Gel P-2 column (2.5×95 cm), eluated with 250 mM NH4HCO3, and precipitation from H2 O/MeOH/acetone gave 34 (134 mg, 91%) as a white solid after lyophilization (Rf 0.40, 2:1 i-PrOH/1M NH4OAc). The 1H NMR spectral data were in agreement with the published ones (Heidlas et al. J. Org. Chem. 1992, 57, 152-157).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:21]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:26]=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:2]([CH3:1])[C:29]([C:28]3[CH:33]=[CH:34][C:25]([C:21]([O:23][CH3:24])=[O:22])=[CH:26][CH:27]=3)=[N:31][N:32]=2)=[CH:5][CH:6]=1
Reactant: CNC(=O)c1ccc(C(=O)OC)cc1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)n2C)cc1

Procedure:
A solution of N-methyl-p-carbmethoxybenzamide in chloroform was treated with phosphorus pentachloride to give E. Then E was reacted with p-carbmethoxybenzoyl hydrazine to yield dimethyl-4,4'-(4-methyl-1,2,4-triazol-3,5-diyl)dibenzoate, (F). Then III was obtained by reacting F in a similar manner as in Example 1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[Cl:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:43][C:42]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[CH:22][C:21]=1[NH:20][C:8]([C:4]1[O:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])=[O:10]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Reactant: Cc1nc(C)c(C(=O)O)o1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2Cl)o1
Yield: 63.5 %

Procedure:
In the same manner as in Example 55 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (51.8 mg, 0.367 mmol), tetrahydrofuran (5 mL), thionyl chloride (63.3 μL, 0.730 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (114 mg, 0.332 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (98.4 mg, 63%) was obtained as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(Cl)(=O)C([Cl:32])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:26])[F:28])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])[C:5]([C:8]([Cl:32])=[O:9])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (450 mg, 1.0 mmol) in 3.0 mL CH2Cl2 and DMF (0.02 mL) was added oxalyl chloride (0.110 mL). The mixture was stirred for 2 h and concentrated to dryness provide 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:16][CH:17]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.2 %

Procedure:
2-Ethyl-5,7-dimethyl-3-(4-nitrobenzyl)-3H-imidazo[4,5-b]pyridine (4.81 g, 15.5 mmol) obtained in Step 1 was dissolved in methanol (155 mL) and palladium/carbon (10%, wet, 1.65 g, 1.55 mmol) and ammonium formate (9.77 g, 155 mmol) were added to the solution, followed by stirring at room temperature for 40 minutes. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Water was added to the residue and precipitated crystals were collected by filtration and washed with water. Ethyl acetate-hexane (2:3) was added to the obtained crude crystals and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, the precipitated crystals were collected by filtration to obtain Compound P7 (3.53 g, 12.6 mmol, yield 81.2%).
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][C@H:11]([NH:23][C:24](=[O:45])[C@@H:25]([NH:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1)[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1.CO.[H][H]>[Pd].C1COCC1>[CH:28]1([CH2:27][CH2:26][C@H:25]([NH:34][C:35](=[O:44])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)[C:24]([NH:23][C@H:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][C:9]([OH:46])=[O:8])=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CC(=O)OCc2ccccc2)CN2CCc3cc(F)ccc32)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CC(=O)O)CN2CCc3cc(F)ccc32)c1
Yield: 95 %

Procedure:
The title compound of Example 46 (300 mg, 0.476 mmol) was treated with 10% Pd/C (40 mg), MeOH (5 mL) and THF (5 mL). The atmosphere in the reaction was exchanged for hydrogen and the reaction was allowed to stir for 1 h under a balloon of hydrogen. The atmosphere was then exchanged back to nitrogen, the reaction was filtered through a pad of celite and the solvent was removed to afford 244 mg (95%) of a crystalline solid; 1H NMR (DMSO, 400 MHz) δ 0.55-0.88 (m, 2H), 1.00-1.22 (m, 7H), 2.93 (dd, 1H, J1=5.8, J2=13.6), 3.11 (dd, 1H, J1=7.6, J2=13.7), 3.25 (dd, 1H, J1=8.7, J2=17.5), 3.34 (s, 3H), 3.41-3.50 (m, 1H), 3.81 (s, 3H), 4.30-4.41 (m, 1H), 6.71-6.79 (m, 1H), 6.85-6.89 (m, 1H), 7.07-7.12 (m, 1H), 7.37 (dd, 1H, J1=J2=7.8), 7.40-7.48 (m, 2H), 7.98 (d, 1H, J=8.6), 8.32 (d, 1H, J=8.1); HPLC-MS calcd. for C30H38FN3O5 (M+H) 483.3, found 483.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH2:16]([C:19]#[N:20])[CH:17]=[CH2:18].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([CH2:16][CH:17]=[CH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1)#[N:20]
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Reactant: C=CCC#N
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(C=CCC#N)cn12
Temperature: 95 °C

Procedure:
A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (500 mg, 1.86 mmol), allyl cyanide (224 uL, 2.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (26 mg, 0.028 mmol), [(t-Bu)3PH]BF4 (16 mg, 0.056 mmol), and N,N-dicyclohexylmethylamine (433 μL, 2.04 mmol) in anhydrous 1,4-dioxane (6 mL) was heated at 95° C. overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated. The crude product was purified by silica chromatography to give ethyl 6-(3-cyanoprop-1-enyl)imidazo[1,2-a]pyridine-3-carboxylate (24v). MS m/z 256.4 (M+1)+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21](O)[CH2:22][C:23](=[O:29])[CH2:24][C:25]([O:27]C)=[O:26].Cl>C(O)C.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]1[O:27][C:25](=[O:26])[CH2:24][CH:23]([OH:29])[CH2:22]1
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CC(O)CC(/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Yield: 107.5 %

Procedure:
Sodium tetrahydridoborate (1.55 g, 41.1 mmole) was added with stirring to a cooled solution (5° C.) of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-5-hydroxy-3-oxo-6-heptenoate (34.8 g, 82.3 mmole) in ethanol (200 ml) at a rate sufficient to maintain the internal temperature at 15°-20° C. The resulting solution was stirred with ice-bath cooling for 15 min. and then acidified with 6N hydrochloric acid. The resulting mixture was diluted with water (500 ml) and extracted with ether (3×250 ml). The organic extracts were combined, washed with brine (4×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as a yellow oil (34.8 g, 99.5%): pmr CDCl3) δ2.45 (2H, d), 3.65 (3H, s), 4.18 (H, m), 4.45 (H, m), 4.98 (2H, s), 7.28 (5H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:3][CH2:2]1.[Br:21]Br>C(O)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:8][C:9]=1[O:10][C:11]1[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: BrBr
Reactant: Nc1ncccc1Oc1cccc(N2CCOCC2)c1
Solvent: CC(=O)O
Product: Nc1ncccc1Oc1cc(N2CCOCC2)ccc1Br
Reaction time: 1 h
Yield: 77.5 %

Procedure:
In a 250 mL round-bottom flask, 3-(3-morpholinophenoxy)pyridin-2-amine (0.720 g, 2.654 mmol) was dissolved in 25 mL of acetic acid and Bromine (2.654 mL, 2.654 mmol) (1M in AcOH) was added slowly. After agitating for 1 hour the mixture was evaporated and the residue was distributed between dichloromethane and sodium bicarbonate solution. The organic phase was separated and evaporated. The residue was purified by column chromatography on silica gel, eluted with 1-3% methanol/dichloromethane to give the title compound (0.72 g, 77%) as white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C.O>[ClH:32].[CH:22](=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]1=[N:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (2.5 g, 6.5 mmol) was dissolved in ethanol (20 ml) and 4N sodium hydroxide (4.9 ml) was added. The mixture was stirred at ambient temperature for 3 h and excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml) and water (15 ml). The phases were separated and the organic phase was dried (MgSO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone and recrystallised from acetone (180 ml) to give 1.5 g of the title compound as a solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C@H:18]4[O:23][CH2:22][CH2:21][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=6)=[CH:26][N:25]=5)[CH2:19]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:43]([OH:45])[CH3:44]>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C@@H:18]4[CH2:19][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH2:31][CH2:32][N:33]([CH2:44][CH2:43][OH:45])[CH2:34][CH:35]=6)=[CH:26][N:25]=5)[CH2:21][CH2:22][O:23]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1
Reactant: CC(O)Br
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCNCC6)cn5)CCO4)c3n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCN(CCO)CC6)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
(S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)morpholine HCl salt 330 mg (0.67 mmol) was dissolved in DMF 10 ml, and potassium carbonate 276 mg (1.99 mmol), bromo ethanol 71 μl (0.99 mmol), and TEA 1 ml were added, followed by stirring at room temperature overnight. When the reaction was completed, the reaction mixture was extracted several times with ethyl acetate and brine, and the organic layer was dried over Na2SO4. 7% MeOH/MC chromatography gave a product 210 mg (62%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.0 g, 21 mmol) in DMSO (30 mL) was added ethyl piperidine-4-carboxylate (5.0 g, 32 mmol) and K2CO3 (5.9 g, 43 mmol). The resulting mixture was stirred at 100° C. for 8 h, and allowed to cool to rt. EtOAc (300 mL) was added. The organic layer was washed with water (3×100 mL) and brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)). Compound 54a was obtained as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H18N2O4: 279.1 (M+H). Found 279.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1.[CH:18](O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[CH:18][N:8]([CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=3)[C:6]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1NCc1cncc(F)c1
Reactant: O=CO
Product: Fc1cncc(Cn2cnc3ccc(Br)cc32)c1

Procedure:
A solution of Example 12B (1.615 g, 5.45 mmol) in formic acid (4.53 mL, 120 mmol) was heated at 95° C. for 1 hour. After cooling, the mixture was concentrated and dissolved in ethyl acetate. The mixture was washed with 10% aqueous potassium carbonate and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with a gradient of 50-100% ethyl acetate/hexane then 10% 2:1 methanol/water in ethyl acetate, followed by recrystallization from ethyl acetate/hexane, afforded the title compound. MS (ESI) m/z 305.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (245 mg, 76%)
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[O:9])[C:6]([O:8][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
With reference to reaction Scheme 2, a slurry of 25 g (0.164 mol) of the sodium salt of 4-methyl-2-oxopentanoic acid, sodium salt in anhydrous N,N-dimethylformamide (50 ml) containing 19.6 ml (0.164 mol) of benzyl bromide was agitated at room temperature for 4 days. The solvent was removed in vacuo. The residue was dissolved in 250 ml of hexane and washed with water (3×50 ml) and brine (50 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 33.2 g (92% yield) of benzyl 4-methyl-2-oxopentanoate (1a) as a viscous, colorless oil. TLC: Rf 0.70 (ethyl acetatehexane 1:4); 1H NMR(CDCl3) δ 0.94(d, 6H), 2.18(m, 1H), 2.71(d, 2H), 5.26(s, 2H), 7.37(m, 5H); 13C NMR (CDCl3) δ 22.5, 24.2, 48.1, 67.9, 128.7, 128.8, 128.9, 134.7, 161.3, 194.0.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:16]3[CH:15]=[C:14]([CH2:13][CH:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[N:22]4[C:17]=3[C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(CC3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 18 h
Yield: 31.1 %

Procedure:
The product from Step 4 (0.10 g, 0.19 mmol) was dissolved in dichloromethane (3 mL) and TFA (0.14 mL, 1.95 mmol) was added. The mixture was stirred for 18 hours and concentrated. The residue was purified by preparative HPLC using 10-90% gradient of acetonitrile/water to provide 25 mg (31%) of the title compound. 1H-NMR (CD3OD-d4) 8.30-8.35 (m, 1H), 7.85-7.80 (m, 2 H), 7.67-7.64 (m, 1H), 7.40-7.22 (m, 5 H), 7.24 (dd, 1 H), 6.64 (s, 1 H), 5.67 (s, 2 H), 3.17-2.94 (m, 3 H), 2.77-2.68 (m, 2 H), 2.08-1.98 (m, 1 H), 1.70-1.59 (m, 1 H); LC-MS [M+H]+=424.2, RT=2.03 min.