Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([CH3:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([N:35]2[CH2:39][C@H:38]([CH2:40][N:41]3[CH:45]=[CH:44][N:43]=[N:42]3)[O:37][C:36]2=[O:46])[CH:19]=[CH:20][C:21]=1[C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH2:32][C@@H:31]([CH2:33]O)[O:30][N:29]=2)=[CH:26][CH:27]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([N:5]([CH3:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:33][C@H:31]1[O:30][N:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[CH:20]=[CH:19][C:18]([N:35]4[CH2:39][C@H:38]([CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[N:42]5)[O:37][C:36]4=[O:46])=[CH:17][C:16]=3[F:15])=[CH:23][N:24]=2)[CH2:32]1)=[O:12])=[O:4]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COC(=O)N(C)CCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N(C)CCCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The carbamate prepared as above (0.37 g, 1.82 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 0.2 g, 0.46 mmol), 4-dimethylaminopyridine (0.01 g, 0.08 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.19 g, 0.99 mmol) were combined in DMF (2 ml). The suspension was allowed to stir for 3.5 hours at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as an off-white powder (0.225 g), melting point: 103° C.
Reaction SMILES: [C:1]([OH:6])(=O)[C@@H:2]([CH3:4])[OH:3].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@H:34]([CH3:38])[CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@H:34]([CH3:38])[CH2:35][N:36]([CH3:37])[C:1](=[O:6])[C@H:2]([OH:3])[CH3:4])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](CN(C)C(=O)[C@@H](C)O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 26 %

Procedure:
The procedure described in Example 1 was repeated using D-(−)-lactic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a white solid in 26% yield; NMR spectrum (DMSO-d6 373K) 1.15 (d, 3H), 1.44 (d, 3H), 2.97 (s, 3H), 3.16 (m, 1H), 4.05 (dd, 1H), 4.43 (m, 1H), 5.16 (m, 1H), 5.27 (s, 2H), 7.23 (m, 2H), 7.35 (m, 2H), 7.59 (m, 2H), 7.70 (t, 1H), 7.84 (dt, 1H), 8.09 (d, 1H), 8.47 (s, 1H), 8.59 (d, 1H), 9.90 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:9]=1.[S:18]1[CH2:24][C:22](=[O:23])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:19]1=[S:20].[Cl-].[NH4+].N>C(O)C>[CH2:14]([O:13][C:11]([C:10](=[C:24]1[S:18][C:19](=[S:20])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:22]1=[O:23])[C:8]1[N:9]=[C:5]([NH:4][C:3]([NH:2][CH3:1])=[O:17])[S:6][CH:7]=1)=[O:12])[CH3:15]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)NC)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)NC)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3.17 g of ethyl 2-(3-methylureido)thiazol-4-ylglyoxylate, 2.2 g of rhodanine-3-acetic acid, 1.2 g of ammonium chloride, 1.2 ml of 28% v/v aqueous ammonia and 50 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].OS(O)(=O)=O.O1CCCC1>O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 4 h
Yield: 91 %

Procedure:
A mixture of 12.97 g (0.0436 mol) of the ketal of (A) and 200 ml of 10% H2SO4 /tetrahydrofuran (2:1) solution is stirred at 60°-70° C. for 4 hrs and is then allowed to stand at room temperature for 3 days. The mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ethyl ether gives 10.07 g (91%) of title compound as a white solid: m.p. 183°-185° C.; IR (KBr) 3410, 1710, 1585, and 1160 cm-1 ; NMR (CDCl3) δ 7.79 (d, 2H), 6.98 (d, 2H), 3.79 (t, 4H), 3.04 (s, 3H), and 2.61 (t, 4H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:13]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:13]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(CCn1c2c(c3ccccc31)CCNCC2)c1ccccc1
Yield: 11.3 %

Procedure:
tert-Butyl 6-[2-(phenylsulfonyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.139 g, 0.306 mmol) was treated with trifluoroacetic acid (1 mL) for 5 min. CH2Cl2 was added and the reaction mixture was concentrated to dryness. The salt was partitioned between CH2Cl2 and a mixture of 1M KOH and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was chromatographed (SiO2, eluted with 1:1 EtOAc:hexane) to give 6-[2-(phenylsulfonyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.0123 g) as a white solid. 1H NMR (300 MHz, CD3OD) δ 3.13, 3.29-3.33, 3.42, 3.50, 3.71, 4.65, 7.07, 7.14, 7.22, 7.42, 7.51, 7.66, 7.70.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4](Cl)=[N:5][OH:6].[C:13]([C:15]1[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1)#[CH:14].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=2)[O:6][N:5]=1
Reactant: C#Cc1cccc(NCCP(=O)(OCC)OCC)c1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Temperature: 25 °C
Yield: 89.2 %

Procedure:
2,6-Dichloro-N-hydroxybenzimidoyl chloride (370 mg, 1.6 mmol) and diethyl 2-(3-ethynylphenylamino)ethylphosphonate (450 mg, 1.6 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL) and triethylamine (0.30 mL, 1.6 mmol). The mixture was then heated at reflux for 5 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography on silica gel, eluting with 98:2 methylene chloride:methanol to give diethyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylphosphonate (670 mg) as a pale yellow oil. 1H NMR (CDCl3): 7.30 (m, 2H), 7.21 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 7.00 (m, 1H), 6.59 (m, 1H), 6.48 (s, 1H), 4.03 (m, 4H), 3.40 (m, 2H), 2.00 (m, 2H), 1.24 ppm (m, 6H). MW=469 confirmed by LC-MS, tr=14.80 min (Method Y) MH+=467-472.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:17])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A mixture of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (2.00 g, 7.83 mmol), ethyl bromoacetate (1.30 mL, 11.75 mmol) and potassium carbonate (1.62 g, 11.75 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature, and then partitioned between ethyl acetate (75 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (75 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate in hexanes to afford the title compound as a colorless solid (2.03 g, 76%): 1H NMR (300 MHz, CDCl3) δ 4.33-4.13 (m, 6H), 4.09 (s, 2H), 3.76-3.69 (m, 2H), 2.62 (s, 3H), 1.37-1.26 (m, 6H); MS (ES+) m/z 342.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:19])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(O)cccc1CCC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cccc(O)c1OC

Procedure:
To a solution of 3-(3-hydroxy-2-methoxyphenyl)propanoic acid (50 mg) in methanol (10 mL) was added dropwise thionyl chloride (2.0 mL) at 0° C. The reaction mixture was heated under reflux for 3 hr. The reaction mixture was concentrated, and ethyl acetate was added. The reaction mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (45 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[CH3:11][NH:12][CH3:13].O1CCOCC1>C1COCC1>[CH3:11][N:12]([CH3:13])[C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:8]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CNC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N(C)C)c(C)o1
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 2,5-dimethylfuran-3-carbonylchloride (2.19 g; 13.8 mmol) in 10 ml of THF was added to a 2M solution of dimethylamine in dioxane (21 ml; 42 mmol) in 80 ml of THF at rt. After stirring for 1 hr, the volatiles were removed in vacuo and the residue was partitioned between EtOAc (100 ml) and water (100 Ml). The organic layer was washed with saturated potassium bisulfate solution (100 ml), 1N NaOH (50 ml) and brine (50 ml). Drying over MgSO4 and concentration in vacuo afforded compound 866A (1.84 g, 80%) as an amber liquid. 1HNMR (CDCl3): δ 2.23 (s, 3H), 2.33 (s, 3H), 3.04 (s, 6H), 5.96 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12]C(=O)OC(C)(C)C)[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])[C:6]2[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:5]1=2)(=[O:3])[CH3:2].[ClH:40]>O1CCOCC1.CCOCC>[ClH:40].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH2:12])[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])[C:6]2[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Yield: 78 %

Procedure:
A rt solution of tert-butyl(3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (316 mg, 598 μmol) in 4 M HCl in dioxane (2.99 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-5-acetyl-3-amino-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (216 mg, 78%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][C:9]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-]>N.CCO>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(C)(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 16.9 %

Procedure:
A solution of 6-bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (292 mg, 0.667 mmol), NH4I (245.7 mg, 1.668 mmol) in a solution of NH3/EtOH (30 mL, 5 N) was heated at 110° C. in a CEM tube in a microwave reactor for 4 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′,2-dimethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 18%). 1H-NMR (MeOD): 1.63 (s, 3H), 1.77 (s, 3H), 2.74 (d, 2H), 6.75 (d, 1H), 7.06 (d, 1H), 7.22 (m, 1H), 7.31 (m, 3H), 7.45 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].O>CN1CCCC1=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]2[NH:29][N:28]=[N:27][N:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(C[C@@H]2CN3C(c4nnn[nH]4)=Nc4nc(C5CCCC5)[nH]c4C3=N2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Compound 75 (69 mg, 0.200 mmol) obtained in Example 75 was dissolved in 1-methyl-2-pyrrolidinone (1 mL), to the solution were added sodium azide (52 mg, 0.800 mmol, 4.0 equivalents) and ammonium chloride (42 mg, 0.800 mmol, 4.0 equivalents), and the mixture was stirred at 120° C. for 2 hours. To the reaction mixture was added water, and the deposited crystals were collected by filtration to obtain the title compound (64 mg, 83%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:5][CH2:6][CH2:7][C@H:8]([OH:22])[C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12].[OH-].[Na+]>O1CCOCC1.O>[C:18]([O:17][C:15]([NH:14][C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@@H:8]([OH:22])[CH2:7][CH2:6][NH:5][C@H:4]([C:3]([OH:27])=[O:2])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@H](CC(C)C)NCC[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@H](NCC[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Yield: 83 %

Procedure:
2 (700 mg) was dissolved in dioxane (8 ml), diluted with H2O (8 ml) and treated with four portions (2 ml each) of 1N NaOH (aqueous) over a 1.5 hour period. The aqueous dioxane was removed in vacuo and the white solid residue dissolved in H2O (10 ml). The product was precipitated by acidification with 1N HCl and collected by filtration to give 3 as a fine white powder (560 mg, 83% yield) after drying.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[N:5]=[C:4]([NH2:15])[N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:15][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[N:5]=1
Reactant: C[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Into a 25 mL sealable tube under nitrogen were combined 4-chloro-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (500 mg, 2.19 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.397 g, 2.4 mmol) in 1,4-dioxane (10 mL). Saturated aqueous NaHCO3 (5 mL) was added, and the resulting mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (0.126 g, 0.11 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 95° C. overnight. The reaction was cooled to room temperature, solids and other insoluble impurities formed during the reaction were filtered, and the orange filtrate was concentrated. The resulting solid was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The organic layer was separated, washed with water and brine, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in CH2Cl2 and purified by flash chromatography on SiO2 (gradient: 100% CH2Cl2 to 15% of 90/10/1 CH2Cl2/CH3OH/NH4OH). Fractions were evaporated, and the solids were triturated with Et2O and filtered to afford the title compound (403 mg) as a yellow solid. LC-MS (ES) m/z=314 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CN(C=O)C.P(Cl)(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:19])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Yield: 95.9 %

Procedure:
3-Bromo-2-hydroxy-5-nitropyridine (8.5 g, 39 mmol) and N,N′-dimethylformamide (0.5 ml) in chloroform (75 ml) were treated dropwise with phosphorous oxychloride (7.3 ml, 80.2 mmol) and heated at reflux for 24 hrs. The mixture was then cooled and concentrated, before being partitioned between ethyl acetate (80 ml) and sodium hydrogen carbonate solution (50 ml). The organic phase was washed with brine (100 ml), dried Na2SO4) and concentrated to give the product as a yellow solid (8.88 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[C:31]([O:33]CC2C=CC=CC=2)=[O:32])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:41]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[C:31]([OH:33])=[O:32])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)isophthalate (170 mg, 0.28 mmol) in MeOH (5.0 mL) was added Pd/C (10%). The reaction mixture was stirred under H2 atmosphere for 2 h. The reaction mixture was then filtered through a small pad of CELITE®, washing thoroughly with MeOH. The filtrate was concentrated in vacuo to provide the title compound (133 mg, 92%), which was used without further purification. MS(ESI+) m/z 506.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].O>CN(C=O)C>[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(Cc2c[nH]c3ccccc23)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(Cc2ccccc2)c2ccccc21
Reaction time: 1 h

Procedure:
To a suspension of NaH (50% dispersion in oil, 170 mg, 3.5 mmol) in DMF (15 mL), at r.t. and under an atmosphere of nitrogen, there was added in portions 3-benzylindole (ref: Tetrahedron 23, 3771-83 (1967)) (621 mg, 3 mmol) and the mixture was stirred for 1 hour. There added methyl bromoacetate (765 mg, 5 mmol) and stirring was continued for 1.5 hours. H2O (100 mL) was added and the mixture was extracted twice with Et2O. These extracts were H2O with water, dried over MgSO4 and evaporated to a residue which was chromatographed on silica gel eluting with a 1:5 mixture of EtOAc acetate and hexane to afford the title product as an oil.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][NH:14][C:15]1[N:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][N:16]=1.Cl[C:31]1[N:39]=[C:38]2[C:34]([N:35]=[CH:36][N:37]2[CH2:40][CH:41]2[CH2:45][CH2:44][O:43][CH2:42]2)=[C:33]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[N:32]=1>O>[CH3:13][NH:14][C:15]1[N:16]=[CH:17][C:18]([C:31]2[N:39]=[C:38]3[C:34]([N:35]=[CH:36][N:37]3[CH2:40][CH:41]3[CH2:45][CH2:44][O:43][CH2:42]3)=[C:33]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[N:32]=2)=[CH:19][N:20]=1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CCOC3)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CCOC4)c3n2)cn1
Yield: 40.8 %

Procedure:
1,4-Dioxane (40 ml), water (20 ml), and sodium carbonate (2 g, 19 mmol) were added to N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.45 g, 6.18 mmol) and 2-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purine (2.0 g, 6.18 mmol) and the atmosphere in the reaction vessel was substituted with nitrogen. Tetrakis triphenylphosphine palladium (0.36 g, 0.31 mmol) was added, then the atmosphere in the reaction vessel was substituted with nitrogen again, and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Methylene chloride-ether was added to the residue and the insoluble matter was collected by filtration and dried to give the title compound (1.0 g, 41%) as a white solid.