Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39].C(Cl)Cl>CN(C=O)C.CCOCC>[Si:1]([O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]([CH2:37][CH2:38][OH:39])[C:25](=[O:27])[O:26][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1ccc2[nH]c(=O)oc2c1)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc2c(c1)oc(=O)n2CCO)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 44.3 %

Procedure:
To a solution of 6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3-benzoxazol-2(3H)-one (Intermediate 78, 218 mg, 0.54 mmol) in DMF (2 mL) were added potassium carbonate (232 mg, 1.68 mmol) and 2-bromoethanol (60 μL, 0.85 mmol) and the reaction mixture was placed in a sealed vessel at 120° C. over a period of 4 hours. CH2Cl2 was added to the mixture and the solids were filtered off and washed with CH2Cl2. The resulting filtrate was washed with water and brine and the organic phase was filtered through a Phase Separator membrane to remove remaining water. The crude oil was purified by column chromatography over silica gel using Hexane:Et2O as eluent (from 0 to 100% of Et2O) to give the title compound as a white solid (107 mg, 44% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:28]1[S:32][CH:31]=[C:30]([C:33](O)=[O:34])[CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[NH2:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[CH:37]1([NH:36][C:33]([C:30]2[CH:29]=[C:28]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)[S:32][CH:31]=2)=[O:34])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)O)cs1)C(=O)N1CCC[C@@H]21
Reactant: NC1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)NC3CCc4ccccc43)cs1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-3-thiophenecarboxylic acid (0.100 g, 0.202 mmol) was dissolved in CH2Cl2. 1-aminoindane (0.039 mL, 0.328 mmol) was added followed by EDCI (0.047 g, 0.243 mmol) and HOBt (0.033 g, 0.243 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 3:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.085 g, 0.139 mmol, 69% yield): 1H NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.46 (s, 1H), 7.35–7.31 (m, 1H), 7.28–7.20 (m, 3H), 7.16 (dd, J=8.5, 5.5 Hz, 2H), 6.97 (t, 2H), 6.17 (m, 1H), 5.67 (dd, J=15.5, 7.8 Hz, 1H), 4.69 (dd, J=10.4, 6.2 Hz, 1H), 4.19 (dd, J=14.3, 7.0 Hz, 2H), 3.76–3.69 (m, 1H), 3.42–3.36 (m, 1H), 3.19–2.99 (m, 5H), 2.96–2.87 (m, 1H), 2.74–2.64 (m, 1H), 2.51–2.43 (m, 1H), 2.39–2.27 (m, 2H), 1.96–1.86 (m, 1H), 1.41–1.34 (m, 1H), 1.09 (t, 7.0 Hz); ESMS m/z 610 (M+H)+, 608 (M−H)+; Anal. Calcd. For C35H32FN3O4S.½H2O: C, 68.44; H, 5.33; N, 6.84; found: C, 68.42; H, 5.50; N, 6.78.
Reaction SMILES: [Ti](Cl)(Cl)(Cl)[Cl:2].C1(C)C=CC=CC=1.[Cl-:13].[C:14]1([N:20]2[CH2:28][CH2:27][N:26]([Ti+3:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-]>C(OCC)C>[Cl-:2].[Cl-:13].[C:14]1([N:20]2[CH2:28][CH2:27][N:26]([Ti+2:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: [Ti+3]N1CCNCCN(c2ccccc2)CC1
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: [Ti+2]N1CCNCCN(c2ccccc2)CC1
Temperature: 40 °C

Procedure:
Separately, 0.647 g (3.41 millimoles) of titanium tetrachloride was dissolved in 20 milliliters of diethyl ether at −50° C. The resulting solution was dropwise added at −60° C. over 2 hours to the toluene mixed solution prepared previously, and the resulting mixture was then heated to 40° C. and then subjected to reaction for a further 6 hours. Subsequently, the reaction mixture obtained was subjected to recrystallization from a hexane/methylene chloride mixed solvent to isolate the product, thereby obtaining N-phenyl-1,4,7-triazacyclononanyltitanium chloride in a yield of 35%.
Reaction SMILES: CC(C)(O[N:5]([C@H:9]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]#[CH:31])[C:25]([Br:32])=[CH:24][N:23]=2)[CH:14]=1)=[O:11])C(=O)[O-])C.S(=O)(=O)(O)O.O>O1CCOCC1>[NH2:5][C@H:9]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]#[CH:31])[C:25]([Br:32])=[CH:24][N:23]=2)[CH:14]=1)=[O:11]
Reactant: C#CCOc1nc(Nc2cc(CO)cc(NC(=O)[C@@H](Cc3ccccc3)N(OC(C)(C)C)C(=O)[O-])c2)ncc1Br
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: C#CCOc1nc(Nc2cc(CO)cc(NC(=O)[C@H](N)Cc3ccccc3)c2)ncc1Br
Yield: 56 %

Procedure:
1,1-Dimethylethoxy[(1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-(hydroxymethyl)phenyl]amino]-2-oxo-1-(phenylmethyl)ethyl]carbamate (22 mg) and sulfuric acid (0.3 ml; 2 n) were stirred in dioxane (3 ml) at 100° C. for 2.5 h. After cooling and dilution with water saturated NaHCO3-solution was added and the resulting preticipate collected by filtration yielding the title compound (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[O:31][C:30]([CH2:32][CH3:33])=[N:29][CH:28]=3)=[O:26])[CH2:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[O:31][C:30]([CH2:32][CH3:33])=[N:29][CH:28]=3)=[O:26])[CH2:16][C@H:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(CC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ncc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@H](C)C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
Next, to a solution of (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoate (264 mg, 0.56 mmol) in MeOH (2 mL) is added aqueous 1N NaOH (4 mL) After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) and then is purified by chiral-HPLC(OJ-H, 15% EtOH(0.1% TFA)/Heptane), and then lyophilized to give (2S,4S)-5-(3′-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoic acid (43 mg), HPLC retention time=1.63 minutes (condition B); MS (m+1)=441.2; 1 H NMR (400 MHz, CD3OD) δ ppm 1 H NMR (400 MHz, CD3OD) δ ppm 1.17 (d, J=7.1 Hz, 3 H) 1.35 (t, J=7.7 Hz, 3 H) 1.69 (ddd, J=14.0, 8.3, 3.9 Hz, 1 H) 2.06 (ddd, J=14.1, 10.8, 5.9 Hz, 1 H) 2.39-2.55 (m, 1 H) 2.85 (q, J=7.6 Hz, 2 H) 2.90 (dd, J=13.4, 7.6 Hz, 1 H) 2.95 (dd, J=13.1, 5.8 Hz, 1 H) 4.31-4.52 (m, 1 H) 7.26-7.35 (m, 3 H) 7.38 (t, J=7.8 Hz, 1 H) 7.46-7.55 (m, 4 H) 7.57 (t, J=1.9 Hz, 1 H) and (2R,4S)-5-(3′-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoic acid (60 mg). HPLC retention time=1.62 minutes (condition B); MS (m+1)=441.2; 1 H NMR (400 MHz, CD3OD) δ ppm 1.18 (d, J=7.1 Hz, 3 H) 1.35 (t, J=7.6 Hz, 3 H) 1.69 (ddd, J=14.1, 10.4, 4.3 Hz, 1 H) 2.01 (ddd, J=14.0, 10.0, 3.8 Hz, 1 H) 2.46-2.63 (m, 1 H) 2.85 (q, J=7.6 Hz, 2 H) 2.91 (d, J=7.1 Hz, 2 H) 4.30-4.49 (m, 1 H) 7.26-7.34 (m, 3 H) 7.38 (t, J=7.8 Hz, 1 H) 7.46-7.52 (m, 3 H) 7.52 (s, 1 H) 7.56 (t, J=1.9 Hz, 1 H) 8.31 (d, J=9.1 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3.Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[F:27][C:28]1([F:32])[CH2:31][N:30]([C:2]2[N:25]=[CH:24][C:5]3[C:6]4[N:10]([CH:9]=[C:8]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=5)[N:7]=4)[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH2:29]1
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: FC1(F)CNC1
Agent: Cl
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(N3CC(F)(F)C3)cc1OCC2

Procedure:
[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol was reacted with 3,3-difluoroazetidine-HCl to give 417 (23 mg) as a colorless solid. LCMS: 418.1. 1H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 7.85 (s, 1H), 6.16 (s, 1H), 5.87 (dt, J=13.2, 6.6 Hz, 1H), 5.18 (t, J=6.0 Hz, 1H), 4.60-4.47 (m, 4H), 4.41 (overlapping m, 6H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH3:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][CH2+:33]1SC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:11]([C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH2:9][CH3:10])=[C:2]([N:1]=[C:33]2[N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36](=[O:37])[C:35](=[C:38]3[N:42]([CH3:43])[C:41]4[CH:44]=[C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:40]=4[S:39]3)[S:34]2)[CH:3]=1)(=[O:13])[CH3:12]
Reactant: CCNc1ccc(C(C)=O)cc1N
Reactant: COCCOc1ccc2c(c1)N(C)C(=C1S[CH2+](SC)N(Cc3ccccc3)C1=O)S2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccc(OCCOC)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was synthesized in a manner similar to that described in Example 146 by condensing 3′-amino-4′-(ethylamino)acetophenone with 3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate. MS(ESI): 546 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]([C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[CH:18]2[C:35]#[N:36])=[CH:13][CH:12]=1.[Al](N=[N+]=[N-])(N=[N+]=[N-])N=[N+]=[N-]>C1COCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]([C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[CH:18]2[C:35]2[NH:36][N:7]=[N:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [N-]=[N+]=N[Al](N=[N+]=[N-])N=[N+]=[N-]
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
To THF (2.5 ml) at -78° C. under an argon atmosphere was added aluminum chloride (90 mg, 0.67 mmol). After slowly warming to room temperature, sodium azide (130 mg, 2.2 mmol) was added, and the resulting mixture was heated at 70° C. for 5 min, then cooled to room temperature. To the reaction mixture was added a solution of (1RS, 2SR, 3SR)-lo(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carbonitrile (125 mg, 0.34 mmol) in THF (2.5 ml). After heating at 70° C. overnight, thin layer chromatographic analysis of the reaction mixture indicated the presence of starting material, so additional Al(N3)3 was prepared as above (1.34 mmol) in THF. To this was added the reaction mixture, and heating at 70° C. was resumed for an additional 5 h. The mixture was partitioned between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was crystallized from EtOAc/hexanes to afford the title compound (78 mg, 56%). A portion of this material was further purified by MPLC (LiChroprep RP-18, MeOH/H2O=60/40) and then recrystallized; m.p. 155°-157° C. (EtOAc/hexanes).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1/[CH:5]=[CH:6]\[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:10]([OH:12])=[O:11].[CH2:22](I)[CH2:23]C>>[CH3:1][CH:2]1[CH2:4][CH:3]1/[CH:5]=[CH:6]\[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([N:16]([CH2:21][CH2:22][CH3:23])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: CC1CC1/C=C\c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Reactant: CCCI
Product: CCCN(c1cc(/C=C\C2CC2C)cc(C(=O)O)c1)S(C)(=O)=O

Procedure:
This compound was prepared analogously to 3-[(Z)-2-(2-methylcyclopropyl)vinyl]-5-[methyl(methylsulfonyl)amino]benzoic acid, the only difference being the substitution of methyl iodide with propyl iodide in Step D.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][OH:17])=[NH:15])[CH:9]=2)=[CH:6][N:7]=1.CN1[C:30]2[CH:31]=[CH:32][C:33](Cl)=[CH:34][C:29]=2[C:28](C2C=CC=CC=2)=NCC1=O.C(Cl)(=O)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:17][N:16]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CNC(=O)c1nc(-c2cccc(C(=N)NO)c2)cnc1N
Solvent: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(-c2cccc(-c3noc(-c4ccccc4)n3)c2)cnc1N
Reaction time: 1 h
Yield: 19.9 %

Procedure:
3-Amino-N-methyl-6-{3-[(hydroxyamino)(imino)methyl]phenyl}pyrazine-2-carboxamide (40 mg, 0.14 mmol) was suspended in DMF (750 uL) followed by addition of PL-DIPAM (diisopropylaminomethyl) resin (100 mg, 2.33 mmol/g) and benzoyl chloride (20 uL, 0.17 mmol). The mixture was agitated for one hour then diluted with ethyl acetate and the spent resin removed by filtration, The organic filtrate was washed with water (3×), brine then dried over anhydrous magnesium sulfate. The mixture was then filtered and concentrated and the solid residue suspended in TIF (1 mmol) followed by addition of tetra-N-butylammonium fluoride (TBAF) (1.0 M in THF, 100 uL) and the solution was allowed to stir at room temperature over 12 hours. The mixture was concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed with water (1×), 1.0 M aqueous hydrochloric acid (lx) then brine and dried over anhydrous magnesium sulfate. The material was filtered and concentrated then the residue purified by preparative reverse phase HPLC (water/acetonitrile/0.1% TFA eluent). The pure fractions were combined and lyophilized to afford 3-amino-N-methyl-6-[3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl]pyrazine-2-carboxamide (10.4 mg, 20% yield) as a yellow solid: MS (EI) for C20H17N6O2: 372 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:21]=[C:20]([CH3:22])[O:19][N:18]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[CH3:22][C:20]1[O:19][N:18]=[C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:24][NH2:25])[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)[CH:21]=1
Reactant: NN
Reactant: Cc1cc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)no1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)no1
Reaction time: 3 h
Yield: 26 %

Procedure:
There was suspended, in 1,4-dioxane (20 mL), 5-chloro-2-(5-methylisoxazol-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine (0.82 g, 2.6 mM) prepared in the foregoing step 1, then hydrazine monohydrate (1.3 mL, 26 mM) was added to the suspension and the suspension was stirred for 3 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was then diluted with water and extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off to thus give a crude product of the title compound (210 mg, yield: 26%). MS (ESI) m/z (M+H)+ 316.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:10]=[C:11](/[CH:15]=[C:16]2/[C:17](=[O:33])[C:18]3[C:23]([CH2:24]/2)=[CH:22][C:21]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:20]([O:31][CH3:32])[CH:19]=3)[CH:12]=[N:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]>CO.[Pd]>[F:34][C:2]([F:1])([F:35])[C:3]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:22]=3)[C:17]2=[O:33])[CH:12]=[N:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Reaction time: 6 h

Procedure:
The 263 (50 mg, 0.090 mmol) was dissolved in methanol 25 ml, Pd/C 40 mg added, and the reaction stirred under H2 balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude, which was purified by flash chromatography using 100-200 mesh silica gel. The crude compound 264 was eluted at 20% ethyl acetate in hexane as half white coloured solid 2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 264.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:31][CH2:30]2)[S:27][CH:28]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(Cl)c3Cl)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (94.3 mg, 0.350 mmol), 1-[4-(2,3-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (100 mg, 0.318 mmol) and diisopropylethylamine (0.111 ml, 0.636 mmol) in dimethyl sulfoxide (1.0 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 34.3 mg (24.8%) of the desired product as a solid. mp 132-133° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH:25]=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([CH2:23][CH2:24][CH:25]([OH:26])[CH3:28])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC=O)(c2ccc(F)cc2)OC1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanal (300 mg, 0.69 mmol) in THF (4 ml) was added dropwise MeMgBr (0.7 ml, 3 mol/L) at −78° C. The mixture was stirred for 2 h and the temperature was allowed to be warm to rt at this stage. The reaction was quenched with aqueous NH4Cl. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by HPLC and chiral HPLC to give two isomers.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15]C(C)(C)[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:17])[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNc1ncnc2c1ncn2[C@@H]1O[C@H](c2nc(C(C)(C)C)no2)[C@@H]2OC(C)(C)O[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)CNc1ncnc2c1ncn2[C@@H]1O[C@H](c2nc(C(C)(C)C)no2)[C@@H](O)[C@H]1O
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of 9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-N-isobutyl-9H-purin-6-amine (14 mg) in a cold mixture of trifluoroacetic acid:water (9:1; 1 ml) was kept at 4° C. for 18 h. The resulting solution was basified in an ice bath with saturated aqueous sodium bicarbonate (20 ml), extracted with ethyl acetate (2×20 ml), the extracts dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound (7.66 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[Cl-].[Li+].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:19]C(Cl)C>CN1CCCC1=O>[Cl:19][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
4.55 parts of 4-chloro-2-nitrobenzonitrile, 0.42 parts of lithium chloride, 1.11 parts of anhydrous aluminum chloride and 15 parts of N-methyl-2-pyrrolidone were reacted at 180° C. for 3 hours after the pattern of EXAMPLE B1. The reaction solution was added with 100 parts of dichloroethane, agitated for 30 minutes and filtered. Dichloroethane was distilled off from the filtrate and the residue was added with water to precipitate the crude crystals. The crude crystals were recrystallized by using a water-methanol mixed solvent to obtain 3.4 parts of 2,4-dichlorobenzonitrile with purity of 99%. Yield: 79.2%.