Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C[O:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH3:46])=[C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]4[CH2:34][CH2:35][N:36](C(OC(C)(C)C)=O)[CH2:37][CH:38]=4)=[CH:29][CH:28]=2)[CH:19]=[CH:18]3)[CH:14]=1)=O.C([Mg]Cl)(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:3][O:2][NH:4][C:7](=[O:6])[C:9]1[CH:10]=[CH:11][C:12]([CH3:46])=[C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=4)=[CH:29][CH:28]=2)[CH:19]=[CH:18]3)[CH:14]=1
Reactant: CON
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)ccc3c2)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(C5=CCNCC5)cc4)ccc3c2)c1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
Methoxylamine hydrochloride (0.12 g) was added to a solution of Example 6 step (ii) (0.4 g) in THF (10 mL). The mixture was stirred at room temperature then 2.0M isopropylmagnesium chloride in THF (1 mL) added. The mixture was stirred for 1 hour then a further portion of 2.0M isopropylmagnesium chloride in THF (1 mL) was added. The mixture was stirred for a further 1 hour then poured into saturated aqueous ammonium chloride and extracted with dichloromethane. The organics were combined and evaporated under reduced pressure. The residue was dissolved in methanol (20 mL) and 2.0M HCl in diethyl ether added (20 mL). This solution was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure and the residue purified (SiO2 10:90:1 methanol:dichoromethane:aqueous ammonia as eluant) to give the title compound as a solid (22 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].Br[C:31]1[CH:32]=[CH:33][C:34]2[NH:43][C:42](=[O:44])[O:41][C:37]3([CH2:40][CH2:39][CH2:38]3)[C:35]=2[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C1COCC1.O>[CH3:1][N:2]1[C:6]([C:31]2[CH:32]=[CH:33][C:34]3[NH:43][C:42](=[O:44])[O:41][C:37]4([CH2:40][CH2:39][CH2:38]4)[C:35]=3[CH:36]=2)=[CH:5][CH:4]=[C:3]1[C:7]#[N:8]
Reactant: Cn1cccc1C#N
Reactant: O=C1Nc2ccc(Br)cc2C2(CCC2)O1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCC1)OC(=O)N2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a solution of 1-methyl-1H-pyrrole-2-carbonitrile (0.84 g, 7.1 mmol) and triisopropylborate (1.8 mL, 7.8 mmol) in THF (15 mL) at 0° C. was added lithium diisopropylamide (4.6 mL, 9.2 mmol). The reaction was allowed to warm to room temperature. Upon completion by TLC, the reaction was added dropwise to a 65° C. solution of 6-bromospiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.38 g, 1.4 mmol), potassium carbonate (0.58 g, 4.2 mmol) dissolved in (5 mL water), and tetrakistriphenylphosphine palladium (0) (0.081 g, 0.07 mmol) in tetrahydrofuran (10 mL). Upon completion by TLC of the reaction the reaction mixture was poured into a saturated solution of ammonium chloride (100 mL), extracted with ethyl acetate (50 mL), dried with magnesium sulfate, and purified on a silica gel column (40% ethyl acetate/hexane) to give 1-methyl-5-(2-oxo-1,2-dihydrospiro[3,1-benzoxazine-4,1′-cyclobutan]-6-yl)-1H-pyrrole-2-carbonitrile (0.33 g, 79%) as a light red solid. 1H NMR (DMSO-d6): δ 10.41 (s, 1H), 7.58 (d, 1H, J=2 Hz), 7.43 (dd, 1H, J=8.2, 1.8 Hz), 7.04 (d, 1H, J=4.0 Hz), 6.39 (d, 1H, J=8.2 Hz), 6.39 (d, 1H, J=4.0 Hz), 3.73 (s, 3H), 2.55-2.49 (m, 2H), 2.05-1.90 (m, 2H), 1.88-1.83 (m, 2H). MS (ESI) m/z 294 ([M+H]+); MS (ESI) m/z 292 ([M−H]−). High resolution mass spectrometry (HRMS): calcd for C17H15N3O2, 293.1164; found (ESI_FT), 294.12311.
Reaction SMILES: CNCCC(C1C=CC=CC=1)C1C2C(=NC=CC=2)NC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[C:36]([O:40][C:41](=[O:62])[N:42]([CH3:61])[CH2:43][CH2:44][CH:45]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:46]1[C:54]2[C:49](=[N:50][CH:51]=[CH:52][CH:53]=2)[NH:48][CH:47]=1)([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([O:40][C:41](=[O:62])[N:42]([CH3:61])[CH2:43][CH2:44][C@H:45]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:46]1[C:54]2[C:49](=[N:50][CH:51]=[CH:52][CH:53]=2)[NH:48][CH:47]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(CCC(c1ccccc1)c1c[nH]c2ncccc12)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CNCCC(c1ccccc1)c1c[nH]c2ncccc12
Solvent: ClCCl
Product: CN(CC[C@H](c1ccccc1)c1c[nH]c2ncccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 31 %

Procedure:
To a 0° C. solution of racemic methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-amine (267 mg, 1.01 mmol) in DCM (40 ml) was added TEA (0.47 ml, 3.37 mmol) followed by Boc2O (416 mg, 1.91 mmol). The mixture was warmed to RT over 1 hour, and then stirred at RT for 22 hours to give a racemic mixture of Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamic acid tert-butyl ester (not isolated). The reaction mixture was concentrated under reduced pressure, and purified via chiral preparative HPLC by multiple injections onto Chiralpak AD preparative 250×20 mm (hexane/i-PrOH, 6 ml/min), affording (R)-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamic acid tert-butyl ester (215 mg, 31% yield) as a first fraction and (S)-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamic acid tert-butyl estere (197 mg, 28% yield) as a second fraction.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH2:14][O:13][C:12]3=[O:23])=[N:7][C:6]=12.[C:24]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)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]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:15]2[CH2:14][O:13][C:12](=[O:23])[N:11]2[C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])=[CH:32][CH:33]=4)=[C:6]3[N:7]=2)=[CH:17][CH:18]=1
Reactant: O=C1OC[C@H](c2ccc(F)cc2)N1c1ccn2ncc(Br)c2n1
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Temperature: 90 °C
Yield: 59 %

Procedure:
To a sealed tube was added (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(4-fluorophenyl)oxazolidin-2-one (Preparation A; 0.200 g, 0.530 mmol), 4-(tert-butoxycarbonyl)phenyl boronic acid (0.177 g, 0.795 mmol) and 2.0 M Na2CO3 (0.795 mL, 1.59 mmol) in dioxane (1 mL). The mixture was degassed by bubbling N2 through the solution. Pd2 dba3 (0.0486 g, 0.053 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0253 g, 0.053 mmol) were added and the vessel was sealed under a N2 atmosphere. The mixture was heated at 90° C. for 18 hours. The reaction mixture was cooled to ambient temperature, filtered through glass fiber filter paper, concentrated and purified on silica gel (10-100% ether in DCM) giving (S)-tert-butyl 4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoate (0.148 g, 59% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([CH2:23][CH:24]4[CH2:26][CH2:25]4)=[N:21][N:22]=[C:16]3[C:15]=2[CH3:27])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:24]1([CH2:23][C:20]2[N:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:15]([CH3:27])[C:16]3=[N:22][N:21]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)ccn2c(CC3CC3)nnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C2CCNCC2)ccn2c(CC3CC3)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of D100 (0.207 g, 0.560 mmol) in dry DCM (3.5 ml), was added trifluoroacetic acid (1.01 ml). The mixture was stirred at r.t. for 2 h and then concentrated in vacuo. The residue was basified with NaOH 50% (aqueous solution) and extracted with DCM. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo to yield intermediate D101 (0.149 g, 99%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]3[OH:17])[CH:13]=[N:14][C:7]=12.[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:21][C@H:20]([CH2:22][O:23][C:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:29]4[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:47][CH:46]=4)[C@@H:18]([OH:19])[C@H:16]3[OH:17])[CH:13]=[N:14][C:7]=12
Reactant: OC[C@H]1O[C@@H](n2cnc3c(-c4cccs4)ccnc32)[C@H](O)[C@@H]1O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(-c5cccs5)ccnc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
Compound 11 (99 mg, 0.29 mmol) was azeotroped three times with anhydrous pyridine and then dissolved in pyridine (3.0 ml). To this solution, 4,4′-dimethoxytrityl chloride (106 mg, 0.31 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 5% aqueous NaHCO3 and then extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous sodium chloride, dried over Na2SO4, and then evaporated under reduced pressure to remove the solvent. The product was purified by silica gel column chromatography (1% methanol-CH2Cl2) to give Compound 12 (131 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]([N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[C:27]([N:34]1[CH2:40][CH2:39][CH2:38][N:37]([C:2]2[CH:3]=[C:4]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
5-(3-Bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (650.0 mg, 1.4 mmol) prepared in Step 1 of Preparation 6, 1-BOC-homopiperazine (432.0 mg, 2.2 mmol), Pd2(dba)3 (66.0 mg, cat.), BINAP (90.0 mg, cat.) and sodium t-butoxide (250.0 mg, 2.6 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 550.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:5]2[N:6]=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([O:10][CH3:11])[N:4]2[N:3]=1.Cl.COC1C=C(OC)N2N=C(N=S(C)C)N=C2N=1.[CH3:33][O:34][C:35]1[C:40]([S:41](Cl)(=[O:43])=[O:42])=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=[CH:37][N:36]=1.N1C=C(C)C=C(C)C=1.Cl>C(#N)C>[CH3:13][O:12][C:7]1[CH:8]=[C:9]([O:10][CH3:11])[N:4]2[N:3]=[C:2]([NH:1][S:41]([C:40]3[C:35]([O:34][CH3:33])=[N:36][CH:37]=[CH:38][C:39]=3[C:45]([F:48])([F:46])[F:47])(=[O:42])=[O:43])[N:14]=[C:5]2[N:6]=1
Reactant: COc1nccc(C(F)(F)F)c1S(=O)(=O)Cl
Reactant: COc1cc(OC)n2nc(N)nc2n1
Agent: COc1cc(OC)n2nc(N=S(C)C)nc2n1
Agent: Cc1cncc(C)c1
Agent: Cl
Solvent: CC#N
Product: COc1cc(OC)n2nc(NS(=O)(=O)c3c(C(F)(F)F)ccnc3OC)nc2n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.9 %

Procedure:
2-Amino-5,7-dimethoxy[1,2,4]triazolo[1,5-a]pyrimidine (9.8 g, 0.050 mol) and N-(5,7-dimethoxy[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-S,S-dimethyl-sulfilimine hydrochloride salt (1.5 g, 0.005 mol) solids were combined with 2-methoxy-4-(trifluoromethyl)-pyridine-3-sulfonyl chloride (14 g, 0.051 mol) in acetonitrile (40 mL). 3,5-Lutidine (31 g, 93% technical) was added, and the mixture was stirred at room temperature for 22 hours. The mixture was warmed to 42° C. and treated with 3 N HCl (65 mL), after which the mixture was allowed to cool to room temperature over 1.5 hours. The solids were collected by filtration, washed with a 2:1 v/v solution of water:acetonitrile (20 mL), and dried under vacuum at 60° C. to afford 18 g of product assaying at 94 wt % (78% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1.[OH-].[Na+]>O.CCO>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[S:21][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)[N:22]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(NC(N)=S)cc1
Reactant: O=C(CBr)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2nc(-c3ccncc3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.0 g (15 mmol) 4-(2-bromo)acetylpyridine (6-2) in 50 mL water was added an equimolar amount of 4-methoxyphenylthiourea (7-1; 2.75 g). The reaction was diluted with 20 mL EtOH. The reaction was allowed to stir at rt overnight, over which time a color change occurred from clear to a thick orange precipitate. The reaction mixture was diluted with 100 mL water then the pH was adjusted to neutral with 1N NaOH. The reaction was allowed to stir at rt and a large amount of precipitate formed which was collected by filtration. The resulting powder was dried under high vacuum to yield N-(4-methoxyphenyl)-4-pyridin-4-yl-1,3-thiazol-2-amine (7-2): 1H NMR (500 MHz, CD3OD) δ 8.98 (d, J=3 Hz, 2H), 8.10 (d, J=3 Hz, 2H), 7.53 (s, 1H), 3.0 (s, 3H): MS 284.3 found 284.2 (M+H+).
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1
Reactant: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(CO)ccn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-ethanone (340 mg, 1.28 mmol) in dry THF (5 mL) was treated at 0° C. with TBAF (1.9 mL of a 1M solution in THF, 1.90 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1 h30. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1 to 1:3 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.10. LC-MS-conditions 02: tR=0.40 min; [M+H]+=152.24.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@H:4]1[C:5](=[O:10])[O:6]2)[CH3:2].[NH:11]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)[NH2:12].C[Al](C)C.Cl>O1CCOCC1.C([C@@H]1C[C@H](O)C[C@@H]1C(NNC1N=C2C=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1)=O)C>[CH2:1]([CH:3]1[CH2:8][CH:7]([OH:6])[CH2:9][CH:4]1[C:5]([NH:12][NH:11][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)=[O:10])[CH3:2]
Reactant: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CC(O)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a scalemic mixture enriched in (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96 mmol) in 1,4-dioxane (12 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (step D, 1.810 g, 5.96 mmol). The reaction mixture was heated at about 80° C. for about 16 h then cooled to ambient temperature. 1,4-Dioxane (25 mL) and trimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for about 30 min then aqueous HCl (1 N, 50 mL) was added dropwise and the reaction mixture was stirred for about 30 min. The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (10 mL), saturated aqueous NaHCO3 (15 mL), brine (15 mL) and dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 100% EtOAc to give a scalemic mixture enriched in (1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbo-hydrazide (1.887 g, 71%): LC/MS (Table 1, Method b) Rt=2.05 min; MS m/z: 444 (M+H)+.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]([C:48]3[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=3)=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(CBr)c1ccncc1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccncc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide and isolated as light-red solid. MS (m/e): 402.3 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([NH:20][C:21]1([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=3)=[CH:34][C:33]=2[Cl:46])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[C:54]([Cl:56])[CH:55]=1)[CH2:51]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[C:13]([O:17][C:18]([NH:20][C:21]1([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:51][C:50]4[CH:49]=[C:48]([Cl:47])[CH:55]=[C:54]([Cl:56])[CH:53]=4)[CH:40]=3)=[CH:34][C:33]=2[Cl:46])[CH2:22][O:23][C:24]([CH3:28])([CH3:27])[O:25][CH2:26]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(O)c3)cc2Cl)COC(C)(C)OC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(OCc4cc(Cl)cc(Cl)c4)c3)cc2Cl)COC(C)(C)OC1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
Diethyl azodicarboxylate (0.31 mL) was added to a THF solution (5 mL) containing the compound of Example 106 (650 mg), 3,5-dichlorobenzyl alcohol (350 mg), triphenylphosphine (530 mg). The mixture was stirred for 18 hours. Subsequently, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (440 mg) as a colorless powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:25][CH2:26][CH3:27])[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.O.[OH-].[Li+].Cl>CO.O.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2
Reactant: CCOC(Cc1ccc(NCCCCC(=O)N2CCOc3ccccc32)cc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(Cc1ccc(NCCCCC(=O)N2CCOc3ccccc32)cc1)C(=O)O
Yield: 67.9 %

Procedure:
Methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate (211 mg, 1 eq, 0.48 mmol) obtained in example 10, was hydrolyzed using lithium hydroxide monohydrate (60 mg, 3 eq, 1.44 mmol) in methanol-water at RT (takes 4-5 h). The reaction mixture was diluted with water, acidified (pH 3-4) with aqueous HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed (ethyl acetate and hexane→methanol/chloroform) to afford the title compound (139 mg, yield 68%) as viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([O:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a stirred solution of 5.4 grams (0.017 mole) of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid in 25 mL of methylene chloride was added 2.4 grams (0.017 mole) of 4-nitrophenol. The reaction mixture was cooled to 0° C., and 3.5 grams (0.017 mole) of dicyclohexylcarbodiimide was added. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes, and then it was warmed to ambient temperature where it was stirred for an additional two hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was stirred with diethyl ether, and the resultant solid was collected by filtration to yield 5.4 grams of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate, m.p. 130°-132° C. The nmr spectrum was consistent with the proposed structure.