Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Br:22]N1C(=O)CCC1=O>O>[Br:22][C:16]1[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(-c2ccccc2)oc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1c(Br)c(-c2ccccc2)oc2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a round-bottom flask was added 2-phenyl-chromen-4-one (0.94 g, 4.23 mmol), acetic acid (40 mL) and N-bromosuccinimide (0.83 g, 4.65 mmol). The reaction mixture was heated to 100° C. using a hot oil bath with a water cooled reflux condenser, while stirring for 1 hour. The reaction mixture was cooled to RT and the solvents were removed in vacuo. The residue was suspended in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10:1 hexane:EtOAc) to give a white solid (527 mg, 41%). 1H-NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 7.75 (d, 2H), 7.72 (dd, 1H), 7.45-7.56 (m, 5H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1)(O)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1)=[O:2]
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 2 h

Procedure:
3.88 g of 2-[4-(5-carboxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine are suspended in 25 ml of toluene and, under N2 and while stirring, 3 times the molar amount of a 20% solution of diisobutylaluminium hydride in toluene is added dropwise, and the mixture is boiled for 2 hours, cooled, decomposition is carried out with water, the usual working up is carried out, and 2-[4-(5-formyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[CH2:32](Br)[C:33]#[CH:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:33]#[CH:32])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 116.7 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (3.0 g), propargyl bromide (0.84 g) and potassium carbonate (1.17 g) in N,N-dimethylformamide (300 ml) was stirred at room temperature for 1.5 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a syrup of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-propynyl)piperazine (3.80 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O:16][N:17]=O)CCC>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[N:17][OH:16])[CH2:5]2
Reactant: CCCCON=O
Reactant: O=C1CCc2cc(Br)ccc21
Product: O=C1C(=NO)Cc2cc(Br)ccc21

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-indan-1-one and n-butylnitrite to give 5-Bromo-indan-1,2-dione 2-oxime. LC-MS: m/e 240 (MH+).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8]2)[C:4](=O)[O:3]1.[NH2:20][OH:21]>C1COCC1>[OH:6][CH:5]([CH:7]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1)[C:4]([NH:20][OH:21])=[O:3]
Reactant: NO
Reactant: CC1(C)OC(=O)C(C2Sc3ccccc3NC2=O)O1
Solvent: C1CCOC1
Product: O=C(NO)C(O)C1Sc2ccccc2NC1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The crude 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-4H-benzo[1,4]thiazin-3-one (0.036 mmol) is dissolved in 0.5 mL of THF and 0.5 mL of NH2OH (1N in MeOH) is added to the mixture. After the addition, the mixture is stirred at 60° C. for 3 hours. The solvent is then removed under vacuum and the residue is purified by preparative thin layer chromatography (silica gel, 10% MeOH/CH2Cl2) to provide the title compound 2,N-dihydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetamide. Yield: 70%. 1H NMR (400 MHz, MeOD) δ 7.30 (dd, 1H, J=1.29 Hz, J=8.0 Hz), 7.18, (dt, 1H, J=1.3 Hz, J=8.0 Hz), 7.01 (dt, 1H, J=1.3 Hz, J=8.0 Hz), 6.95 (dd, 1H, J=1.3 Hz, J=8.0 Hz), 4.74 (d, 1H, J=3.80), 3.97 (d, 1H, J=3.8). MS: (ES+): 255.1[M+1].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[CH2:7][OH:8].Cl[C:14]1[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=1>O1CCCC1>[NH2:20][C:17]1[CH:16]=[N:15][C:14]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([F:12])=[C:4]([Cl:3])[CH:5]=2)=[N:19][CH:18]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: OCc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cnc(OCc2ccc(F)c(Cl)c2)nc1
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
Sodium hydride (60% dispersion in oil-50 mg, 1.25 mmol) was added to a solution of 3-chloro-4-fluorobenzyl alcohol (177 mg, 1.1 mmol) in tetrahydrofuran (5 ml) under an atmosphere of nitrogen. After 10 minutes, 2-chloro-5-nitropyrimidine (159 mg, 1 mmol) was added and the reaction heated at reflux for 2 hours before quenching by the addition of methanol (1 ml). Purification by flash chromatography on silica gel, eluting with 12% ethyl acetate in isohexane yielded the title compound (86 mg, 30% yield):
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:25])[CH3:24].[NH4+].[Cl-]>C1COCC1.CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23]1([CH3:4])[CH2:24][O:25]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(Oc3ccc(Cl)cc3)cc2Cl)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMSO (150 mL) was added dropwise to a mixture of sodium hydride (22 g) in THF (600 mL). After completion of the addition a solution of trimethylsulfonium iodide (171 g) in DMSO (300 mL) was added slowly at 5° C. whereupon a solution of 1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (107 g) in DMSO (300 mL) was added carefully. The mixture was stirred for 1 h at room temperature and dil. NH4Cl solution was added. The mixture was extracted with MTBE (3×) and the combined organic phases were washed with water, dried and evaporated to obtain the desired compound that was used without further purification.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8].Cl.O>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1>[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](=[O:8])[CH3:1]
Reactant: CON(C)C(=O)c1cc(Cl)ccc1Br
Reactant: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ccc1Br
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (4.26 mL of a 1.4M solution in tetrahydrofuran/toluene, 5.97 mmol) was added dropwise to a stirred solution of 2-bromo-5-chloro-N-methoxy-N-methylbenzamide (3-1) (0.554 g, 1.99 mmol) in tetrahydrofuran (20 mL) at approximately 0° C. After 1 h, 1N hydrochloric acid (5 mL) was added and the resulting biphasic mixture was stirred vigorously for about 10 min. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-10% ethyl acetate/hexanes as eluent) provided 3-3 (0.44 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[NH:23][N:22]=2)=[N:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl>CO.[Pd]>[NH2:8][CH2:7][C:6]1[C:5]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH3:12])=[N:4][C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[NH:23][N:22]=2)=[C:2]([F:1])[CH:9]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reaction time: 6 h
Yield: 77 %

Procedure:
The mixture of (S)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol -3-ylamino)nicotinonitrile (Example 16; 0.90 g, 2.26 mmol), conc. HCl (0.3 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.55 g) in MeOH (20 ml) was flushed with N2, evacuated, and then placed under H2 (40 psi) for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml) and treated with a saturated aqueous Na2CO3 solution (100 ml). The mixture was shaken vigorously for 30 min and allowed to separate. The aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were dried, filtered and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.7 g, 77%). 1H NMR (400 MHz, CD3OD) δ 7.45-7.41 (m, 2H), 7.35 (d, J=10.9 Hz, 1H), 7.03-6.99 (m, 2H), 5.35 (s, 1H), 5.09-5.04 (m, 1H), 4.55-4.49 (m, 1H), 4.18 (d, J=14.2 Hz, 1H), 4.08 (d, J=14.2 Hz, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.31 (d, J=8.3 Hz, 6H). MS: Calcd.: 402. Found: [M+H]+ 403.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:47]CC2C=CC=CC=2)[C@@H:15]([N:32](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([O:24]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])[C@@H:9]1[CH3:61])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(C)(C)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:47])[C@@H:15]([NH2:32])[CH2:16][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:55][CH2:56][C:57]([F:60])([F:58])[F:59])[C@@H:9]1[CH3:61])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H]1[C@H](OCC(F)(F)F)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C[C@H]1[C@H](OCC(F)(F)F)OC[C@H]([C@@H](O)[C@@H](N)Cc2cc(O)cc(F)c2)N1C(=O)OC(C)(C)C
Yield: 115.6 %

Procedure:
Add 20% palladium hydroxide on carbon (200 mg) to a solution of (2S,3S,5R)-5-[(1S,2S)-1-benzyloxy-3-(3-benzyloxy-5-fluoro-phenyl)-2-dibenzylamino-propyl]-3-methyl-2-(2,2,2-trifluoro-ethoxy)-morpholine-4-carboxylic acid tert-butyl ester (116 mg, 0.138 mmol) in tert-butanol (10 mL). Heat to 45° C. and hydrogenate at 50 psi hydrogen gas for 18 hours. Filter and evaporate to give the desired compound (77 mg). MS(ESI): m/z=483 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC=C(C)C=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[C:5]([CH3:24])[CH:4]=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 15 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), m-toluidine (175 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 40 mg (0.13 mmol, 15% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1)=[O:14])[CH3:2]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCOCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.00 mmol) 4-piperidin-4-yl-morpholine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH:33]([CH3:35])[CH3:34])[N:3]=1>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH:33]([CH3:35])[CH3:34])[N:3]=1
Reactant: CC(C)Nc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)Nc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Reaction time: 1.5 h
Yield: 51.2 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (74 mg, 0.15 mmol) was dissolved in 5 mL of MeOH. Pd(OH)2 (30 mg) was added, and the contents were stirred under a hydrogen balloon for approximately 90 min. The contents were then filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The resulting crude product was purified via reverse phase HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (32 mg, 51%). LCMS: (M+H)+: 417.0.
Reaction SMILES: [Br:1][CH2:2]/[C:3](/[CH3:14])=[CH:4]\[C@@H:5]([CH3:13])[C@H:6]([OH:12])[C@@H:7]([O:10][CH3:11])[CH:8]=[CH2:9].N1C(C)=CC=CC=1C.[Si:23](OS(C(F)(F)F)(=O)=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][CH2:2]/[C:3](/[CH3:14])=[CH:4]\[C@@H:5]([CH3:13])[C@H:6]([O:12][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:7]([O:10][CH3:11])[CH:8]=[CH2:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=C[C@H](OC)[C@@H](O)[C@H](C)/C=C(/C)CBr
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=C[C@H](OC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C(/C)CBr
Temperature: -15 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of secondary alcohol 12 (5.04 g, 19.23 mmol) in CH2Cl2 (150 mL) at −15° C. was added 2,6-lutidine (3.4 mL, 28.85 mmol) and TBSOTf (6.2 mL, 26.92 mmol). After stirring at −15° C. for 1 h, the reaction mixture was quenched with MeOH (20 mL) at −15° C. The mixture was treated with saturated NH4Cl aqueous solution. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Purification of the crude product by flash chromatography (EtOAc-hexanes, 1:9) to afford bromide 13 (6.6 g, 91%) as a yellow oil. [α]20D 2.76 (c 1.5, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 5.61 (m, 1 H), 5.35 (d, 1 H, J=9.8 Hz), 5.23 (m, 2 H), 3.88 (s, 2H), 3.48 (dd, 1 H, J=3.0, 7.1 Hz), 3.30 (t, 1 H, J=7.5 Hz), 3.15 (s, 3H), 2.53 (m, 1H), 1.75 (s, 3H), 0.88 (m+s, 12 H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 136.8, 135.6, 130.1, 119.2, 86.5, 78.0, 56.6, 35.1, 32.8, 26.5, 22.3, 18.9, 13.9, −3.4, −4.4; HRMS (ESI) calcd for [C17H33BrO2Si+Na]+: 399.1331. found: 399.1321.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([OH:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:21][C:20]([CH3:22])([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([OH:24])=[O:23]
Reactant: CC(C)C(=O)O
Reactant: ClCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of diisopropylamine (48.91 g, 483 mmol) in THF (100 mL) under nitrogen at 0° C. was added a solution of 2.5M n-butyllithium in hexane (179 mL, 447.5 mmol.) followed by the dropwise addition of isobutyric acid (15.77 grams, 179 mmols). The reaction mixture was stirred at room temperature for 1.5 hours, then cooled to −15° C. Benzyl chloride (22.66 g, 179 mmol) was added dropwise while maintaining the temperature below −5° C., and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between Et2O and water. The aqueous layer was acidified by the addition of concentrated HCl (36%, 50 mL), and extracted with Et2O (4×150 mL), The organic layer was dried over MgSO4 and concentrated to afford the title compound (21.36 g) as a colorless liquid. LC-MS (ES) m/z=177 [M−H]−.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([C:11](=O)[CH:12]([CH3:14])[CH3:13])=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>C1COCC1>[Cl:4][C:5]1[C:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[N:2][NH:3][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: NN
Reactant: CC(C)C(=O)c1c(Cl)ccnc1Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1n[nH]c2ccnc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Normal-butyllithium (a 1.6 M solution in hexane, 8.13 mL) was dropwise added to a solution of N,N-diisopropylamine (1.99 mL) in THF (30 mL) at −78° C. under a nitrogen atmosphere, followed by increasing the temperature to 0° C. Then, the solution was cooled to −78° C., and a solution of 2,4-dichloropyridine (1.0 g) in THF (3 mL) wad dropwise added thereto at −78° C., followed by stirring for 1.5 hr. Then, a solution of isobutylaldehyde (1.85 mL) in THF (3 mL) was dropwise added to the reaction solution at −78° C., followed by stirring at the same temperature for 30 min. Then, the reaction solution was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with saturated saline, and the organic layer after the washing was dried over anhydrous sodium sulfate. Then, the solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.48 g, 99%) as a colorless oily substance. A solution of DMSO (0.9 mL) in dichloromethane (5 mL) and a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.39 g) in dichloromethane (5 mL) were sequentially added to a solution of oxalyl chloride (0.8 mL) in dichloromethane (30 mL) at −78° C., followed by stirring for 30 min. Then, triethylamine (3.52 mL) was added to the reaction solution at 0° C., followed by stirring for 1 hr. The reaction solution was poured into ice water and was extracted with chloroform. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (1.18 g, 86%) as a colorless oily substance. Hydrazine monohydrate (1.3 mL) was added to a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (0.93 g) in THF (13 mL), followed by stirring at room temperature for 12 hr and then at 50° C. for 25 hr. The reaction solvent was distilled away under reduced pressure, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (4a) (0.55 g, 66%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[N:80]=[C:81]([C@@H:84]3[CH2:88][CH2:87][CH2:86][N:85]3[C:89](=[O:97])[CH2:90][C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)[NH:82][CH:83]=2)=[CH:75][CH:74]=1>CS(C)=O.O>[CH:36]([C:33]1[CH:34]=[CH:35][C:27]2[C:26]([NH:25][C:17]3[CH:18]=[C:19]([C:20](=[O:22])[NH:72][C:73]4[CH:78]=[CH:77][C:76]([C:79]5[N:80]=[C:81]([C@@H:84]6[CH2:88][CH2:87][CH2:86][N:85]6[C:89](=[O:97])[CH2:90][C:91]6[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=6)[NH:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:23]=[CH:24][C:16]=3[S:15][C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:14][CH:13]=3)=[N:31][CH:30]=[N:29][C:28]=2[N:32]=1)([CH3:37])[CH3:38]
Reactant: Nc1ccc(-c2c[nH]c([C@@H]3CCCN3C(=O)Cc3ccccc3)n2)cc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)Cc6ccccc6)n5)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
To a solution of the Product from Example 1E (0.16 g, 0.30 mmol) and HATU (0.12 g, 0.316 mmol) in DMSO (5 mL) was added diisopropylethylamine (0.184 mL, 1.05 mmol) followed by the Product from Example 1J (0.115 g, 0.33 mmol). The solution was stirred at ambient temperature for 18 hours, then diluted with water and the crude product was filtered off an purified by combi-flash 12 g column, eluting with 0-10% Methanol in dichloromethane to give a solid (0.092 g, 36%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[N:2]1.F[B-](F)(F)F.[CH3:19][O+](C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:19][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[C:5]2[C:10]([O:12][CH3:13])=[O:11])=[N:1]1
Reactant: COC(=O)c1cccc2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a solution of methyl 1H-indazole-4-carboxylate (63.0 g, 358 mmol) in ethyl acetate (1.19 L) was added trimethyloxonium tetrafluoroborate (68.8 g, 465 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 12 hr. The reaction solution was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (57.0 g, yield 84%).