Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:28]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=O)[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[C:3]1=[O:36].[C:38]1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.NC1C=C2C(C(C)(C)C(=O)N2C(OC(C)(C)C)=O)=CC=1.BrC1N=C2C=CC=C(C(C3CCOCC3)=O)N2N=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.O.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]>[CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:28]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]([CH:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH3:38])[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:36]
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)c2ccc(Nc3nc4cccc(C(=O)C5CCOCC5)n4n3)cc21
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1C(=O)C(C)(C)c2ccc(N)cc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(c1cccc2nc(Nc3ccc4c(c3)NC(=O)C4(C)C)nn12)C1CCOCC1
Temperature: 100 °C
Yield: 67 %

Procedure:
tert-Butyl 3,3-dimethyl-2-oxo-6-(5-(tetrahydro-2H-pyran-4-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)indoline-1-carboxylate. A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.050 g, 0.054 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.063 g, 0.109 mmol) in 1,4-dioxane (2 mL) was heated briefly with a heat gun until very hot and then added to tert-butyl 6-amino-3,3-dimethyl-2-oxoindoline-1-carboxylate (0.150 g, 0.543 mmol), (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (0.168 g, 0.543 mmol) and finely ground potassium carbonate (0.308 g, 2.226 mmol) in a sealable vessel with a stirbar. Nitrogen was blown in to blow out air. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for 1.5 h. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and water with vigorous stirring. The resulting mixture was filtered through a syringe filter and the filter cake washed with ethyl acetate. The layers of the filtrate were separated in a reparatory funnel and the organics were concentrated on a rotary evaporator. The residue was taken up in dichloromethane and purified using flash chromatography (Biotage) (20-80% ethyl acetate in hexane) to give the desired product (0.183 g, 0.362 mmol, 67% yield) as a yellow solid. MS (ESI) m/z 506.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]1[CH2:19][N:18]([C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17](=O)[CH2:16]1)[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]1CCCC1>>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]1[CH2:16][CH2:17][N:18]([C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:19]1=[O:29])[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(NC(=O)OC(C)(C)C)c2ccco2)CC1=O
Reactant: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC[C@H](C(NC(=O)OC(C)(C)C)c2ccco2)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 79 %

Procedure:
In an atmosphere of nitrogen, 1Mborane-tetrahydrofuran complex (14.8 ml) was added dropwise to a tetrahydrofuran solution (40 ml) of 4-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (2.03 g, 5.28 mmol) under ice-cooling, and then the mixture was stirred at room temperature for 17 hours. After evaporation of the solvent under a reduced pressure, the resulting residue was dissolved in 80% hydrous ethanol (40 ml) and heated under reflux for 1 hour in the presence of triethylamine (1 ml). After spontaneous cooling of the reaction solution, the solvent was evaporated under a reduced pressure, chloroform (100 ml) was added to the resulting residue, and then the resulting organic layer was washed with saturated ammonium chloride aqueous solution (80 ml) and saturated brine (80 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with chloroform to chloroform:methanol (97:3), 1.54 g (79%) of the title compound was obtained as white crystals.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:7][C:8]=1[CH:9]([CH3:12])[CH:10]=[O:11])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[CH:1]([C:4]1[N:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)[S:7][C:8]=1[CH:9]([CH3:12])[CH2:10][OH:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)CO
Temperature: 0 °C
Yield: 97.1 %

Procedure:
2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde (4.05 g, 12.5 mmol) is dissolved into denatured ethanol (60 mL) at room temperature then cooled to 0° C. in an ice bath. Sodium borohydride (0.467 g, 12.5 mmol) is then carefully added in small portions. The reaction is allowed to warm slowly to room temperature and is monitored by TLC. Upon complete consumption of starting material, the reaction is carefully quenched with water and diluted with ethyl acetate. The ethanol is removed and the residue is extracted with ethyl acetate, washed, dried, and concentrated. The 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol (4.0 g, 12.14 mmol), 97%, is obtained in pure form after flash column chromatography.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.[CH2:17]([C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](Cl)[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.O>[CH2:17]([C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[N:9]=3)[CH2:11][CH2:12]2)[N:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Cc1nccc(N2CCC(N)CC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3ccnc(C)n3)CC2)n1

Procedure:
A solution of 1-(2-methyl-pyrimidin-4-yl)-piperidin-4-ylamine dihydrochloride (53 mg, 0.2 mmol), 4-benzyl-2-chloro-6-methylpyrimidin (48.1 mg, 0.22 mmol) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in N-methyl-pyrrolidinone (1 mL) was heated at 200° C. in a microwave oven for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with AcOEt/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a light yellow solid (16 mg, 21%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9]O)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].P(Br)(Br)[Br:12]>C1COCC1>[Br:12][CH2:9][C:3]1[C:2]([F:1])=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccnc(CO)c1F
Solvent: C1CCOC1
Product: Cc1ccnc(CBr)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
Intermediate 6 ((3-fluoro-4-methyl-2-pyridinyl)methanol, 246 mg, 1.743 mmol) was dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 519 mg, 1.917 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated and residue was partitioned between Et2O and NaHCO3 (aqueous saturated solution). Organic layer was dried over MgSO4 (anh), filtered and concentrated to give the title compound (372 mg, quantitative yield). 1H NMR (300 MHz, DMSO-d6) ppm: 8.23-8.24 (m, 1H), 7.34-7.37 (m, 1H), 4.66 (s, 2H), 2.28 (s, 3H). [ES+MS] m/z 204 (M).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+:9]([O-:24])[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1ccc(CC(C)(C)C)nc1
Solvent: ClCCl
Product: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Reaction time: 4 h
Yield: 99.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine (11.0 g, 52.6 mmol) was dissolved in CH2Cl2 (200 mL) to which mCPBA (18.1 g, 105 mmol) was added, and the mixture was stirred under N2 for about 4 h. The mixture was quenched with 1M NaOH (200 mL) and stirring was continued vigorously for 10 min. The mixture was extracted with CH2Cl2 (2×200 mL), the combined organic layers were washed with saturated NaCl, dried (Na2SO4), and evaporated to give 5-(methoxymethoxy)-2-neopentylpyridine-N-oxide (11.8 g, 99.7% yield) as a brown oil which was used without purification in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14]C(=O)OC(C)(C)C)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(Cl)Cl>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH2:14])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Agent: Cl
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reaction time: 3 h

Procedure:
(S)-tert-Butyl 1-(1H-imidazol-2-yl)-2-phenylethylcarbamate (355 mg, 1.18 mmol) was dissolved in DCM (5 mL) and treated with 4N HCl in dioxanes (12 mL). After 3 hr, solvents were removed in vacuo and the crude product was used directly in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)[C@@H](C1C=CC=CC=1)O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@@H:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(Cc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Agent: O=C(O)[C@H](O)c1ccccc1
Product: C[C@@H](Cc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Yield: 32.4 %

Procedure:
A sample of 2.0 g (7.3 mmol) of 1-(4′-nitrophenyl)-2-benzylaminopropane (43) was reacted with 1.13 g (7.3 mmol) of (R)-(−)-mandelic acid to give 640 mg (65% based on enantiomeric abundance) of the free amine after workup. 1H NMR (CDCl3) δ□ 1.60 (d, 3H, J=6.3 Hz), 2.73-2.85 (m, 1H), 3.00-3.12 (m, 2H), 3.86 (dd, 2H, J=26, 60 Hz), 7.23-7.40 (m, 5H), 7.30 (d, 2H, J=9.0 Hz), 8.14 (d, 2H, J=8.7 Hz); MS (APCI+) m/z (rel): 271 (100); [α]D=+8.2° (c=1.0 MeOH).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C#N)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4′-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 3, step (iv), 0.70 g) in dichloromethane (15 mL) was treated with Burgess' reagent (0.356 g) and the mixture was stirred at room temperature for 6 h. Additional Burgess' reagent (0.15 g) was added and the reaction was stirred overnight. The mixture was absorbed onto silica and purified by chromatography on silica eluting with 33% ethyl acetate in isohexane and then 100% ethyl acetate to afford the sub-titled compound as a solid (0.420 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: CO
Reactant: O=C(O)C=Cc1ccccc1F
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C=Cc1ccccc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
15 gm of 2-fluorocinnamic acid was suspended into 100 ml of methanol. While maintaining the suspension at 0° C., 1.7 gm of thionyl chloride was added slowly. After the addition, the mixture was stirred for 30 minutes at 0° C. and for 4 hour at room temperature. The residue obtained by the removal of the solvent was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 17.8 gm of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](O)([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:37])([F:36])[F:35])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.CS(OS(C)(=O)=O)(=O)=O.CCN(CC)CC.FC(F)(F)C(O)=O.[OH:61][C@H:62]1[CH2:66][NH:65][C@H:64]([C:67]([N:69]([CH3:71])[CH3:70])=[O:68])[CH2:63]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([N:65]3[CH2:66][C@H:62]([OH:61])[CH2:63][C@H:64]3[C:67]([N:69]([CH3:71])[CH3:70])=[O:68])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:35])([F:36])[F:37])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3cc(C)ccc3OC)c3cc(Cl)cnc32)c(OC(F)(F)F)c1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)cnc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, to a solution of 280 mg of the compound obtained in Step 118-6 in CHCl3 (2.8 ml) was added sequentially 107 mg of methanesulfonic acid anhydride and Et3N (104 mg), then, the reaction mixture was stirred for 30 minutes under the same condition. Under nitrogen atmosphere, to a suspension of (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (2.57 mmol) in CHCl3 (5 ml) was added Et3N (520 mg) under dry ice-acetone cooling. To the reaction solution was added dropwise over 30 seconds the reaction solution of the mesyl form prepared above, then the reaction mixture was warmed to room temperature over two hours. To the reaction solution was added water and CHCl3, liquid separation was performed, and the aqueous layer was extracted with CHCl3. The combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration and the filtrate was concentrated. The obtained residue was separated and purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH/NH4OH=95/5/0.5; v/v/v) to obtain respectively 33 mg (Isomer A: brown amorphous) and 24 mg (Isomer B: pale brown amorphous) of two species of diastereoisomers of the title compound.
Reaction SMILES: [OH:1][B:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:24][N+:25]([O-:27])=[O:26])[O:3]1.C1C(=O)N([Cl:35])C(=O)C1>CN(C=O)C>[C:19]([O:18][C:17](=[O:23])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:7]1[C:6]2[B:2]([OH:1])[O:3][CH:4]([CH2:24][N+:25]([O-:27])=[O:26])[C:5]=2[C:10]([Cl:35])=[CH:9][CH:8]=1)([CH3:21])([CH3:22])[CH3:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NCCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCOc1ccc(Cl)c2c1B(O)OC2C[N+](=O)[O-]
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 4-(1-hydroxy-3-(nitromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-7-yloxy)-butylcarbamate (640 mg, 1.7 mmol) in DMF (20 mL) was added NCS (226 mg, 1.7 mmol) in DMF (5 mL). The mixture was heated to 80° C. for 2 h. After the reaction was quenched with an aqueous LiCl solution (100 mL), the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the product (280 mg, yield 67.5%). 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.47-7.49 (d, 1H), 6.96-6.98 (d, 1H), 6.80 (s, 1H), 5.74-5.77 (m, 1H), 5.31-5.35 (m, 1H), 4.67-4.72 (m, 1H), 4.02-4.05 (m, 2H), 2.94-2.99 (m, 2H), 1.68-1.72 (m, 2H), 1.50-1.56 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].Cl.C([O:16][C:17](=O)[CH2:18][NH:19][CH3:20])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][N:19]1[CH2:18][C:17](=[O:16])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1N1C(=O)CN(C)C1=S
Yield: 80 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 14.2 g of 2-isopropylphenyl-isothiocyanate, 12.29 g of sarcosine ethyl ester hydrochloride, 16.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (15.9 g) as a peach solid, m.p. 129°-131° C. Anal. Calcd. for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.89; H, 6.38; N, 11.28. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH2:15][N:16]([C:24](=[O:49])[C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([O:32][CH2:33][CH2:34][N:35](C(OC(C)(C)C)=O)[C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[O:7])(C)(C)C.C(OC([C@H]1CCCN1CCCNC1C=CC=CC=1F)=O)(C)(C)C.[F:73][C:74]([F:79])([F:78])[C:75]([OH:77])=[O:76]>>[F:73][C:74]([F:79])([F:78])[C:75]([OH:77])=[O:76].[Cl:31][C:29]1[CH:30]=[C:25]([CH:26]=[C:27]([O:32][CH2:33][CH2:34][NH:35][C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[CH:28]=1)[C:24]([N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH2:15][CH2:14][CH2:13][N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:49]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1F
Agent: CC(C)(C)OC(=O)[C@H]1CCCN1CCCNc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F

Procedure:
A solution of (R)-1-{3-[{3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-fluoro-phenyl)-amino]-propyl}-pyrrolidine-2-carboxylic acid tert-butyl ester and (R)-1-[3-(2-fluoro-phenylamino)-propyl]-pyrrolidine-2-carboxylic acid tert butyl ester (0.110 g) in trifluoroacetic acid (5 ml) for 18 h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.027 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:35])([CH3:34])[CH2:23][CH2:24][N:25]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[N:27]=[C:26]3Cl)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3([CH3:34])[O:35][C:26]4=[N:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][N:25]4[CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
4-{4-[4-(2-Chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylbutoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester (2.12 g) was dissolved in dimethylformamide (21 ml). 60% sodium hydride (0.24 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was subjected to extraction with methylene chloride, and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=1:1) to afford the title compound as a colorless powder (1.05 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CS(C)=O.CCOC(C)=O.O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-3-nitropicolinonitrile (5.0 g, 22 mmol) in DMSO (30 mL) was added morpholine (3.8 mL, 44 mmol). The reaction was stirred at rt for 2 h. After this time the reaction was diluted with EtOAc (300 mL) and water (100 mL). The separated organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was washed with MeOH (15 mL) to give 5-morpholino-3-nitropicolinonitrile. Mass Spectrum (ESI) m/e=235.2 (M+1).
Reaction SMILES: [Sn](Cl)Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:25].[OH-].[Na+]>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:25]
Reactant: COc1ccc2oc(-c3ccc([N+](=O)[O-])cc3)cc(=O)c2c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(N)cc3)cc(=O)c2c1

Procedure:
Tin(II) chloride (3.32 g, 17.5 mmol) was slowly added to an ethanol solution (30 ml) that contained compound 23 (520 mg, 1.75 mmol), while stirring. The obtained mixture was heated to reflux for 1 hour. After completion of the reaction, a 1 N sodium hydroxide aqueous solution (150 ml) was added to the reaction solution, and the obtained mixture was then extracted with 50 ml of ethyl acetate (150 ml). The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain a product of interest, 6-methoxy-4′-aminoflavone (compound 24) in the form of a yellow crystal. Yield: 360 mg (yield constant: 74.8%) 1H NMR (300 MHz, DMSO-d6) δ7.91 (d, J=8.7 Hz, 2H), 7.69-7.70 (m, 1H), 7.38-7.42 (m, 2H), 6.93 (d, J=9.0 Hz, 2H), 6.82 (s, 1H), 3.86 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:2]3[N:3]=[CH:4][C:5]4[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:11]=4[N:12]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4[nH]ccc4c3)ncc21

Procedure:
The title compound was prepared using Buchwald reaction from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 5-aminoindole. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (m, 4 H) 1.69 (m, 2 H) 1.97 (m, 2 H) 3.3 (s, 3 H) 3.99 (t, J=14.3 Hz, 2 H) 4.75 (t, J=8.0 Hz, 1 H) 6.29 (br. s., 1 H) 7.18-7.41 (m, 3 H) 7.96 (s, 1 H) 8.18 (s, 1 H) 9.16 (s, 1 H) 10.91 (br. s., 1 H). [M+H] calc'd for C21H22F2N6O, 413; found 413.