Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:12]1[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[CH:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:13]=1
Reactant: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(S(C)(=O)=O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-4-(6-(5-fluoropyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 6) (132 mg, 0.19 mmol) was heated in phosphorus oxychloride (8 mL) overnight at 95° C. The reaction mixture was allowed to cool to room temperature and then portion wise added to ice water (100 mL) and left to stir for 1 hour. Carefully, NaOH pellets were added to basify the mixture. The resulting aqueous layer was extracted with DCM (100 mL), passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a brown gum (110 mg) used without further purification.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17]>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][NH:17][CH2:16][C:15]([F:19])([F:18])[F:14]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CC(C)(CNCC(F)(F)F)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with 2,2,2-trifluoro-ethyl amine to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.59 (s, 6H), 2.98 (s, 2H), 3.10 (m, 2H), 7.56 (s, 1H), 7.90 (s, 1H) MS m/z 267.3 (M+1).
Reaction SMILES: [H-].[OH-].[Li+].C[O:5][C:6](=[O:39])[CH:7]([NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10]>O1CCCC1.O>[CH3:10][CH:9]([CH3:11])[CH2:8][CH:7]([NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)=[O:14])[C:6]([OH:39])=[O:5]
Reactant: COC(=O)C(CC(C)C)NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
Lithium hydroxide monohydride (25 mg, 0.595 mmol) was added to a solution of 4-methyl-2-({6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carbonyl}-amino)pentanoic acid methyl ester (130 mg, 0.256 mmol) in tetrahydrofuran (3 mL) and water (1.5 mL), the reaction mixture was stirred at ambient temperature for 3 hours, THF was removed by evaporation, the residue was adjusted with 5% citric acid to pH about 6, and diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated to afford 4-methyl-2-({6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carbonyl}amino)pentanoic acid (94 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.17, 8.02, 7.78, 7.66-7.53, 7.38, 6.99, 6.72, 4.88-4.73, 4.25-3.60, 3.44-3.21, 1.79-1.06, 1.33-1.19, 1.03, 0.99.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[C:57]([C:59]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)#[N:58]>ClCCl.CN(C)C=O>[C:57]([C:59]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:60][CH2:61][N:62]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:63][CH2:64]1)#[N:58]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)N2CCC(C#N)(c3ccccc3)CC2)cc1
Reaction time: 16 h
Yield: 16.6 %

Procedure:
To 300 mg (0.90 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy-phenyl)propanoic acid dissolved in 3.5 mL of dichloromethane and 1.5 mL of dimethylformamide are added 0.46 mL (2.7 mmol) of diisopropylethylamine, 318 mg (0.99 mmol) of TBTU and 220 mg (0.99 mmol) of 4-cyano-4-phenylpiperidine hydrochloride. After 16 hours, the solution is washed with saturated sodium hydrogen carbonate solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by filtration on a pad of silica (eluent: 7/3 dichloromethane/methanol). 75 mg of 1-[2-(4-cyano-4-phenylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea in the form of a white powder are obtained in a yield of 17%.
Reaction SMILES: [H][H].[CH2:3]([C:6]1[S:7][C:8]([CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]=1)[CH2:4][CH3:5]>C(O)C>[CH2:3]([C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]=1)[CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCc1ncc(C=CC=CC(=O)OCC)s1
Solvent: CCO
Product: CCCc1ncc(CCCCC(=O)OCC)s1
Yield: 90.5 %

Procedure:
Hydrogen was added with stirring for 2 hours to a mixture of 25 g of ethyl 5-(2-propyl-5-thiazolyl)-2,4-pentadienoate, 250 ml of ethanol and 12.5 g of activated carbon containing 10% palladium and the mixture was filtered. The fiter was washed with ethanol and the filtrate was evaporated to dryness under reduced pressure to obtain 23 g of raw ethyl 2-propyl- 5-thiazolepentanoate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][C:15]=3[S:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (50 mg, 0.280 mmol) was reacted with the product from Example 35a (91 mg, 0.280 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (21.5 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.07 (s, 3H), 2.78 (s, 3H), 6.43 (d, J=6.99 Hz, 1H), 7.09-7.15 (m, 1H), 7.44 (d, J=8.46 Hz, 2H), 7.68 (d, J=8.46 Hz, 2H), 7.78 (dd, J=8.64, 1.65 Hz, 1H), 7.84 (d, J=8.82 Hz, 1H), 7.92 (d, J=1.84 Hz, 1H), 8.52 (d, J=7.35 Hz, 1H), 9.00 (d, J=8.46 Hz, 1H), 10.19 (s, 1H), 11.12 (s, 1H); MS (ESI+) m/z 469 (M+H−TFA)+, (ESI−) m/z 467 (M−H−TFA)−.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[Li]CCCC.CN(C)[CH:19]=[O:20]>O1CCCC1>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:19]=[O:20])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: Ic1ccc2c(c1)CCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 6-iodochroman (13.8 g, 53.1 mmol) in tetrahydrofuran (THF) (143 mL) was cooled to −78° C. in a dry ice/acetone bath and then treated with n-BuLi, 2.5M solution in hexanes (23.35 mL, 58.4 mmol). The mixture was stirred for 10 minutes before being treated with N,N-dimethylformamide (6.16 mL, 80 mmol) and the resultant was warmed to ambient temperature and stirred for 10 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude chroman-6-carbaldehyde as a yellow solid which was used without further purification. LC/MS (m/z) ES+=163.22 (M+1). A solution of the crude chroman-6-carbaldehyde, methyl 3-oxobutanoate, piperidine (0.263 mL, 2.66 mmol) and AcOH (0.152 mL, 2.66 mmol) in Benzene (113 mL) was refluxed (DS-trap) overnight. The mixture was concentrated and diluted with ethyl acetate. The dilution was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-30% hexanes/ethyl acetate) the afford methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (mixture of E and Z isomers, 8.352 g, 32.08 mmol, 60.47% yield) as a thick yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, major isomer) δ ppm 7.48 (s, 1 H), 7.22-7.12 (m, 2 H), 6.78 (d, J=8.6 Hz, 1 H), 4.27-4.18 (m, 2 H), 3.92-3.81 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.39 (s, 3 H), 2.06-1.99 (m, 2 H); 1H NMR (400 MHz, CHLOROFORM-d, minor isomer) δ ppm 7.58 (s, 1 H), 7.16-7.08 (m, 2 H), 6.79-6.71 (m, 1 H), 4.23-4.18 (m, 2 H), 3.84-3.78 (m, 3 H), 2.76 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.03-1.96 (m, 2 H); LC/MS (m/z) ES+=261.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=O.[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: Cn1cccc1C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cccc1C=CC1=CC(=O)C(C)(C)O1
Temperature: 70 °C
Yield: 64.6 %

Procedure:
To a solution of 1methyl-2-pyrrolecarboxaldehyde (1.4 g, 12.7 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 70° C. for 48 hours. After the reaction solution was cooled to 0° C., saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give orange crystals (1.8 g, 65% yield), m.p. 98.5°-100° C.
Reaction SMILES: [H-].[Na+].I[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]=[O:12].C([Li])CCC.[C:18]1(=[O:22])[CH2:21][CH2:20][CH2:19]1>O1CCCC1>[OH:22][C:18]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][CH:11]=[O:12])[CH2:21][CH2:20][CH2:19]1
Reactant: O=CNc1ccccc1I
Reactant: O=C1CCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CNc1ccccc1C1(O)CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (65% dispersion in mineral oil, 71 mg, 1.775 mmol) was suspended in tetrahydrofuran (6 mL), and to this stirred slurry was added dropwise a solution of N-(2-iodophenyl)formamide (250 mg, 1.012 mmol) in tetrahydrofuran (4 mL). The mixture was stirred at room temperature for 20 minutes, then chilled to −78° C. To the cold suspension was added dropwise 2.5 M n-butyllithium in hexanes (0.506 ml, 1.265 mmol). The mixture was stirred at −78° C. for 30 minutes, then cyclobutanone (0.083 ml, 1.113 mmol) was added dropwise. The mixture was stirred at −78° C. for 2 hours and quenched with saturated NH4Cl (20 mL) solution and warmed to room temperature. The mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The product was purified by flash chromatography (Analogix, 20 to 50% ethyl acetate-hexanes over 25 min, 4 g silica cartridge, 18 mL/min) to give the title compound as a 2:1 ratio of two rotational isomers.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (142 mg, 0.46 mmol), 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (153 mg, 0.46 mmol) and N,N-dimethylaminopyridine (55.7 mg, 0.46 mmol) in DMF (10 ml) was added EDC.HCl (95.7 mg, 0.50 mmol) at it, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (260 mg, 90%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 2.00–2.19 (m, 3 H), 2.35–2.44 (m, 1 H), 3.35 (s, 2 H), 3.76 (s, 3 H), 3.89 (s, 3 H), 4.38–4.48 (m, 2 H), 4.63 (br s, 1 H), 4.94 (t, J=7.2 Hz, 1 H), 6.53 (d, J=8.4 Hz, 1 H), 6.66 (s, 1 H), 6.96–7.01 (m, 3 H), 7.12–7.42 (series of m, 8 H), 7.87 (d, J=8.0 Hz, 1 H), 7.98 (d, J=8.8 Hz, 2 H), 8.17–8.19 (m, 1 H); MS (ESI) m/z, 627(+), 628 (M++H).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:3]([C:5]([OH:7])=O)[CH3:4].[NH:18]1[CH2:29][CH2:28][CH2:27][C@H:19]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:1][N:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:3]([C:5]([N:18]1[CH2:29][CH2:28][CH2:27][C@H:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[O:7])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)N(C)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of N-methyl-N-[(phenylmethoxy)carbonyl]-L-alanine (4.74 g., 20 mmole) in distilled tetrahydrofuran (50 ml.) is added L-proline, 1,1-dimethylethyl ester (3.42 g., 20 mmole), hydroxybenzotriazole hydrate (3.06 g., 20 mmole) and dicyclohexylcarbodiimide (4.12 g., 20 mmole). The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue is dissolved in ethyl acetate (50 ml.) and washed with saturated sodium bicarbonate (twice), 10% potassium bisulfate (twice), and water (twice), dried (Na2SO4), and concentrated to give 6.4 g. of 1-[N-methyl-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline,1,1-dimethylethyl esters as an oily residue.
Reaction SMILES: C([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:36])[CH2:5][CH2:6][CH2:7][N:8]=[N+:9]=[N-:10])(=O)C.O>O1CCOCC1.Cl>[N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:36])=[N+:9]=[N-:10]
Reactant: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN=[N+]=[N-])C(C)=O)c(F)c3)cc(=O)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN=[N+]=[N-])c(F)c3)cc(=O)c12
Yield: 56.6 %

Procedure:
51 mg (0.10 mmol) of the resulting 2-[4-[N-acetyl-N-(3-azidopropyl)amino]-3-fluorophenyl]-6,8-difluoro-5-pentylamino-4H-1-benzopyran-4-one was dissolved in a mixed solvent of 1.5 ml of dioxane and 1.5 ml of concentrated hydrochloric acid and the mixture was heated at reflux for 3 hours. The reaction solution was cooled, water was added, the solution was made weak alkaline and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform) to give 26 mg (56%) of 2-[4-(3-azidopropylamino)-3-fluorophenyl]-6,8-difluoro-5-pentylamino-4H-1-benzopyran-4-one.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(OC([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)=O)(C)(C)C>>[NH:27]1[CH:31]=[C:30]([C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:29]=[N:28]1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: O=C(Nc1nc2cccc(-c3cn[nH]c3)n2n1)c1ccccc1
Yield: 31.5 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B1), 75 mg; 0.24 mmol; 1.0 eq.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (139 mg; 0.47 mmol; 2.0 eq.), at 140° C. for 14 h. Further treatment with a 1 N methanolic HCl solution (0.5 mL) and purification by flash chromatography on silica (EtOAc/c-Hex, 80:20) gave the title compound as a white powder (23 mg, 32%). HPLC, Rt: 2.07 min. (purity 96.9%). LC/MS, M+(ESI): 305.3, M−(ESI): 303.3.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1>>[ClH:1].[CH:13]1([NH:16][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:19]3[C:18]([CH3:17])=[CH:22][C:21]([CH3:23])=[N:20]3)[N:11]=2)[CH2:15][CH2:14]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NC1CC1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(NC3CC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclopropylamine and 3,5-dimethylpyrazole. Mp. 254° C.
Reaction SMILES: [Na].[CH3:2][C:3]1[O:9][CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[OH:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO.O>[CH3:2][C:3]1[O:9][CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Cc1occc(=O)c1O
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1occc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.5 g of sodium were dissolved in 300 ml CH3OH and 63g of maltol were added and stirred at room temperature for one hour. 200 ml CH3OH were added and then 102 g benzylbromide were dropped in (30 minutes). Refluxing for 3 hours and distilling off the CH3OH then yielded a residue which was dissolved in 300 ml H2O/300 ml ethyl acetate. The organic phase was washed with water and evaporated. The remaining oil was distilled in vacuo. B.P. (43 mm) =148°-150° C., 81.5 g colorless oil of the title compound was isolated.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[B:13]([OH:15])[OH:14].B(Br)(Br)Br.COC>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=1[B:13]([OH:15])[OH:14]
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Agent: BrB(Br)Br
Agent: COC
Solvent: ClCCl
Product: OB(O)c1cc(C(F)(F)F)ccc1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
To a suspension of 2-methoxy-5-(trifluoromethyl)phenylboronic acid (24.93 g, 0.1133 mol) in dichloromethane (150 mL) cooled to 0° C. was added dropwise boron tribromide (11.0 mL, 0.116 mol) over 30 minutes. After stirring for 5 hours, more boron tribromide (2.0 mL, 0.021 mol) was added. After stirring for 2 more hours, the reaction mixture was added to ice water and stirred for 20 minutes. The resulting white precipitate was filtered and washed with water to give a white solid that contained product. The layers of the filtrate were separated and extracted with dichloromethane (2×). The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to give a white solid which also contained product. It was determined by NMR that there was some methyl ether remaining, so all the material recovered was suspended in dichloromethane (100 mL) and cooled to 0° C. To this was added boron tribromide (7.0 mL, 0.074 mol) dropwise over 10 minutes and then boron tribromide (1M in dichloromethane, 11.0 mL, 0.0110 mol) dropwise over 10 minutes. After stirring for 5 hours, the reaction was complete as indicated by TLC. The reaction mixture was added to ice water, filtered, and washed with water to provide product (15.24 g, 65%) as a white solid. The layers of the filtrate were separated and extracted with dichloromethane (2×) and 4:1 dichloromethane:isopropyl alcohol. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to give additional product (5.7 g, 24%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C1CCc2c(O)cccc21
Product: CN(C(=O)Oc1cccc2c1CCC2=O)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxyindanone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (77%, light yellow oil). HPLC-MS: m/z=282.1 (M+1); Rt: 3.54 min.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-])=O.C(O)C.O.NN>[C].[Pd].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(ccc3ccccc32)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
First, 13.4 g of 2-nitrophenanthrene, 0.10 g of palladium carbon, and 120 mL of ethanol were loaded, and then 7 mL of hydrazine monohydrate were added to the mixture. The reaction solution was stirred for 4 hours under heating reflux. After having been cooled to room temperature, the reaction solution was poured into 300 mL of water. Then, the mixture was extracted with 200 mL of toluene. After the water layer had been removed, the organic layer was dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 10.0 g of a pale yellow solid were obtained (in 86% yield).