Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([NH:27][CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][C:30](O)=[O:31])(=[O:26])=[O:25].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH:28]([NH:27][S:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)(=[O:26])=[O:25])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:3][CH2:4][O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: N#Cc1ccc2c(c1)OCCC2N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 23.5 °C
Reaction time: 8 h

Procedure:
4-Amino-chroman-7-carbonitrile (Step E) (50 mg, 0.28 mmol), 3-(naphthalen-2-ylsulfonylamino)-3-phenyl-propionic acid (100 mg, 0.28 mmol), HOBt (42 mg, 0.31 mmol), and DIEA (72 mg, 0.56 mmol) were dissolved in CH2Cl2 (10 mL). EDC (52 mg, 0.34 mmol) was added and the reaction was stirred at 22-25° C. overnight until completed. The reaction solution was washed with dilute (˜5%) NaHCO3—H2O and H2O, and solution was dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (silica gel, 25% hexane in EtOAc) to provide the title compound as a white solid mixture of diastereomers (ca. 3:2 by 1H NMR after flash column chromotography).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:30]=[N:29][CH:28]=[N:27][CH:26]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3cncnc3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3cncnc3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14]Br)=[CH:9][CH:8]=1)C.[O:20]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CO>C(#N)C.[OH-].[Na+].[Cl-].[Na+].O>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH2:14][O:33][C:30]2[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:32][CH:31]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C(=O)CBr)cc1)OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CO[C@@H](Cc1ccc(C(=O)COc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from a solution of (2S)-3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl ester (0.076 mmol) from Example 124, Step C in acetonitrile (5 ml). 4-phenoxyphenol (0.152 mmol) and K2CO3 (0.23 mmol) were added. The solution was stirred for 30 min at 80° C. and then cooled to room temperature. The mixture was concentrated to dryness under vacuum and chromatographed in silica gel (hexanes/Ethyl ether 8:2 to 7:3). Fractions corresponding to the coupled compound were collected (Rf: 0.27) and concentrated to dryness. The mixture thus obtained was dissolved in 4 mL of NaOH 1N and 12 mL of Methanol and stirred at room temperature until TLC indicates the disappearance of starting material. The methanol was eliminated under vacuum and the aqueous solution diluted with 20 mL of brine and washed with diethyl ether (3×15 mL). The aqueous phase was acidulated with HCl 1N (until pH 3); extracted with ethyl acetate (3×15 mL) and the organic layer dried (MgSO4) and concentrated under vacuum. Obtained a colourless oil. 1H-NMR (200.15 MHz, CDCl3): 7.96 (d, 2H, J=8.4), 7.55–7.33 (m, 5H), 7.04–6.83 (m, 6H), 5.24 (s, 2H), 4.08 (dd, 1H, J=7.4, 4.4), 3.40 (s, 3H), 3.22 (dd, 1H, J=14.3, 4.4), 3.15 (dd, 1H, J=14.3, 7.2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH:15]C(OCC1C=CC=CC=1)=O)[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH2:15])[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](N)CCO[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
In a Parr shaker bottle was placed (S)-2-benzyloxycarbonylamino-4-(t-butyl-dimethyl-silanyloxy)-butyric acid methyl ester (478 mg, 1.25 mmol), methanol (10 mL) and 10% palladium on activated carbon (100 mg). The bottle was placed on the Parr Shaker and charged with hydrogen to 40 psi and shaken for 1.5 h. After this time, the mixture was filtered through celite and the filterate concentrated in vacuo to afford (S)-2-amino-4-(t-butyl-dimethyl-silanyloxy)-butyric acid methyl ester (291 mg, 94%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:18]N1C(=O)CCC1=O>CN(C)C=O>[Cl:18][C:10]1[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][C:3]([C:4]([NH:6][CH3:7])=[O:5])=[C:2]([CH3:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNC(=O)c1cc(N2CCOCC2)ccc1C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N2CCOCC2)c(Cl)cc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
100 mg (0.427 mmol) of 2,N-dimethyl-5-morpholin-4-ylbenzamide prepared in Step A was dissolved in 3 ml of N,N-dimethylformamide, and thereafter, 63 mg (0.47 mmol) of N-chlorosuccinimide was added thereto under cooling on ice. The obtained mixture was stirred at 50° C. for 1 hour. Thereafter, the reaction solution was concentrated, and water was then added thereto. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. The extract was concentrated, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate:methylene chloride=1:5), so as to obtain 54.5 mg (47%) of 4-chloro-2,N-dimethyl-5-morpholin-4-ylbenzamide in the form of a colorless solid, as well as 46 mg (40%) of 2-chloro-6,N-dimethyl-3-morpholin-4-ylbenzamide in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.C([O:19][C:20](=[O:30])[CH2:21]P(OCC)(OCC)=O)C.O.[OH-].[Li+].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:21]/[C:20]([OH:30])=[O:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a THF (40 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (4.00 g) obtained in Example 1, diethylphosphonoacetic acid ethyl ester (4.00 mL) and lithium hydroxide monohydrate (932 mg) were added one by one, and the reaction solution was agitated overnight at room temperature. 2N sodium hydroxide solution (30 mL) and ethanol (5 mL) were added to the reaction solution after confirming disappearance of the starting materials, and the reaction solution was agitated at room temperature overnight. The reaction solution was cooled to 0° C., 2N hydrochloric acid (30 mL) was added to the reaction solution, and the precipitation consequently deposited was separated by filtering with Kiriyama funnel. The obtained precipitation was washed with water and ethyl acetate, and 4.61 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][C:20]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)([C:23]([F:26])([F:25])[F:24])[CH2:19]2)[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][C:20]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)([C:23]([F:26])([F:25])[F:24])[CH2:19]2)[CH:15]=[CH:14][C:3]=1[C:4](=[S:44])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(NCc1ccccn1)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(c2ccc(C(=S)NCc3ccccn3)c(Cl)c2)C1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
To the solution of 2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin1-yl]-N-(pyridin-2-ylmethyl)benzamide (0.35 g) in toluene was added Lawesson reagent (0.28 g) and the mixture was heated to reflux for 3 hours. After the mixture was cooled to room temperature, the solvent was distilled away under the reduced pressure, and the residue was purified by silica gel chromatography to yield 2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin1-yl]-N-(pyridin-2-ylmethyl)benzenecarbothioamide (0.10 g). 1H-NMR (CDCl3) δ: 2.51-2.61 (1H, m), 2.84-2.92 (1H, m), 3.45-3.61 (2H, m), 3.79 (1H, d), 4.08 (1H, d), 5.08 (2H, d), 6.49-6.54 (2H, m), 7.22-7.28 (3H, m), 7.36 (1H, d), 7.40 (1H, t), 7.72 (1H, td), 7.79 (1H, d), 8.54 (1H, d), 9.27 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].Cl[Sn]Cl>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1C(=O)OC
Temperature: 50 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
2-methoxycarbonylmethyl-5-nitro-benzoic acid methyl ester (2.2 g, 8.8 mmol) was dissolved in MeOH (30 mL), then heated to 50° C. To the solution was added SnCl2 (5.89 g, 31 mmol) in batches. The reaction mixture was stirred at this temperture for 1 day. TLC monitored the reaction. After the reaction completed, the solvent was evaporated. To the residue was added ethyl acetate and base, adjusted pH to 8˜9, then filtered though celite and washed with ethyl acetate. The organic layer of the filtrate was collected and washed with water, dried over anhydrous Na2SO4 and concentrated to give 1.3 g of 5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (18D).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@@H:8]([CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.[O:35]1CC(O)O[CH2:37][CH:36]1O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@@H:8]([CH2:14][N:15]([CH2:16][CH2:17][C:18]([N:20]1[CH2:21][CH2:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=3[CH2:25][CH2:26]1)=[O:19])[CH2:37][CH2:36][OH:35])[CH2:7]2
Reactant: OC1COC(O)CO1
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCNC[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(CCO)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Reaction time: 0.75 h

Procedure:
1 g (2.2 mmol) of (7S)-N-[(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-3-oxopropan-1-amine (obtained by returning the compound of Example 4 to the base), 0.4 g (3.3 mmol) of 1,4-dioxane-2,5-diol, 0.7 g (3.3 mmol) of sodium triacetoxyborohydride and 8 mL of methylene chloride are mixed together. After 45 minutes at ambient temperature, the reaction mixture is rendered basic with 10 mL of 1N sodium hydroxide solution and stirring is carried out for half an hour. The phases are separated, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, washed with water and then with saturated NaCl solution and dried over MgSO4. After evaporating off the solvent, a residue is isolated which is chromatographed over silica (eluant: CH2Cl2/EtOH/NH4OH 95/5/0.5) to yield the expected compound, which is converted into its hydrochloride using 2N ethereal HCl solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:5]O.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:5][N:34]=[N+:35]=[N-:36]
Reactant: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CO)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1

Procedure:
3,5-dichloro-4-(4-chlorobenzoyl)benzyl alcohol (858.B) (1 mole) is reacted with diphenylphosphoryl azide (diphenylphosphonic azide) (DPPA) (1.2 mole, and 1,8-Diazabicyclo[5.4.0]undec-7-ene, (Synonym: DBU) (1.2 mole)) in toluene at cold temperature, followed by aqueous work-up and alcohol titration, to give 3,5-dichloro-4-(4′-chlorobenzoyl)benzyl azide (858.D). DPPA is an organic compound that is used in the synthesis of other organic compounds. Aust. J. Chem 26:1591-1593 (1973). The stability of DPPA towards heating is shown by its distillation at 157° C. and by the fact that vigorous evolution of nitrogen is not observed until a temperature of 175° C. is reached.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:30]#[N:31])=[N:11][N:12]([CH2:26][CH2:27][CH2:28][CH3:29])[C:13]=1[CH2:14][CH2:15][CH2:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(O)C>[C:20]1([S:17]([CH2:16][CH2:15][CH2:14][C:13]2[N:12]([CH2:26][CH2:27][CH2:28][CH3:29])[N:11]=[C:10]3[C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:2]=[C:30]3[NH2:31])(=[O:19])=[O:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCn1nc(C#N)c(-c2ccccc2N)c1CCCS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCn1nc2c(N)nc3ccccc3c2c1CCCS(=O)(=O)c1ccccc1
Yield: 63.7 %

Procedure:
Hydrochloric acid (0.98 mL, 3.90 mmol) in ethanol was added dropwise to a solution of 4-(2-aminophenyl)-5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrile (550 mg, 1.30 mmol) in 10 mL of ethanol. The resultant solution was stirred for 2 hours, concentrated under reduced pressure, and diluted with water. The pH of the mixture was adjusted to 8-9 by slow addition of solid sodium carbonate. The aqueous layer was extracted with several portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a pale yellow solid. The material was purified via flash column chromatography on silica gel (eluting with a 97:3 mixture of dichloromethane/methanol) to afford 350 mg of 1-(3-benzenesulfonylpropyl)-2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a white crystalline solid, mp 206-207° C. 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=6.9 Hz, 2H), 7.77 (dd, J=1.2, 8.1 Hz, 1H), 7.69 (dd, J=0.9, 8.1 Hz, 1H), 7.63 (m, 1H), 7.53 (m, 2H), 5.37 (br s, 2H), 4.35 (app t, J=7.2 Hz, 2H), 3.45 (m, 2H), 3.22 (t, J=7.1 Hz, 2H), 2.23 (m, 2H), 1.94 (m, 2H), 1.40 (qd, J=7.2, 14.6 Hz, 2H), 0.98 (t. J=7.3 Hz, 3H); MS (APCI) m/z 423 (M+H+); Anal. calcd for C23H26N4O2S: C, 65.38; H, 6.20; N, 13.26. Found: C, 65.40; H, 6.01; N, 13.26.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:9][C:10]([C:12]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[C:26](=[O:32])[NH:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:20])[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:13]=1)=[O:11])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:28]1([NH:27][C:26]([C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[C:19](=[O:20])[CH2:18][O:17][C:15]2[N:14]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:13]=[C:12]([C:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:39])=[O:5])=[O:11])[CH:16]=2)=[O:32])[CH2:29][CH2:30][CH2:31]1
Reactant: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reaction time: 6 h

Procedure:
To a solution of 634 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid tert-butyl ester in 5 ml dichloromethane were added 0.8 ml TFA. After stirring for 6 h it was concentrated and codistilled twice with toluene to give the crude product. Yield: 905 mg
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([N+:18]([O-])=O)=[CH:12][CH:13]=3)[C:8](=[CH:21][CH:22]=[C:23]3[N:27]([CH3:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[O:24]3)[C:7]=2[CH:6]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>[Zn].C(O)C>[NH2:2][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([NH2:18])=[CH:12][CH:13]=3)[C:8](=[CH:21][CH:22]=[C:23]3[N:27]([CH3:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[O:24]3)[C:7]=2[CH:6]=1
Reactant: CN1C(=CC=C2c3cc([N+](=O)[O-])ccc3-c3ccc([N+](=O)[O-])cc32)Oc2ccccc21
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CN1C(=CC=C2c3cc(N)ccc3-c3ccc(N)cc32)Oc2ccccc21

Procedure:
Zinc dust in an amount of 40 g was added with 50 ml of 10% hydrochloric acid, and the resulted solution was lightly stirred and was then filtrated. The resulted matter was washed with ethanol, so that an active zinc dust was obtained. The resulted active zinc dusts were put into a flask of 300 ml capacity, and whereto 4.13 g (0.01 mole) of 2,7-dinitro-9-(3-methylbenzoxazolinylidene)ethylidenefluorene and 100 ml of ethanol were added, and further 2.5 ml of an aqueous solution of 0.56 g (0.005 mole) of calcium chloride were added thereto, and the resulted mixture was refluxed for 4 hours, and was then heat-filtrated. The mother liquid thereof was condensed, so that the objective matter was obtained. The yield thereof was 1.84 g (52%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](OC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(=O)OCC>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH2:15][OH:16])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1CCCC(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCCc1ccccc1CO)Cc1ccccc1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
30h (1.8 g, 4.55 mmol) in THF (5 mL) was added dropwise to a stirred solution of LiAlH4 (0.35 g, 9.1 mmol) in THF (25 mL) at 0° C. Then the mixture was stirred at rt until TLC analysis indicated the total consumption of the SM. The reaction was quenched carefully by the slow addition of water (10 mL), and then the liquid was decanted away from the precipitate. The precipitate was washed with DCM (3×50 mL) and the organic layers were combined and dried over Na2SO4. The solvent was removed and the residue was purified by CC using PE:EA=5:1 as mobile phase to afford the desired product (1.3 g, 79% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1([CH:14]([CH3:24])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:26][CH2:27][CH2:28][C:29]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)OCC[O:30]1>CC(N(C)C)=O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:11]2[CH2:12][CH2:13][C:8]([CH:14]([CH3:24])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])([OH:7])[CH2:9][CH2:10]2)=[CH:39][CH:38]=1
Reactant: CC(C(=O)Nc1ccccc1)C1(O)CCNCC1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C(=O)Nc1ccccc1)C1(O)CCN(CCCC(=O)c2ccc(F)cc2)CC1
Reaction time: 4 h

Procedure:
11.0 g of potassium carbonate are added to a solution of 11.0 g of crude 2-(4-hydroxy-4-piperidyl)-N-phenylpropionamide in 150 cc of dimethyl acetamide and the mixture is heated to 100° while stirring. A solution of 13.1 g of 2-(3-chloropropyl)-2-(p-fluorophenyl)-1,3-dioxolane in 20 cc of dimethyl acetamide is subsequently added dropwise while stirring vigorously and the temperature is kept at 100° for 4 hours. The solution is subsequently cooled and the potassium carbonate is filtered off and the filtrate concentrated by evaporation at reduced pressure. The resulting compound is used for the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.[F-].[K+].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:27][C:10]([C:23]([F:26])([F:25])[F:24])([CH2:9][C:8]([C:6]1[CH:7]=[C:2]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:3]=[CH:4][C:5]=1[O:30][CH3:31])([CH3:29])[CH3:28])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (200 mg, 0.4 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), DCyBPP ((2-dicyclohexylphosphino)biphenyl, 28 mg, 0.08 mmol), KF (93 mg, 1.6 mmol) in toluene/THF (3/2 mL) at room temperature was treated with phenylboronic acid (98 mg, 0.8 mmol). The reaction mixture stirred overnight at room temperature and filtered through CELITE® filter aid. The residue was diluted with EtOAc (20 mL), washed with aqueous NaOH (11.0M, 10 mL), water, and brine (10 mL). The organic phase was dried over sodium sulfate, filtered, and solvent was evaporated in vacuo. The residue was purified silica gel chromatography and then by reverse phase HPLC to provide 1-[2-hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one as white solid.