Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:7][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:8]=1
Reactant: COc1ccc(F)cc1N
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: COc1ccc(F)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 57.5 %

Procedure:
5-fluoro-2-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-fluoro-2-methoxyphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (54 mg, 56%) as a white solid. Mass Spectrum: M+H+ 470. NMR Spectrum (DMSOd6): 1.58 (d, 3H), 2.71 (bs, 3H), 2.94 (bs, 3H), 3.51-3.64 (m, 4H), 3.70-3.78 (m, 4H), 3.82 (s, 3H), 4.97-5.06 (m, 1H), 5.61 (s, 1H), 6.60 (s, 1H), 6.67 (s, 1H), 6.73 (d, 1H), 6.74 (s, 1H), 7.54 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[NH:14][NH2:15].[CH3:16][C:17]([CH:19]([C:21]([CH3:23])=O)[CH3:20])=O.C(O)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:14]1[C:21]([CH3:23])=[C:19]([CH3:20])[C:17]([CH3:16])=[N:15]1
Reactant: CC(=O)C(C)C(C)=O
Reactant: CS(=O)(=O)Oc1cc(NN)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1C

Procedure:
A mixture of (2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)hydrazine (25.5 g) of the formula: ##STR53## 3-methylpenta-2,5-dione (CH3COCH(CH3)COCH3) (11.4 g), ethanol (100 ml) and water (100 ml) was heated to reflux for one hour. After the reaction mixture was cooled, toluene was added thereto to form two layers. The toluene layer separated was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (29.3 g) as a pale yellow crystalline solid. Recrystallization of this solid from a mixture of n-hexane and ethyl acetate afforded a white crystalline solid. m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[O:25][CH2:24]3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.FC(F)(F)S([O-])(=O)=O.[Er+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+].[CH3:56][OH:57]>>[CH3:56][O:57][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]3[CH2:3][O:4]3)=[CH:7][CH:8]=2)([CH3:14])[CH3:13])=[CH:16][CH:17]=1
Reactant: CO
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Er+3]
Product: COCC(O)COc1ccc(C(C)(C)c2ccc(OCC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of racemic derivative Bisphenol A diglycidyl ether (500 mg, 1.46 mmol, 1 equiv) in methanol (5 mL) was added solid Erbium(III) trifluoromethanesulfonate (90 mg, 0.146 mmol, 1/10 equiv) in one portion and the mixture was stirred at room temperature for 1 h. Sodium bicarbonate was added (1 mL), the organic solvent was evaporated under reduced pressure and the residue was extracted with dichloromethane (3×5 mL). The organic layer was washed with deionized water (2×5 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% to 40% ethyl acetate in hexane) to provide the title compound (128 mg, 23%) as a pale foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(O)c(C(=O)O)c2)cc1
Yield: 92 %

Procedure:
The general procedure described in Example 3 was used with 5-chloro-2-hydroxy-benzoic acid (173 mg, 1.00 mmol), 4-cyanophenylboronic acid (176 mg, 1.20 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (552 mg, 4.00 mmol), water (2.0 mL), 12 h, 80° C. The product was isolated as a white solid (220 mg, 92%). Mp=227° C. 1H NMR (400 MHz, d4-MeOH) δ: 8.11 (d, 1H, J=2.4 Hz), 7.81-7.70 (m, 5H), 7.02 (d, 1H, J=8.4 Hz). 13C NMR (125 MHz, d4-MeOH) δ: 173.2, 163.5, 145.5, 135.4, 134.0, 131.2, 130.1, 128.3, 120.1, 119.4, 114.6, 111.5. IR (neat, cm−1): 3429, 2229, 1667, 750. Anal. Calcd for C14H9NO3: C, 70.29; H, 3.79. Found: C, 69.96; H, 3.52.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].Cl.Cl.[N:8]1([C:14]2[CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[O:4]1[CH2:1][CH2:18][CH:19]([N:11]2[CH2:12][CH2:13][N:8]([C:14]3[CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:10]2)[CH2:14][CH2:15]1
Reactant: O=C([O-])O
Reactant: OCc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OCc1cccc(N2CCN(C3CCOCC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to [3-(piperazin-1-yl)phenyl]methanol dihydrochloride (240 mg) to carry out liquid separation. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was mixed with dichloromethane (5 ml), and tetrahydro-4H-pyran-4-one (100 mg) and acetic acid (168 mg) were added thereto, followed by stirring at room temperature for 15 minutes. Sodium triacetoxyborohydride (576 mg) was added to the reaction mixture at 0° C., followed by stirring at room temperature for 5 hours. Water and CHCl3 were added to the reaction mixture, and the aqueous layer was adjusted to a pH of 8 to 9 by the addition of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {3-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}methanol (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH:40][C:41]([C:43]1[C:51]2[NH:50][C:49]([NH2:52])=[N:48][C:47]=2[CH:46]=[CH:45][CH:44]=1)=[O:42]>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:37]1[CH:38]=[CH:39][N:35]=[C:36]1[NH:40][C:41]([C:43]1[C:51]2[N:50]=[C:49]([NH:52][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:48][C:47]=2[CH:46]=[CH:45][CH:44]=1)=[O:42]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc(Cl)cc1
Yield: 19.7 %

Procedure:
70 mg (0.45 mmol) of 4-chloro-benzoic acid 170 mg (0.45 mmol) of HBTU in a mixture of 3 ml of DMF and 1 mL of DIEA was reacted with 100 mg (0.4 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide synthesized above as described in general procedure A and 2-(4-chloro-benzoylamino)-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (30 mg, 17.24%) was isolated. LCMS: 382 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 11.99 (d, 1H), 8.16 (d, 2H), 7.94 (d, 1H), 7.70 (dd, 3H), 7.30 (t, 1H), 6.81 (d, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:22]=[O:23])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[N:7]2.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:22][OH:23])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:20])([F:21])[F:19])=[N:7]2
Reactant: O=Cc1cc2c(Cl)cccc2nc1-c1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2c(Cl)cccc2nc1-c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde (2.1673 g, 6.456 mmol) in 32 mL of THF at 0° C. was added sodium borohydride (0.3664 g, 9.684 mmol) and the mixture was stirred at 0° C. After 1 hr at 0° C., the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), and the organic layer was washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (5-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68-8.73 (1 H, m), 7.96-8.02 (1 H, m), 7.90-7.95 (1 H, m), 7.83-7.87 (1 H, m), 7.68-7.83 (3 H, m), 7.50-7.58 (1 H, m), 5.63 (1 H, t, J=5.3 Hz), 4.36 (2 H, br. s.); LC-MS (ESI) m/z 338.0 [M+H]+. The product was carried on crude without purification for the next step.
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:30]([O:32]C)=[O:31])=[C:25]([F:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH2:11][CH2:10]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1([C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:30]([OH:32])=[O:31])=[C:25]([F:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: COC(=O)c1c(F)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)C1(N)CC1)c1ccc(-c2cccc(F)c2C(=O)O)cc1

Procedure:
A solution of methyl 4′-{(1R)-1-[({1-[(tert-butoxycarbonyl)amino]-cyclopropyl}carbonyl)amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate (466 mg, 1.0 mmol) in DCM (15 mL) and TFA (15 mL) was stirred under N2 for 20 minutes at ambient temperature, then the organic solvent was removed under vacuum. The residue was dissolved in MeOH (20 mL), 4N NaOH (10 mL) and water (10 mL). This mixture was heated at reflux for 4 hours and then neutralized with 6N HCl. Purification was achieved by preparative HPLC on a delta-pack C18 column, 300 Å, pore size 15 μM with 0.05% HCl acid-aqueous acetonitrile solvent systems using various linear gradients. Fractions containing product of 99% purity as measured by HPLC were combined and lyophilized to give 4′-((1R)-1-{[(1-aminocyclopropyl)-carbonyl]amino}ethyl)-3-fluoro-1,1′-biphenyl-2-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:10][C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCNc1ncccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNc1ncccc1N
Yield: 88 %

Procedure:
A solution of 2-(ethylamino)-3-nitropyridine (52 g) in MeOH (600 mL) was stirred overnight at room temperature under hydrogen (1 atm.) in the presence of 20% Pd(OH)2/C (10.4 g). The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the title compound as a black solid (39 g, 88% yield over steps a) and b).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[S:11]1)(C(C)(C)C)(C)C>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([C@H:12]1[S:11][C@@H:10]([CH2:9][OH:8])[CH2:14][S:13]1)=[O:16])[CH3:19]
Reactant: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)Cl
Product: CCOP(=O)(OCC)[C@@H]1SC[C@H](CO)S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of cis-4-(t-butyldimethylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-dithiolane (example 49) (3.70 g, 9.56 mmol) in anhydrous methanol (50 mL) was added acetyl chloride (6 drops) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for 4.5 hrs. A saturated solution of ammonium chloride (3 drops) was added and the solution was stirred for 15 min followed by evaporation of solvents. The crude material was purified by flash chromatography with a mixture of dichloromethane and methanol (95:5) to give the compound (2.02 g) in 77% yield.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:31][NH:32][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])[C:15]=2[O:14]1
Reactant: COc1ccc(Cl)cc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cccc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.058 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.213 mmol) and methylamine (0.045 g, 2.1 mmol). mp 201-203° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19]>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9])=[O:19]
Reactant: CON(C)C(=O)C=Cc1ccccc1Cl
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(2-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (22 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (17 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][CH:12]=[C:11]3[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:6][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=1.FC(F)(F)C(O)=O>>[F:44][C:2]([F:1])([F:43])[C:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][CH:12]=[C:11]3[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:6][NH:5][N:4]=1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCOCC3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1n[nH]cc1-c1ccc2nccc(N3CCOCC3)c2c1
Yield: 79.2 %

Procedure:
122 mg 4-[6-(3-trifluoromethyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]morpholine obtained in Example 174 and 1.5 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 57 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:44])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[C:39][Si](C)(C)C)[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2.Cl.C[OH:47]>>[C:38]([C:34]1[CH:33]=[C:32]([N:5]2[C:4](=[O:44])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[N:7]=[C:6]2[CH:12]([NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][NH:19]3)[CH3:13])[CH:37]=[CH:36][CH:35]=1)(=[O:47])[CH3:39]
Reactant: CO
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Agent: Cl
Product: CC(=O)c1cccc(-n2c(C(C)Nc3ncnc4[nH]cnc34)nc3cccc(C)c3c2=O)c1

Procedure:
Compound 139 was treated with 4N HCl in MeOH at 70° C. for 16 hours in accordance with the procedure described for compound 0.121 (step D). This reaction afforded compound 144, the structure of which is shown below. m/z=440 (M+H)
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccsc12
Product: Clc1ccnc2ccsc12
Temperature: 105 °C
Yield: 72 %

Procedure:
A stirred suspension of thieno[3,2-b]pyridin-7-ol (1, 5.0 g, 33.1 mmol) in POCl3 (15 mL) was heated to 105° C. in an oil bath for 4 hrs. The resultant solution was cooled to room temperature and the POCl3 was removed under reduced pressure. The residue was cooled in an ice/water bath and cold water was added. The water was made basic with concentrated NH4OH solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate and concentrated to produce an oil which was purified by column chromatography (eluent EtOAc-hexane, 1:4) to afford the title compound as a brown solid (4.5 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.60 (d, J=4.9 Hz, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.60 (d, J=5.5 Hz, 1H), 7.30 (d, J=4.9 Hz, 1H).
Reaction SMILES: CC1C=CC=C(C#CC=C2CCNCC2)N=1.[CH3:17][Si:18]([CH3:36])([CH3:35])[C:19]#[C:20][CH:21]=[C:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1>>[CH3:36][Si:18]([CH3:17])([CH3:35])[C:19]#[C:20][CH:21]=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#C[Si](C)(C)C)CC1
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: C[Si](C)(C)C#CC=C1CCNCC1

Procedure:
The title compound was synthesized following the procedure described for the compound of Example 3 starting from Compound 2a instead of the Compound of Example 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8]1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[C:33]1[C:37]([C:38](Cl)=[O:39])=[C:36]([CH3:41])[O:35][N:34]=1>C1COCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[C:33]1[C:37]([C:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:14]=3)[CH2:11][CH2:12]2)=[O:39])=[C:36]([CH3:41])[O:35][N:34]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Solvent: C1CCOC1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride. ESMS m/e: 585.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:45])[O:6][C@@H:5]([C@@H:7]([CH2:27]/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:32]([F:43])[CH:31]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])[C:4](=[O:44])[O:3]1.C(OCC)(=O)C>C(O)C.[Pd]>[CH3:45][C:2]1([CH3:1])[O:6][C@@H:5]([C@@H:7]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:32]([F:43])[CH:31]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:12]([CH3:13])([CH3:14])[CH3:15])=[O:9])[C:4](=[O:44])[O:3]1
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(Oc2ccccc2)c(F)c1)[C@@H]1OC(C)(C)OC1=O)C(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)[C@@H]1OC(C)(C)OC1=O)C(C)(C)C)c1ccccc1
Yield: 49 %

Procedure:
A solution of (2R, 5E)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-5-(3-fluoro-4-phenoxyphenyl)pent-4-enamide (210 mg, 0.34 mmol) in ethanol:ethyl acetate=5:1 (10 mL) was hydrogenated over 10% palladium on charcoal (20 mg) at 3 bar and 20° C. for 3 h. The mixture was filtered through Arbocel filter aid and concentrated under reduced pressure to give (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-5-(3-fluoro-4-phenoxyphenyl)pentanamide (103 mg, 49%), as a colourless solid, which was used for Example 9 without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: O=[N+]([O-])c1ccc(Br)c(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc([N+](=O)[O-])ccc1Br

Procedure:
To a stirring solution of (2-bromo-5-nitrophenyl) methan-1-ol (1 eq) in methylene chloride (0.1 M) at room temperature was added pyridinium chlorochromate (2 eq). After 2 hr the reaction mixture was filtered through celite and the product was purified by flash chromatography (15% EtOAc/Hexane). EI-MS m/z 230 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O1CCCC1>[C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
4,5-cis-Diphenyl-2-oxooxazolidine (48.6 g, 203 mmol) was suspended in tetrahydrofuran (330 ml) and, under ice-cooling, sodium hydride (8.12 g, 203 mmol) was added carefully. Thereafter, ethyl bromoacetate (33.9 g, 203 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours, poured into a mixture of a 10-fold dilution of conc. hydrochloric acid (60 ml) and ice-water (50 ml) and extracted twice with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (4:1)] to give the title compound (40.6 g) as yellow oil.