Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=S)[NH:10][NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:13][CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[ClH:13].[CH2:1]([NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCCCCCCNC(=S)NN
Solvent: CCO
Product: CCCCCCCNc1n[nH]c(C)c1C(=O)OCC
Product: Cl
Temperature: 25 °C
Yield: 30.9 %

Procedure:
A stirred solution of 30.3 g (0.16 mole) of 4-heptyl-3-thiosemicarbazide in 500 mL of absolute ethanol under nitrogen atmosphere was treated with the rapid addition of 26.3 g (0.16 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for ~16 hr, heated at reflux for 3 hr and filtered hot. Concentration of the filtrate in vacuo gave a deep red oil. The oil solidified on standing for ~16 hr and was recrystallized from 2-propyl alcohol to give 15 g of fine white crystals, mp 83°-84° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:21]=1)=[C:18]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]=[CH:16][CH:15]=3)(=[O:8])[O:5]CC)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>ClCCl.C(O)(=O)C>[CH2:1]([O:3][P:4]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:21]=1)=[C:18]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]=[CH:16][CH:15]=3)(=[O:5])[OH:8])[CH3:2].[CH2:36]([N-:38][CH2:39][CH3:40])[CH3:37]
Reactant: CCNCC
Reactant: CCOP(=O)(OCC)c1cc2c(cn1)[nH]c1cccc(OCc3ccccc3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOP(=O)(O)c1cc2c(cn1)[nH]c1cccc(OCc3ccccc3)c12
Product: CC[N-]CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.2 g of 5-benzyloxy-β-carboline-3-phosphonic acid diethyl ester (example 61) and 0.1 g of oxalyl chloride in 10 ml of dichloromethane is stirred for 24 hours at room temperature and then mixed with an excess of diethylamine. It is heated to boiling for 2 more hours for completion of the reaction. It is diluted with acetic acid and extracted with water. The evaporation residue of the organic phase yields 0.15 g of the title compound after crystallization from tetrahydrofuran.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=O)(C)(C)C.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>C(#N)C>[NH2:8][C@@H:9]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:10]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1)=[O:12]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)[C@H](N)C(=O)Nc1ccccn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3,3-dimethylbutanoic acid (1.00 g, 4.32 mmol), pyridine-2-amine (1.506 g, 16.00 mmol), DIEA (8.36 mL, 48 mmol), and HATU (7.87 g, 20.80 mmol) were taken up in ACN (5 mL) and heated at 120° C. for 30 minutes under microwave irradiation. ACN was removed under reduced pressure and the residue was dissolved in water and extracted with EtOAc (2×50 mL). The organic extracts were concentrated under reduced pressure and purified by preparative HPLC. Hydrogen chloride (4 M in THF, 4 mL, 16 mmol) was added to the resulting solid and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The residue was dissolved in water and extracted with EtOAc (2×50 mL). The aqueous layer was basified with 30% NaOH solution. The resulting solid precipitate was removed by filtration. The filtrate was extracted with DCM (2×50 mL). The DCM layer was dried and concentrated to give the title compound (83 mg) as a brown liquid. LCMS m/z=208.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:14])([CH3:13])[CH3:12])[CH:5]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:31]Br)=[CH:26][C:25]=1[CH2:41][OH:42])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:31][C@@H:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:25]([CH2:41][OH:42])[CH:26]=2)[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CC(C)(C)N)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1

Procedure:
3-(2-amino-2-methylpropyl)benzoic acid methyl ester (Preparation 34) (1.36 g, 6.60 mmol), [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 23) (2.96 g, 6.60 mmol), sodium iodide (980 mg, 6.60 mmol) and diisopropylethylamine (3.44 ml, 19.7 mmol) in acetonitrile (10 ml) were heated to reflux for 48 hours under a nitrogen atmosphere. The solvent was then removed in vacuo and saturated aqueous sodium hydrogen carbonate solution (20 ml) added and the product extracted with ethyl acetate (3×30 ml). The combined organics were washed with brine (3×20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the purified product was dissolved in diethylether and evaporated (×3) to yield a white foam (1.70 g).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Li].[Cl-].[Li+].[O:9]=[C:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH2:11]1>C1COCC1.C(OCC)C.C(OCC)(=O)C>[OH:9][C:10]1([CH3:5])[CH2:15][CH2:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[CH:12][CH2:11]1
Reactant: COC(=O)c1ccc(C2=CCC(=O)CC2)cc1
Reactant: [Li]C
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2=CCC(C)(O)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of anhydrous cerium(III) chloride (2.71 g, 11 mmol) in THF (10 mL) at −78° C. was slowly treated with 1.5M methyllithium complexed with lithium chloride in diethyl ether (6.7 mL), warmed to room temperature over 2 hours, and added to a solution of Example 420C (1.15 g, 5.0mmol) in THF (10 mL) at −78° C. The reaction was gradually warmed to room temperature over 4 hours, diluted with ethyl acetate (100 mL), washed with water (45 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:22]1[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([C:7](=[N:8][CH:9]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cnn(C)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
To a solution of 2.54 g of ethyl N-(diphenylmethylene)glycinate in 15 ml of toluene were added 1.52 g of 4-bromo-1-methyl-1H-pyrazole, 522 mg of bis(tri-tert-butylphosphine)palladium(0), and 6 g of tripotassium phosphate, followed by stirring at 100° C. for 12 hours. The reaction mixture was left to be cooled to room temperature and then filtered over Celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 328 mg of ethyl [(diphenylmethylene)amino](1-methyl-1H-pyrazol-4-yl)acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1.CN(C=O)C>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:26])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
In THF (30 ml) and DMF (30 ml) was dissolved 2-piperazinone (3.00 g), and to the solution was added triethylamine (5.02 ml). Under ice-cooling, to the mixture was added dropwise a solution of naphthalene-2-sulfonyl chloride (8.16 g) in THF (30 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was washed with sodium hydrogen carbonate solution, water and ethanol to give pale brown crystals of the title compound (7.15 g).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=3)=[CH:16][CH:15]=2)=[CH:10][N:9]=1)[C:3]([OH:5])=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:37])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[NH:24][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:22][N:21]=3)=[CH:18][CH:19]=2)=[CH:10][N:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cc2)cn1)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cc2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
In trifluoroacetic acid (10 mL) and water (1 mL) was dissolved 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-phenyl}pyridin-2-yl)oxy]propanoic acid (287 mg), and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in acetic acid, and the mixture was concentrated under reduced pressure. The obtained solid residue was pulverized by adding ether, collected by filtration, washed with ether and dried to obtain 2,2-dimethyl-3-[(5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]propanoic acid (175 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:31]([CH2:32][CH3:33])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C22H20FN5O2, 405.2
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(O)(=O)C.O.CCOCC>[F:25][C:26]1[CH:32]=[CH:31][C:29]([N:30]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:11][CH:12]=[C:13]2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:28][CH:27]=1
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(-c2ccc(-c3ccc([N+](=O)[O-])cc3)n2-c2ccc(F)cc2)cc1
Temperature: 70 °C
Yield: 90.6 %

Procedure:
To a slurry of the product from Example 1A (1.5 g, 4.57 mmol) in acetic acid (22.85 mL) was S added 4-fluoroaniline (4.33 ml, 45.7 mmol). The mixture was heated to 70° C. for 24 h. After cooling to rt the mixture was diluted with water and ether and stirred vigorously, filtered and dried to provide 1.67 g (91%) of the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH3:13])(=O)=O)=CC=1.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:12]([CH3:13])[CH2:11][N:36]2[CH2:37][CH2:38][C:33]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:34][CH2:35]2)=[CH:19][CH:18]=1)(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)OCC(C)c2ccc(C(=O)c3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CN1CCC2(CC1)OCCO2)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
Reaction of the 2-(4-benzoylphenyl)propyl p-toluenesulfonate described above with 1,4-dioxa-8-azaspiro[4,5]decane in DMF in the presence of anhydrous potassium carbonate affords 8-[2-(4-benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane.
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:39])[C:22]([O:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21)=O)C1C=CC=CC=1.[ClH:40].[H][H]>C(OCC)(=O)C.CO.[Pd]>[ClH:40].[NH2:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:39])[C:22]([O:30][C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:32])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N)CC1
Yield: 97.6 %

Procedure:
To a mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (16 g, 30.1 mmol) in ethyl acetate (300 mL) and methanol (150 mL) was added 1N HCl (31.6 mL, 31.6 mmol) followed by Pd/C (3.20 g, 3.01 mmol) and the mixture was stirred under balloon hydrogen atmosphere for 2 h. The mixture was then filtered through a pad of CELITE® and the pad was thoroughly washed with ethyl acetate. The filtrate was concentrated under reduced pressure and dried under high vacuum overnight to afford the title compound (12.75 g, 98% yield),as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.11-8.16 (2 H, m), 7.62 (1 H, t, J=7.40 Hz), 7.48 (2 H, t, J=7.78 Hz), 4.19 (2 H, q, J=7.11 Hz), 4.13 (2 H, d, J=3.51 Hz), 2.71-2.83 (2 H, m), 2.53 (1 H, brs), 2.32-2.46 (2 H, m), 2.01-2.13 (2 H, m), 1.74-1.85 (2 H, m), 1.03 (3 H, t, J=7.03 Hz). LCMS (M+H)=398.10.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:27])=[C:6]([CH3:26])[C:7]([CH3:25])=[N:8]2.[H-].[Na+].[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1.O>CN(C)C=O>[CH:32]1([C:35]([O:27][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:12]([O:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[C:3]=3[C:2]([F:28])([F:1])[F:29])[N:8]=[C:7]([CH3:25])[C:6]=2[CH3:26])=[O:36])[CH2:34][CH2:33]1
Reactant: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(O)c1C
Reactant: O=C(Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
5-Trifluoromethyl-6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline (30 mg) prepared in Synthesis Example 3 was dissolved in 1 mL of dimethylformamide. Under ice cooling, 4.3 mg of 60% sodium hydride was added to the solution, and the mixture was stirred for one hr. Thereafter, 10.4 mg of cyclopropanecarbonyl chloride was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was added to 5 mL of water, and the mixture was extracted with 5 mL of ethyl acetate. The ethyl acetate layer was washed with a saturated sodium hydrogencarbonate solution and saturated brine, was dried over anhydrous sodium sulfate, and was then concentrated under the reduced pressure. The crude product thus obtained was purified by chromatography on silica gel (Mega Bond Elut SI (Varian) 10 mL, solvent: n-hexane/ethyl acetate) to give 4-Cyclopropanecarbonyloxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline (13.8 mg, yield 39.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19](CC=C)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[C:25]([OH:29])(C)([CH3:27])[CH3:26].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:51]C)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:26][CH:25]([OH:29])[CH2:27][OH:51])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: C=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CC(O)CO)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Chloro-5-(2-propenyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (prepared as described in Example 5a) (1.99 g), tert-butanol (40 mL) and water (40 mL) were stirred together under nitrogen and AD-mix-α was added. The mixture was then stirred at room temperature for 20 hours. Sodium sulfite (2 g) was added and the mixture was stirred for 10 minutes. Water (100 mL) and ethyl acetate (100 mL) were then added. The layers were separated and the aqueous layer was further extracted with ethyl acetate (2×100 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. Purification was performed by column chromatography eluting with 5:95 methanol/ethyl acetate to give the sub-titled compound as a solid (1.77 g).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37].C=O.[BH4-].[Na+]>C1COCC1.CC(=O)OCC>[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:1])[CH2:33]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C)C1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
TFA (15 μL) was added to a cold (0° C.) mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), formaldehyde (0.26 mL; 3.49 mmol; 10 eq.) and NaBH4 (66 mg; 1.74 mmol; 5 eq.) in THF (12 mL) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA, washed with 0.1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (50 mg, 32%) as yellow foam. 1H NMR (DMSO-d6) δ 7.39-7.30 (m, 1H), 6.98 (dd, J=11.5, 2.3 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.01-4.92 (m, 1H), 4.85-4.78 (m, 2H), 4.66-4.45 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.70 (m, 1H), 2.62 (s, 1.5H), 2.60-2.52 (m, 2H), 2.55 (s, 1.5H), 2.35-2.2.20 (m, 2H), 2.17 (s, 1.5H), 2.16 (s, 1.5H), 1.81-1.60 (m, 1H). HPLC (max plot) 96.7%, Rt 2.74 min. UPLC/MS: (MS+) 444.5 ([M+H]+).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:7][CH2:6][C:5]1=[O:23])[CH:2]=[CH2:3].[Mn]([O-])(=O)(=O)=[O:25].[K+].[OH2:30]>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:4]([CH2:1][CH:2]([OH:25])[CH2:3][OH:30])[C:5](=[O:23])[CH2:6][N:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[CH:14]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: C=CCN1C(=O)CN=C(c2ccccc2F)c2cc(Cl)ccc21
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO

Procedure:
33.0 g of 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one are dissolved in 200 ml of pyridine. 16 g of potassium permanganate in 300 ml of water are added dropwise within 20 minutes at room temperature to the well-stirred solution. After the potassium permanganate addition, the mixture is extensively concentrated on a rotary evaporator. The residue is briefly boiled out with ethyl acetate and filtered off under vacuum. The ethyl acetate filtrate is extracted with water, dried over magnesium sulfate, filtered and concentrated. The residue is dissolved in a small amount of ethyl acetate and seeded. By recrystallization of the first crystals there is obtained pure 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 117°-118°C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](B(O)O)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3].Br[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc2oc(B(O)O)cc2c1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Cc1ccc2oc(-c3ccc(C=O)cc3)cc2c1
Yield: 64.2 %

Procedure:
A mixture of 5-isobutylbenzofuran-2-ylboronic acid (70 mg, 0.33 mmol), 4-bromobenzaldehyde (61 mg, 0.33 mmol), triethylamine (1.7 mL, 12.6 mmol) and bis(triphenylphosphine)palladium(II) chloride (12 mg, 0.017 mmol) in ethanol (10 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (59 mg, 65% yield): >99% purity by LCMS, ESI-MS: 279.2 (M+H)+.