Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:26][CH2:25][CH2:24][C@@H:23]2[CH3:27])[C:9]1=[O:28])C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH3:27][C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:10]1[C:9](=[O:28])[NH:8][C:17]2[C:12]([N:11]=1)=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2
Reactant: COC(=O)c1ccc2c(c1)nc(N1CCC[C@@H]1C)c(=O)n2Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of (S)-methyl 1-benzyl-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (2.2 g, 5.84 mmol, 1.00 equiv) in dichloromethane (100 mL). This was followed by the addition of AlCl3 (7.7 g, 58.33 mmol, 10.00 equiv) in several batches. The resulting solution was stirred overnight at 30° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:100). This resulted in 900 mg (53%) of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[C:12]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:30]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:30]=1[O:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[C:12]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCO)cn1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cc(Cl)c(Cl)cc2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
In an oven dried 1-dram vial was a mixture of ethyl 2-(4-(1-(4-hydroxybutanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate (40 mg, 0.108 mmol), 2,4,5-trichlorophenol (34.0 mg, 0.172 mmol), triphenylphosphine (45.2 mg, 0.172 mmol) in CH2Cl2 (35.9 mL). DIAD (29.2 μL, 0.172 mmol) was added, and the reaction mixture was stirred at room temperature overnight. At the conclusion of this period, the reaction mixture was concentrated and purified by preparative HPLC (PHENOMENEX® Axia Luna column, 5μ, C18, 21.2×250 mm; 25 min gradient from 40% A:60% B to 0% A:100% B and 3 min 100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (18.9 mg, 32% yield) as a colorless oil. LCMS, [M+H]+=550.1. 1H NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.28-7.16 (m, 4H), 5.06 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.04 (br. s, 2H), 3.77 (t, J=6.8 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 2.66 (br. s, 2H), 2.13 (dt, J=12.7, 6.4 Hz, 2H), 1.92-1.80 (m, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(O)CCC>[O:19]([CH2:18][CH:17]([OH:26])[CH2:16][CH2:15][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)O
Product: OC(CCN1CCN(c2ccc(F)cc2)CC1)COc1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 3.6 g (0.02 mole) of 1-(4-fluorophenyl)piperazine, 4.0 g (0.02 mole) of 4-chloro-1-phenoxy 2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 5.1 g (74%) of offwhite powder, m.p. 97°-99° C. Recrystallizing solvent used was isopropyl alcohol.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH2:8]([O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:9]=[CH2:10].C(N(CC)CC)C.Cl.[NH2:27][CH2:28][CH2:29][SH:30]>C(Cl)Cl.C(O)C>[CH2:8]([O:11][C:12]([NH:14][CH2:15][C:16]([NH:27][CH2:28][CH2:29][SH:30])=[O:18])=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)NCC(=O)O
Reactant: NCCS
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: C=CCOC(=O)NCC(=O)NCCS
Reaction time: 0.25 h

Procedure:
Add pivaloyl chloride (2.4 ml) in CH2Cl2 (10 ml) to a cooled (0°-5° C.) and stirred solution of N-allyloxycarbonylglycine (3.18 g) and triethylamine (2.8 ml) in dry CH2Cl2 (50 ml). Stir the mixture at 0°-5° C. for 15 mins. and then add a solution of 2-aminoethanethiol hydrochloride (2.4 g) and triethylamine (2.8 ml) in ethanol (15 ml) and CH2Cl2 (40 ml). Stir at room temperature for 1 hour, wash the mixture with aqueous 2 N-H2SO4 and aqueous NaHCO3, dry and evaporate. Triturate the resulting solid with ether, filter and dry to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1.CC(O)=O>CCOC(C)=O.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:9])[F:10])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c(F)cccc2C(F)(F)F)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.7 %

Procedure:
A mixture of tert-butyl 4-(2-fluoro-6-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (21, 0.479 g, 1.41 mmol) and PtO2 (0.095 g, 0.42 mmol) in EtOAc (15 mL) and HOAc (82 μL, 1.4 mmol) stirred at ambient temperature for 72 h under an atmosphere of H2 (1 atm). The mixture was diluted with EtOAc (50 mL) and filtered over Celite. The filtrate was concentrated and the residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 24 g Redisep column, 0% to 15% EtOAc in hexanes) to provide tert-butyl 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carboxylate (22) as a white solid (0.219 g, 45%): 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.48 (m, 3H), 4.15-3.94 (m, 1H), 3.10-2.94 (m, 2H), 2.93-2.67 (m, 2H), 2.00-1.79 (m, 2H), 1.67-1.55 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1.CN(C)C=O.[I-].[K+]>[CH:13]1([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[O:9][CH3:10])[NH2:1])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(N)cc1O
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
A stirred solution of 5-amino-2-methoxyphenol (10 g) in dry dioxane (150 mL) is treated portionwise with an oil suspension of sodium hydride (60%; 3 g; 75 mmol) and the mixture is then warmed at 60° C. for 30 minutes. It is then treated dropwise with a solution of cyclopentyl bromide (9.2 mL) and potassium iodide (50 mg) in dry dimethylformamide (20 mL) and heated at reflux for 5 hours. The mixture is then concentrated and the residue is treated with ethyl acetate (200 mL) and water (200 mL). The organic layer is then separated, washed with water (100 mL), aqueous sodium hydroxide solution (250 mL;1N), and with water (100 mL), and dried over magnesium sulfate. The concentration of the reaction mixture gives a dark oil, which is subjected to flash chromatography, eluting with a mixture of n-hexane and ethyl acetate (1:1 v/v), to give 3-cyclopentyloxy-4-methoxyaniline (4.43 g), in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:5]2.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1)=[CH:5]2
Reactant: Oc1ccc(Oc2cnc3ccc(Cl)cc3c2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(Oc2cnc3ccc(Cl)cc3c2)cc1

Procedure:
Ethyl 2-{4-[(6-chloroquinolin-3-yl)oxy]phenoxy}-2-methylpropionate (13) was prepared from 4-[(6-chloroquinolin-3-yl)oxy]phenol and ethyl 2-bromo-2-methylpropionate following essentially the same procedure as that described in Example 1 part (c). The product, a pale yellow oil, was characterised by mass spectrometry. Mass spectrum (m/e, %): 387 (M+, 13); 385 (M+, 35), 271 (100).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(N(C2C=CC=CC=2)C([O:32][C:33](=O)[C:34]2[CH:39]=[CH:38][C:37]([CH2:40][N:41]3[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([NH:50][C:51](=[O:59])[CH:52]([CH2:57][CH3:58])[CH2:53][CH2:54][CH2:55][CH3:56])[CH:48]=4)[CH:43]=[CH:42]3)=[C:36]([O:60][CH3:61])[CH:35]=2)=O)C=CC=CC=1.P([O-])(O)(O)=O.[K+]>C1COCC1>[CH2:57]([CH:52]([CH2:53][CH2:54][CH2:55][CH3:56])[C:51]([NH:50][C:47]1[CH:48]=[C:49]2[C:44]([CH:43]=[CH:42][N:41]2[CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:33]([CH:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])[C:19]([O:21][CH3:22])=[O:20])=[O:32])=[CH:35][C:36]=2[O:60][CH3:61])=[CH:45][CH:46]=1)=[O:59])[CH3:58]
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC(=O)N(c4ccccc4)c4ccccc4)cc3OC)c2c1
Agent: CC(C)[N-]C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)C(C(=O)OC)S(=O)(=O)c4ccccc4)cc3OC)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium diisopropylamide (6.0 ml of a 0.5M solution in THF) was added to a solution of methyl 2-(phenylsulphonyl)acetate (650 mg) in THF (5.0 ml) at -78° C. A solution of 4-[6-(2-ethylhexanamido)indol-1-ylmethyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (A) (617 mg) in THF (5.0 ml) was added to the resultant mixture. After 2 hours, the reaction solution was allowed to warm to room temperature overnight and an excess of a solution of potassium dihydrogen phosphate was then added. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated, dried (Na2SO4) and evaporated. The resultant yellow oil was purified by chromatography on silica gel (42 g) using an increasing gradient of ether:methylene chloride (up to 1:19 v/v ether:methylene chloride). The title compound was thus obtained as an oil which was crystallized by treatment with methyl t-butyl ether to give an off-white solid (172 mg, 17%); mp 148°-149° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[CH:24][C:23]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)=[CH:22]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].[ClH:43]>C1COCC1.O1CCOCC1>[ClH:43].[ClH:43].[ClH:43].[NH:11]1[CH2:12][CH2:13][CH:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:21]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]5[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22]3)[CH2:7]2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(CC#N)(n3ccc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)c3)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxylate (3.3 g, 5.6 mmol) in THF (17 mL) was added a 4 N solution of HCl in dioxane (17 mL). The mixture was stirred at room temperature for 2 hours and concentrated to afford {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a white powder solid, which was used for the next reaction. Yield: 99%; LC-MS: [M+H]+=492.3.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 80 °C
Reaction time: 16 h
Yield: 133.7 %

Procedure:
A solution of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (1.48 g, 4.12 mmol) and 2,4-dichlorophenyl boronic acid (858 mg, 4.5 mmol) in benzene (41 mL) and 2M sodium carbonate (7 mL) was purged with nitrogen and treated with a single portion of bistriphenylphosphinepalladium(II)chloride (287 mg, 0.41 mmol). The resulting golden 2-phase solution was heated to 80° C. gradually darkening in color. After 16 hours, the reaction was cooled to room temperature, transferred to a separatory funnel, and washed with water (50 mL). The aqueous layer was extracted twice with ethyl acetate (75 mL) and the combined organics were washed once with brine (75 mL), dried over MgSO4, filtered, and concentrated to give 2.36 g of a brown syrup. This material was purified by biotage MPLC (90 g column, 20% ethyl acetate/heptane) to afford 1.25 g (71%) of the title compound as a tan solid. OAMS supporting ions at: ESI+ 428.0; HRMS (FAB) calcd for C23H23CL2N3O+H1 428.1296, found 428.1292.
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].CCCCCCC>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][N:5]([S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Br:15])(=[O:24])=[O:23])[C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)ONC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1Br

Procedure:
tert-Butyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate (41) is prepared according to Scheme 2. A solution of [(tert-butoxy)carbonyl]amino acetate (0.68 g, 3.9 mmol) in THF (5 ml) is added dropwise to a stirred solution of sodium hydride (0.16 g of a 60% dispersion, 3.9 mmol) in THF (10 ml). Stirring is continued for 30 minutes, whereupon 2-bromobenzene sulfonyl chloride (1.0 g, 3.9 mmol) is added. The reaction mixture is stirred at room temperature for 3 hours after which time tlc (1:1 heptane:ethyl acetate) shows no starting material remains. The reaction mixture is quenched by the addition of water (30 ml) and extracted into ether (2×50 ml). The combined organics are dried over sodium sulfate, filtered and concentrated in vacuo to yield the desired material as a yellow oil, which is purified by silica column chromatography eluting with heptane: ethyl acetate (4:1; v:v). (0.96 g, 60%), 1H NMR (360 MHz, DMSO-d6) δ ppm 8.12-8.26 (1H, m), 7.87-8.06 (1H, m), 7.61-7.79 (2H, m), 2.32 (3H, s), 1.26 (9H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[C:13](=[O:21])[C:12]2[C:11]([OH:22])=[CH:10][CH:9]=[CH:8][C:7]1=2>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:19]2[C:14](=[C:15]([O:20][C:15](=[O:20])[CH3:14])[CH:16]=[CH:17][CH:18]=2)[C:13]([O:21][C:13](=[O:21])[CH3:12])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[O:22][C:11](=[O:22])[CH3:10]
Reactant: O=C1c2c(O)cccc2C(c2cccs2)c2cccc(O)c21
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc2c(-c3cccs3)c3cccc(OC(C)=O)c3c(OC(C)=O)c12
Temperature: 80 °C
Reaction time: 3 h
Yield: 170.3 %

Procedure:
In a three-necked flask equipped with a magnetic agitator, there are stirred 250 mg of 10-(2-thienyl)-1,8-dihydroxy anthrone, obtained according to example 8, in 5 cm3 of acetic anhydride and several drops of pyridine. The mixture is stirred for 3 hours at 80° C. under an inert atmosphere, then cooled. The expected triester crystallizes and is then filtered and washed with hexane, yielding 300 mg of light yellow crystals having a melting point of 260° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O.O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-formylbenzoic acid (7.5 g), triethylamine (5.2 g) and p-methoxybenzyl chloride (7.6 g) in dimethylformamide (75 ml) was stirred at room temperature for 2 hours and then at 80° C. for 6 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The ether extract was washed with aqueous sodium bicarbonate and then water, dried over anhydrous sodium sulfate and evaporated to give 4-formylbenzoic acid p-methoxybenzyl ester which was then converted into 4-carboxybenzoic acid p-methoxybenzyl ester by the procedure similar to that described in Example 185.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[CH:6][C:5]=1[NH:12]C(=O)C)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[OH-].[K+].[K+].[Br-]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(N2CCNCC2)c(F)cc1[N+](=O)[O-]
Yield: 77.7 %

Procedure:
2-Nitro-4-fluoro-5-(piperazin-1-yl)aniline (5.6 g, 77%) was prepared by a procedure analogous to that described in preparation 1 (step 3) using N-(2-nitro-4-fluoro-5-chlorophenyl)acetamide (7.4 g, 0.03 mol) (obtained in preparation 1, step 2), piperazine (27.2 g, 0.3 mol), potassium hydroxide (2.5 g, 0.045 mol) and dimethyl sulfoxide (30 mL). mp 120-121° C.; IR (KBr) 3334, 1504, 1251 cm-1 ; 1H NMR (CDCl3 +CD3OD) δ 3.00 (t, J=5.4 Hz, 4H, N(CH2)2); 3.20 (t, J=5.6 Hz, 4H, N(CH2)2), 3.82 (brs, 3H, NH), 6.18 (d, J=8.2 Hz, 1H), 7.74 (d, J=13.8 Hz, 1H); Mass (m/z) 240 (M+.).
Reaction SMILES: ClC1C=C(C(Cl)=O)C=C(Cl)C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][C:35]1[CH:36]=[C:37]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:34][C:35]1[CH:36]=[C:37]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:38]=[C:39]([Cl:41])[CH:40]=1)[C:42]([NH:44][C:45]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][N:18]=2)=[CH:28][CH:29]=1)=[S:46])=[O:43]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(N=C=S)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cc(Cl)cc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
3,5-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,5-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 45%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH:9]2[CH:7]([CH:8]2[C:11]([NH2:13])=O)[CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C(OCC)C>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][N:5]1[CH2:6][CH:7]2[CH:9]([CH:8]2[CH2:11][NH2:13])[CH2:10]1
Reactant: CC(C)(C)CCN1CC2C(C1)C2C(N)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)CCN1CC2C(CN)C2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
The 3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (170 mg, 0.808 mmol) prepared in Example 6 was dissolved in 7.42 mL of methylene chloride and 1 M lithium aluminum hydride (LAH; 3.23 mL, 3.23 mmol) dissolved in diethyl ether was added dropwise at 0° C. After stirring for 5 minutes, the mixture was heated to room temperature. 15 minutes later, the mixture was stirred for 23 hours at 55° C. under reflux. The completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=10:1). After the reaction was completed, sodium sulfate hydrate was cautiously added at 0° C. The reaction mixture was filtered sequentially through Celite and anhydrous sodium sulfate, concentrated under reduced pressure and dried to obtain 130 mg (82.0%) of the target compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:26][CH:27]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 429 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=2)[CH:5]=1)[CH3:27]
Reactant: CCN
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CCNC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid and ethylamine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.