Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21](=[O:23])[O:22][CH2:26][C:27]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
To a stirred solution of 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (6.0 g, 0.01 mol) in acetonitrile (50 mL) were added TEA (2.58 mL, 0.02 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (6.16 g, 0.02 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 30 minutes, cooled to 0° C., and then DBU (5.5 mL, 0.03 mol) was added. The reaction was stirred for an additional 15 minutes and then quenched with HCl (1 N) and extracted with DCM (2×300 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (500 mg) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.64 (d, J=7.8 Hz, 2H), 8.50-8.44 (m, 1H), 8.04-7.98 (m, 2H), 7.8 (t, J=7.2 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.38-7.32 (m, 3H), 7.26-7.22 (m, 1H), 5.55 (s, 2H), 5.38 (s, 2H). MS: M+H: m/z=429.1. HPLC: 90%, (Condition-I).
Reaction SMILES: [CH3:1][C:2]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:10]([NH:11]1)[CH2:9][C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>>[CH3:1][C@:2]12[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C@H:10]([NH:11]1)[CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=1
Reactant: CC12NC(Cc3ccccc31)c1ccccc12
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: C[C@]12N[C@H](Cc3ccccc31)c1ccccc12
Reaction time: 2 h

Procedure:
[3H]MK-801 binding was performed using Triton X-100 washed synaptic plasma membranes (SPM) prepared from rat forebrain (30-45 day old, male Sprague-Dawley; Sasco, St. Charles, MO) as described previously [J. W. Thomas, W. F. Hood, J. B. Monahan, P. C. Contreras and T. L. O'Donohue, Brain Res., 442, 396-398 (1988)]. The assay was initiated by the addition of SPM (0.20-0.30 mg) to an incubation containing 2.0 nM [3H]MK-801 (15 Ci/mmole; New England Nuclear, Boston, MA) and various concentrations of the appropriate test compound in a total volume of 0.5 ml (all additions were made in 50mM Tris/acetate buffer, pH 7.4) and continued for 120 min at 25° C. The samples were then filtered through glass fiber filters (Schleicher and Schuell #32) which were pretreated with 0.05% (v/v) polyethylenimine. The filters were washed and the radioactivity quantitated by liquid scintillation spectrometry. Inhibition of [3H]MK-801 binding was measured as a decrease in specific basal binding (basal binding=2583 ±381 DPM) with nonspecific binding as the residual binding in the presence of 60 μM MK-801 (562 ±30 DPM). The IC50 values for the inhibition of [3H]MK-801 binding were determined using a logit-log analysis and are reported in Table III, below.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.ClC(OCC(C)C)=O.[C:35]([O:38][CH2:39][C:40]1[CH2:47][S:46][CH:45]2[N:42]([C:43](=[O:49])[CH:44]2[NH2:48])[C:41]=1[C:50]([OH:52])=[O:51])(=[O:37])[CH3:36].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CCOCC.C(N(CC)CC)C.C1COCC1>[C:35]([O:38][CH2:39][C:40]1[CH2:47][S:46][CH:45]2[N:42]([C:43](=[O:49])[CH:44]2[NH:48][C:3](=[O:5])[CH:2]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][CH2:12][CH2:11][C:10]=3[CH:14]=2)[OH:1])[C:41]=1[C:50]([OH:52])=[O:51])(=[O:37])[CH3:36]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=C(O)C(O)c1ccc2c(c1)CCO2
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3ccc4c(c3)CCO4)C2SC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
α-Hydroxy-(2,3-dihydro-5-benzofuranyl)acetic acid (10 mmole) triethylamine (10 mmole) and bistrimethylsilylacetamide (BSA) (10 mmole) are added to 50 ml of THF and refluxed for two hours. The reaction mixture is cooled to about -10° C. and 10 mmole of isobutyl chloroformate is added dropwise. After 30 minutes at -10° C., 10 mmole of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 50 ml of water--20 ml of THF containing 10 mmole of triethylamine is added dropwise to the cooled reaction mixture. The temperature is maintained between -10° C. and 0° C. during the addition. The reaction mixture is allowed to come to room temperature very slowly. About 50 cc of saturated aqueous sodium bicarbonate and 100 ml of water are added to the reaction mixture. This mixture is treated several times with ether which is then discarded. The aqueous phase is layered with ethyl acetate and the pH of the aqueous solution is adjusted to 1.5. The ethyl acetate is then separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[Cl:21][CH2:22][C:23]([N:25]=[C:26]=[O:27])=[O:24].O>ClCCl>[CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:26]([NH:25][C:23]([CH2:22][Cl:21])=[O:24])=[O:27])[C@H:10]1[O:18][CH3:19])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: O=C=NC(=O)CCl
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of fumagillol (314 mg) in dichloromethane (5 ml) was added dropwise chloroacetyl isocyanate (160 mg) under ice cooling, followed by addition of dimethylaminopyrldine (130 mg). The mixture was stirred at 0° C. for 2 hours. To this reaction mixture was added water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The eluate obtained with a mixture of n-hexane and ethyl acetate (3:1) was concentrated under reduced pressure to give colorless, powdery O-chloroacetylcarbamoylfumagillol (318 mg) (71% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]1[C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[NH:16][C:26]1=[O:28])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 204.9 %

Procedure:
To a chilled solution of (2-amino-4-cyanophenyl)-carbamic acid tert-butyl ester (2.1 g, 8.8 mmol) in CH2Cl2 (50 mL) and triethylamine (1.22 mL, 8.8 mmol) was added a solution of triphosgene (0.94 g, 3.2 mmol) in CH2Cl2 (50 mL) slowly. The reaction was stirred at room temperature for 3 hours, diluted with CH2Cl2, washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using a gradient from 30% to 60% ethyl acetate in n-heptane as eluent to afford 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (1.7 g, 75%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][C:14]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:13]=2[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Cl-].[NH4+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([NH:8][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][C:17]([O:20][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:16][C:14]=2[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (1.7 g) in toluene (56 ml) was added portionwise sodium hydride (60% dispersion in mineral oil; 0.31 g). After the addition was complete, the mixture was stirred at 70° C. for 1 hour. After cooling, a mixture of ethyl bromoacetate (0.81 ml) and tetra-n-butylammonium bromide (0.10 g) in toluene (14 ml) was added, and the mixture was stirred at 70° C. for 4 hours. After cooling, the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted once with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; chloroform-ethanol; 25:1 to 5:1) to give N-benzyl-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (2.0 g) as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([CH2:42]O)[CH2:38][CH2:37]3)[N:30]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:58]1(=[O:68])[NH:62][C:61](=[O:63])[C:60]2=[CH:64][CH:65]=[CH:66][CH:67]=[C:59]12>C1(C)C=CC=CC=1.O>[N:20]1([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C@H:36]3[CH2:37][CH2:38][C@H:39]([CH2:42][N:62]4[C:58](=[O:68])[C:59]5[C:60](=[CH:64][CH:65]=[CH:66][CH:67]=5)[C:61]4=[O:63])[CH2:40][CH2:41]3)[N:30]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: OC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (972 mg, 1.2 eq) was added to a solution of trans-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanol (1 g, 1 equivalent; prepared in a similar manner as described in Example 4) in toluene (100 mL), it was then followed by the dropwise addition of DIAD (0.73 mL, 1.2 eq). The reaction mixture was stirred at RT for 10 minutes and then phthalimide (545 mg, 1.2 eq) was added. The mixture was stirred overnight at RT, water was then added and the resulting mixture was extracted 3 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude residue was triturated with MeOH to give 976 mg (70% yield) of trans-2-[4-(4-benzo-triazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-isoindole-1,3-dione; MS=454.40 (M+1)+.
Reaction SMILES: [CH2:1]1[C@H:3]2[C:4](=[O:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3>O1CCCC1.C(OCC)C>[CH2:1]1[C@H:3]2[CH:4]([OH:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Yield: 99.5 %

Procedure:
9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-one is stirred in 90 ml of tetrahydrofuran with 10 g of lithium tri-tert-butoxy-alanate for 2.5 hours at room temperature. The reaction solution is diluted with diethyl ether, washed with 2N sulfuric acid and water, dried, and evaporated, yielding as a residue 9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-ol.
Reaction SMILES: [CH2:1]1[O:13][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([NH2:18])[CH2:15][CH2:16][NH2:17]>C(O)(C)C>[CH2:14]([NH:18][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCCN
Reactant: CCCCCCCCCCC1CO1
Solvent: CC(C)O
Product: CCCCCCCCCCC(O)CNCCCNCC(O)CCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-dodecene oxide (100 g.) and 1,3-propanediamine (20.1 g.) and three recrystallizations of the resulting product from isopropyl alcohol gave N,N'-(1,3-propylene)-bis[2-hydroxydodecylamine] (I: R = CH3 (CH2)9, R' = H, X = (CH2)3, Z = H) (11.9 g., 96.0°-106.0° C.).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC.[F-].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:23](=[O:25])[CH3:24])[CH:11]=3)[CH2:6][CH2:7][N:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Brc1ccc2c(c1)C(C1CCCCC1)=NCC2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)C(C1CCCCC1)=NCC2
Temperature: 80 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
7-bromo-1-cyclohexyl-3,4-dihydroisoquinoline (4.01 g) was dissolved in 1,4-dioxane (100 mL), to which tributyl(1-ethoxyvinyl)tin (7.43 g), potassium fluoride (2.39 g), and tetrakis(triphenylphosphine)palladium (1.58 g) were then added, followed by stirring at 80° C. for 5 hours. Thereafter, to the reaction liquid were further added tributyl(1-ethoxyvinyl)tin (2.47 g) and tetrakis(triphenylphosphine)palladium (1.58 g), followed by stirring for 14 hours. Then, the reaction liquid was filtered through celite and the insoluble materials were separated. 4 M HCl/dioxane (20 mL) was added to the insoluble materials, followed by stirring at 60° C. for 30 minutes. The solvent was evaporated and water was added to the mixture which was then extracted with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-(1-cyclohexyl-3,4-dihydroisoquinolin-7-yl)ethanone (2.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])(O)=O.[Na+].Cl[CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)Cl.CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-]>[O:8]1[CH2:15][C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccccc2N1
Temperature: 0 °C

Procedure:
Into a 100 mL round bottom flask was placed a solution of 2-aminophenol (5.45 g, 49.98 mmol) in CHCl3 (30 mL). To this was added TEBA (11.4 g, 50.00 mmol). To the mixture was added NaHCO3 (16.8 g, 200.00 mmol). This was followed by the addition of a solution of 2-chloroacetyl chloride (8.16 g, 72.21 mmol) in CHCl3 (5 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. over a time period of 20 minutes. The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at 0-5° C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 55° C. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The product was precipitated by the addition of H2O. A filtration was performed. The filter cake was washed 2 times with 50 mL of H2O. The final product was purified by recrystallization from ethanol. This resulted in 4.5 g (60%) of 2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH:20](C(O)=O)[CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH3:24])[C:10]=3[CH2:9]2)=O)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]([C:31]#[C:32][C:33]([O:35][CH3:36])=[O:34])=[O:30]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[N:8]3[C:20]([CH2:19][C:18]4[C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[N:11]([CH3:24])[C:10]=4[CH2:9]3)=[C:31]([C:29]([O:28][CH3:27])=[O:30])[C:32]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:4][CH:3]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cn1c2c(c3ccccc31)CC(C(=O)O)N(C(=O)c1ccc(Cl)cc1)C2
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)cc2)n2c1Cc1c(n(C)c3ccccc13)C2
Temperature: 80 °C

Procedure:
A mixture of 2-(4-chlorobenzoyl)-9-methyl-1,2,3,4-tetra-hydropyrido[3,4-b]indole-3-carboxylic acid (4 g, 10.8 mmol), DMAD (2.3 g, 16.3 mmol) in AC20 (30 mL) was heated at 80° C. for 2 h. The reaction mixture evaporated in vacuo to dryness. The residue was recrystallized from MeOH to give dimethyl 3-(4-chlorophenyl)-6-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate, 3.5 g, (72%); mp 264-265° C. 1H NMR (DMSO-d6) δ 3.60 (6H, s, 2×COOMe), 3.78 (3H, s, NMe), 4.30 (2H, s, CH2), 5.18 (2H, s, CH2), 7.06-7.10 (1H, m, ArH), 7.17-7.20 (1H, m, ArH), 7.45-7.47 (1H, m, ArH), 7.54-7.59 (5H, m, 5×ArH). Anal. Calcd for (C25H21ClN2O4): C, 66.89; H, 4.72; N, 6.24. Found: C, 66.82; H, 4.63; N, 6.24.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of (S)—N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH3:28])[N:26]=1)[C:21](O)=[O:22]>>[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH3:28])[N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: COc1cc(C(=O)O)cc(N)n1
Agent: Cl
Product: COc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(N)n1
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (187 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.78 mmol, Amine-1, single enantiomer) and 2-amino-6-methoxyisonicotinic acid (131 mg, 0.78 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4ccccc4nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate(56 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(111 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and concentrated was purified by column chromatography(Hexane:ether=5:1) to obtain the titled compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH3:19])=[N:13]3)[CH2:4][CH2:3]1.C(O)(=O)C>[C].[Pd].C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][CH:12]([CH3:19])[NH:13]3)[CH2:4][CH2:3]1
Reactant: Cc1ccc2c(N3CCC(O)CC3)c(F)ccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1CCc2c(ccc(F)c2N2CCC(O)CC2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
5-(4-Hydroxy-1-piperidyl)-6-fluoroquinaldine (3.7 g) was dissolved in a mixed solvent consisting of 100 ml of acetic acid and 10 ml of ethyl acetate, and 1 g of 5% palladium-carbon was added to the mixture which then was placed in a vitrified autoclave. The reaction mixture was stirred at room temperature under a hydrogen gas pressure of 5 kg/cm2 for 3 hours. After removing hydrogen gas the reaction mixture was taken out. After removing the catalyst, the content was concentrated to dryness, dissolved in 100 ml of chloroform and neutralized with 50 ml of an aqueous 5% sodium hydroxide solution. After separation and washed with 100 ml of water twice, the chloroform layer was dried and concentrated to dryness. To the residue were added 20 ml of hexane and 0.5 g activated carbon and the mixture was heated to dissolve. After removing activated carbon by filtration the hexane layer was cooled to precipitate crystals which then were collected to give 3.4 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-1,2,3,4-tetrahydroquinaldine.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=[O:36])[CH2:28][CH2:27][C:26]1=[O:37]>>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29](=[O:36])[CH2:28][CH2:27][C:26]3=[O:37])[CH2:18][CH2:19]2)[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1cc(N2CCNCC2)nc(C(C)(C)C)n1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Product: CC(C)c1cc(N2CCN(CCCCN3C(=O)CCC(=O)c4ccccc43)CC2)nc(C(C)(C)C)n1

Procedure:
Analogously to Example 3b, reaction of 2-tert-butyl-4-isopropyl-6-piperazin-1-ylpyrimidine (0.95 mmol, 0.25 g) with 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione afforded 0.04 g of the title compound.