Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:13]1([CH3:20])[C@H:14]([C:16]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:18])[CH2:15][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Step 3, 0.9 g, 3.25 mmol) in DCM (5 ml) EDCI (0.747 g, 3.89 mmol) and HOBt (0.527 g, 3.89 mmol) were added at about 0° C., after 10 minutes morpholine (0.6 ml, 6.5 mmol) and Et3N (2.3 ml, 16.26 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 0.6 g; Yield: 53.4%; 1H NMR (300 MHz, CD3OD): δ 7.40-7.22 (m, 5H), 5.19 (d, 1H, J=8.7 Hz), 5.08 (q, 2H, J=12.0 Hz), 3.95 (q, 1H, J=9.0 Hz), 3.79-3.38 (m, 8H), 2.80 (t, 1H, J=8.4 Hz), 2.49-2.35 (m, 1H), 2.34-2.20 (m, 1H), 1.33 (s, 3H), 0.89 (s, 3H); Mass: [M+1]+ 347 (10%), [M+Na]+ 346 (100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([OH:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([OH:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: O=S(=O)(O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (300 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (example B.2, step 1) (214 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (280 mg, 54%). MS (ISN) 510.9 [(M−H)−]; mp >288° C.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCCC1.[Na].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)[CH3:25]>C(O)C>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:25]
Reactant: CCOC(=O)CCCBr
Reactant: Sc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 50 °C

Procedure:
A solution of 5 g of the crude 4-(1-adamantyl)-thiophenol obtained above, in 25 ml of absolute ethanol and 25 ml of absolute tetrahydrofurane is added dropwise to a solution of 500 mg of sodium in 20 ml of absolute ethanol whilst stirring in a dry nitrogen atmosphere, and 2.9 ml of 4-bromobutyric acid ethyl ester are then added under the same conditions. After completion of the addition, the mixture is heated to 50° C for 14 hours. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 100 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 240 g of silica gel, with benzene as the eluant, yields chromatographically pure 4-[4-(1-adamantyl)-phenylthio]-butyric acid ethyl ester in the form of a yellow-brown oil (IR spectrum: C=O band at 1,740 cm-1 (in CH2Cl2)).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](O)(=[O:25])[CH:23]=[CH2:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.N1(C2C=CN=CC=2)CCCC1>ClCCl>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a stirred solution of N1-(4-(phenylthio)pyrimidin-2-yl)benzene-1,3-diamine (80 mg, 0.27 mmol) and acrylic acid (37 μL, 0.54 mmol) in anhydrous dichloromethane (2 mL), was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride salt (78 mg, 0.41 mmol), triethylamine (114 μL, 0.82 mmol) and 4-pyrrolidinopyridine (5 mg). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. It was diluted with dichloromethane (20 mL), washed with water, 2.0 Maqueous sodium carbonate solution, and dried (Na2SO4). After removal of the solvent in vacuo, the residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (50:50→100:0) as eluant to give the desired product (31 mg, 33%).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH:19](Br)[CH3:20]>CN(C)C=O.O>[Br:18][CH2:19][CH2:20][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1
Reactant: CC(Br)Br
Reactant: O=c1[nH]nnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2nnn1CCBr
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
To a solution of the compound 1,2,3-benzotriazin-4(3H)-one (500 mg) (commercially available) in dimethylformamide (13 ml) was added anhydrous potassium carbonate (2.8 g) and stirred for 20 minutes. To it was added dibromoethane (2 g) and stirred the reaction mixture first at room temperature for few minutes and then at 60° C. for 2 hours. The solid thus obtained was filtered and the filterate was concentrated under reduced pressure. The residue thus obtained was diluted with water and extracted with ethylacetate. The organic layer was separated, washed with water and brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluant to furnish the title compound (590 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](Cl)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1.CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1nc(N2CCCNCC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(N2CCCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 2-amino-6-(homopiperazin-1-yl)-8-(4-fluorophenyl)-9H-purine (0.2 mmol) in dioxane/methanol (1:1; 5 ml) was added potassium carbonate (55 mg, 0.4 mmol) and a solution of 4-chlorophenoxyacetyl chloride (60 mg, 0.24 mmol) in dioxane (1 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (methanol/dichloromethane 1:40), yielding the pure title compound (60 mg, 60%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][C:11]2[CH:30]=[CH:29][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:3][CH:2]([O:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][C:11]2[CH:30]=[CH:29][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(OCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(OCc2ccc(CN3CCNCC3)cc2)cc1
Reaction time: 8 h
Yield: 136.8 %

Procedure:
To a solution of tert-butyl 4-(4-{[4-(propan-2-yloxy)phenoxy]methyl}benzyl)-piperazine-1-carboxylate (5.42 g) in CH2Cl2 (41 mL) was added TFA (10 mL) at room temperature, then the reaction mixture was stirred for 8 hours. The reaction mixture was basified with 5 M aqueous NaOH, and extracted with CH2Cl2. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 1-(4-{[4-(propan-2-yloxy)phenoxy]methyl}benzyl)piperazine as a colorless solid (5.73 g).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:30]([O:29][C:27]([N:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:14]1[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of ethyl (2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (5.45 g) in toluene (55 ml) was added 1-chloroethyl chloroformate (2.59 g) at room temperature and stirred at 20° C. for 1 hour. 1-Chloroethyl chloroformate (795 mg) and N,N-diisopropylethylamine (0.736 ml) was added to the mixture, and the solution was stirred at 20° C. for 15 minutes. After it was concentrated under reduced pressure, the resulting residue was dissolved in EtOH (70 ml). The mixture was stirred at 65° C. for 30 minutes, and concentrated under reduced pressure. The residue was poured into a mixture of aq NaHCO3 solution (80 ml) and dichloromethane (100 ml). The organic layer was separated and dried over sodium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified by column chromatography (silica gel 125 g, dichloromethane/MeOH (60/1 to 15/1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as oil (2.0 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C([N-]C(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][CH2:25]I>O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: ClCCCI
Reactant: CCOC(=O)N1CCC(C#N)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C#N)(CCCCl)CC1
Temperature: -10 °C
Yield: 64.6 %

Procedure:
To a solution of ethyl 4-cyano-1-piperidinecarboxylate (6.0 g) in tetrahydrofuran (120 ml) at −70° C., under nitrogen, was added a solution of lithium diisopropylamide (4.6 g) in tetrahydrofuran (21.5 ml), dropwise, with stirring. The reaction was allowed to warm to −10° C. and after 30 min was recooled to −70° C. A solution of 1-chloro-3-iodopropane (7.4 g) in tetrahydrofuran (20 ml) was added to the mixture over 30 min. The reaction mixture was quenched with water and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was flash chromatographed (silica), eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to afford 5.5 g (64%) of product.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.ClCCl>CS(C)=O>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:4](=[O:28])[CH2:3]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Reactant: Brc1ccncc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
To a stirring solution of 700 mg (1.89 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in DMSO is added 370 mg of Cu powder (5.8 mmol, 3 equiv), 380 mg of potassium acetate (3.88 mmol, 2 equiv) and 500 mg of 4-bromopyridine (3.16 mmol, 1.7 equiv, freshly free-based from the hydrochloride salt). The reaction is heated to 100° C. for 16 h then poured onto ice. Dichloromethane is added, and the mixture is filtered through celite. The filtrate is poured into a separatory funnel containing 100 mL of H2O, and the layers separated. 2 mL of a 30% solution of NH4OH were added to the aqueous layer, and the resulting blue solution is extracted with dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography to afford 437 mg of 2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a white solid: mp. 211°-213° C.; 1H NMR (CDCl3, 400 MHz) δ8.61 (d, br, 2H, J=5.4), 7.43 (d, 1H, J=8.1), 7.36-7.14 (m, 5H), 6.99-6.22 (m, 4H), 5.03 (m, 1H), 4.26 (dd, br, 2H, J=16.6, 28.5), 3.87 (s, 3H), 3.55 (dd, 2H, J=12.0, 36.4), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 459 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([O:19][CH:20]1[CH2:29][C:28]2[C:27]([NH2:30])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1)(C(C)(C)C)(C)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:30][C:27]1[C:28]2[CH2:29][CH:20]([OH:19])[CH2:21][CH2:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2c1CC(O)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Benzylchloroformate (6.96 g, 40.8 mmol) was added dropwise to a solution of Example 18B (10.3 g, 37.1 mmol,) and diisopropylethylamine (7.20 g, 55.7 mmol) in 120 mL CH2Cl2 at 0° C. The mixture was stirred for 18 hours gradually warming to ambient temperature after which the volatiles were evaporated under reduced pressure. The residue was purified on silica gel eluting with 25% EtOAc/hexanes which yielded the benzyl carbamate as a light brown oil (15.2 g, 36.9 mmol). This product was taken up in 100 mL THF followed by addition of 1.79 g (111 mmol) of triethylamine trihydrofluoride. After 24 hours, the mixture was concentrated under reduced pressure and the residue partitioned between EtOAc and 1N aq. HCl. The separated organic layer was washed with 1N aq. HCl, brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated with Et2O, and the solid was collected by vacuum filtration and dried under vacuum at 50° C. resulting 8.82 g (80%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.82 (s, 1H), 7.45-7.30 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 6.90 (d, J=7.0 Hz, 1H), 5.12 (s, 2H), 4.77 (d, J=3.7 Hz, 1H), 3.87 (m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.43 (m, 1H), 1.84 (m, 1H), 1.58 (m, 1H); MS (ESI+) m/z 298 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (26.1 g) in N,N-dimethylformamide (350 ml) were added potassium tert. butoxide (9.2 g) and ethyl bromoacetate (13.7 g) at room temperature. The mixture was stirred overnight. After neutralization with diluted hydrochloric acid, the mixture was evaporated and chromatographed on silica gel using chloroform. Fractions containing the object compound were evaporated and the residue was triturated in ethanol to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethoxycarbonylmethyl-methyl-4(2,4,6-trimethylphenylimino)-2(1H)pyrimidinone (15.3 g). mp. 112°-113° C.
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14].O.Cl>CCOCC>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]([OH:14])[CH3:1]
Reactant: CCCCC(C=O)c1ccc(Cl)cc1Cl
Reactant: C[Mg]I
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCCC(c1ccc(Cl)cc1Cl)C(C)O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To 14.3 g (0.088 mole) of methylmagnesium iodide in 75 ml of ether is slowly added at less than 10°, 14.5 g (0.059 mole) of the α-(2,4-dichlorophenyl) hexanal. When the addition is complete, the reaction is stirred for 1 hour then heated up to reflux for 2 hours. The reaction is cooled and poured into water. The mixture is acidified with hydrochloric acid and the oil which separates is extracted out with ether. The ether solution is dried and concentrated to give 11.7 g (76%) of the crude product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][C:38]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and triethylamine (93 μL, 0.66 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere at 0° C. was added dropwise a solution of phenylacetyl chloride (93 μL, 0.66 mmol) in anhydrous dichloromethane (2 mL). After stirring for 3 h at 0° C., the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (98:2) to give the title compound (34 mg, 12%). 1H NMR (400 MHz, CDCl3) δ7.32-7.31 (m, 3H), 7.12-7.10 (m, 2H), 6.89-6.87 (d, 2H), 6.76-6.74 (d, 2H), 4.91 (t, 1H), 4.02 (t, 2H), 3.79-3.74 (m, 2H), 3.53-3.51 (m, 2H), 3.47 (s, 2H), 3.37-3.35 (d, 2H), 2.62 (m, 6H), 2.08-2.06 (m, 2H), 1.93-1.85 (m, 6H), 1.76-1.74 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Tert-butyl (±)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (55 mg, 0.12 mmol) was dissolved in 20% TFA in methylene chloride (4 mL) and was stirred at RT for 2 h. The reaction was solution was cooled to 0° C. and basified with 1M NaOH until pH>14. The layers were separated. The aqueous phase was extracted the methylene chloride (2×10 ml). The organic layers were washed with brine and dried. Concentration afforded the title compound (43 mg, 100%) as a pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.37 (dd, 1H, J=2.6, 7.3 Hz), 7.15-7.23 (m, 2 H), 6.97 (s, 1H), 6.92 (s, 1H), 3.43-3.46 (m, 1H), 3.31 (dt, 1H, J=4.4, 10.2), 3.03-3.11 (m, 2H), 2.81-2.94 (m, 2H), 2.60-2.80 (m, 4H), 2.11-2.20 (m, 2H), 1.89-1.98 (m, 1H), 1.74-1.85 (m, 1H) ppm. MS (CI, NH3): 359 (base, M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O:7][CH3:17])=[O:6])[C:3]=1[OH:11]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1O

Procedure:
To a slurry of 3-methylsalicylic acid (200 g) in 600 ml of methanol at −15° is added 65.7 g of concentrated sulfuric acid. The mixture is treated at reflux temperature for 5 days. The reaction mixture is concentrated, and methyl4-butyl ether (500 mL) and water (250 mL) are added. The ether layer is separated, washed with bicarbonate solution and evaporated to dryness to give methyl 3-methylsalicylate an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:20]C(=O)C1C=CC=CC=1)=[N:9]2.C1CCN2C(=NCCC2)CC1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:20])=[N:9]2
Reactant: CO[C@H]1CC[C@]2(c3ccccc3F)N=C(NC(=O)c3ccccc3)SC[C@@H]2C1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@H]1CC[C@]2(c3ccccc3F)N=C(N)SC[C@@H]2C1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,6S*,8aS*)-8a-(2-Fluorophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 59-(8) (3.11 g) was dissolved in methanol (100 mL). Then, DBU (2.34 mL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for two hours and 15 minutes. Then, the reaction solution was stirred at 64° C. for 13 hours and 30 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (1.96 g).