Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:4]([C:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[S:22]([CH3:25])(=[O:23])=[O:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:3])=[CH:29][CH:28]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2S(C)(=O)=O)n(C)c(=O)c1O
Product: Cn1c(-c2ccc(F)cc2S(C)(=O)=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 4-fluorobenzylamine (125 mg, 1.0 mmol). The title product was obtained as a white solid (61 mg, 68% yield). 1HNMR (500 MHz, CDCl3) δ: 12.16 (1H, s), 7.87 (1H, dd, J=7.78, 2.59 Hz), 7.53 (1H, t, J 5.50 Hz), 7.48 (1H, td, J=7.86, 2.65 Hz), 7.41 (1H, dd, J=8.54, 4.88 Hz), 7.23 (2H, dd, J=8.55, 5.50 Hz), 7.00 (2H, t, J=8.54 Hz), 4.55 (1H, dd, J=14.95, 6.40 Hz), 4.51 (1H, dd, J=14.95, 6.10 Hz), 3.26 (3H, s), 3.01 (3H, s). HRMS (ESI) calcd for C20H18F2N3O5S (M+H): 450.0935; found: 450.0941.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)#[N:3].[CH2:17]([O:19]CC)[CH3:18]>C(O)C>[ClH:1].[CH2:13]([O:12][C:10]([CH2:9][O:8][C:7]1[CH:15]=[CH:16][C:4]([C:2](=[NH:3])[O:19][CH2:17][CH3:18])=[CH:5][CH:6]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)COc1ccc(C#N)cc1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(OCC(=O)OCC)cc1
Reaction time: 72 h

Procedure:
Dry hydrogen chloride was passed through a mixture of ethyl 2-p-cyanophenoxyacetate (30.75 g.), diethyl ether (500 ml.) and ethanol (10 ml.) at 0°-5° C. until the solution was saturated with hydrogen chloride, and the mixture was kept at 0° C. for 3 days and then filtered. There was thus obtained as solid residue ethyl p-(ethoxycarbonylmethoxy)benzimidate hydrochloride, m.p. 124°-126° C. A mixture of this compound (6.51 g.), diethyl ether (100 ml.) and a solution of potassium carbonate (3.6 g.) in water (15 ml.) was shaken, the ethereal phase was separated and to it was added a solution of ethyl glycinate hydrochloride (3.1 g.) in water (10 ml.). The mixture was stirred at laboratory temperature for 45 hours and the organic phase was separated, washed with water, dried and evaporated to dryness. The residual oil, which consisted of ethyl N-(ethoxycarbonylmethyl)-p-(ethoxycarbonylmethoxy)benzimidate (5.8 g.) was dissolved in ethanol (75 ml.) hydrazine hydrate (1 ml.) was added and the mixture was heated under reflux for 18 hours and then evaporated to dryness. The residue was purified by chromatography on silica gel using chloroform containing increasing amounts (up to 5% v/v) of ethanol as eluant. There was thus obtained ethyl p-(1,4,5,6-tetrahydro-6-oxo-1,2,4-triazin-3-yl)phenoxyacetate, m.p. 135° C.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[C:8]=2[F:12])[C:3]1=[O:14].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([OH:29])=[O:28])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CC#N.CCOC(C)=O>[N:22]1([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]([O:29][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[C:8]=2[F:12])[C:3]1=[O:14])=[O:28]
Reactant: O=C1c2ccc(Br)c(F)c2CCC1Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)O[C@H]1CCc2c(ccc(Br)c2F)C1=O
Temperature: 55 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To a solution of 2,6-dibromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one in MeCN (30 mL) was added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.12 g, 5.2 mmol) and triethyl amine (0.62 mL, 4.48 mmol) and the solution was heated to 55° C. After stirring for 15 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/hexanes) to afford (2S)-2-(6-bromo-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate (648 mg, 38%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:11]([C:8]4[CH:7]=[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[O:10][N:9]=4)=[O:13])[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc(-c2cccs2)on1
Reactant: COc1ccc2ncc(OCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4cc(-c5cccs5)on4)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (39 mg, 30% yield) following Scheme 1 and in analogy to Example 1 using 5-thiophen-2-yl-isoxazole-3-carboxylic acid (51 mg, 0.26 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine (80 mg, 0.26 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH2:3]1.[H-].[Na+].[CH2:35](Br)/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:35][CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: BrC/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(CC=Cc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a stirring solution of 250 mg (0.58 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide in 3 mL of DMF at 0° C. is added 127 mg (0.70 mmol, 1.2 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 10 min, then 95 mL (0.64 mmol, 1.1 equiv) of trans-cinnamyl bromide is added. The reaction mixture is stirred 10 min at 0° C. then 2 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent followed by lyophilization of the product afforded 262 mg of the 2-[2,4-Dioxo-5-phenyl-3-(3-phenyl-allyl)-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.46-7.07 (m, 18H), 6.92 (dd, 1H, J=1.2, 8.1), 6.46 (d, H, J=15.9), 6.25 (m, 1H), 5.04 (m, 1H), 4.31 (d, 1H, J=16.6), 4.13 (d, 1H, J=16.6), 3.46 (dd, 1H, J=6.1, 7.8), 2.93 (m, 2H), 1.10 (2×d, 6H, J=6.9); low resolution MS (FAB) m/e 544 (MH+), 409, 223.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH:18]=[C:17]([C:19](OCC)=[O:20])[CH:16]=[N:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>O1CCCC1>[OH:20][CH2:19][C:17]1[CH:16]=[N:15][N:14]([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:18]=1
Reactant: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Lithium aluminium hydride (1M solution in tetrahydrofuran, 4.45 ml, 4.45 mmol) was added dropwise to a stirred solution of ethyl 1-(triphenylmethyl)-pyrazole-4-carboxylate (2.27 g, 5.93 mmol) in anhydrous tetrahydrofuran (300 ml) under nitrogen at 0° C. After 1 h, the mixture was treated sequentially with water (3 ml), 15% aqueous sodium hydroxide (3 ml) and water (6 ml). The mixture was filtered through Arbocel filter aid, the filtrate was dried (MgSO4) and concentrated under reduced pressure, to give 4-hydroxymethyl-1-(triphenylmethyl) pyrazole (1.746g, 86%), as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](O)=[O:19])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Li]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:19])[CH3:24])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]C
Reactant: CC(C)c1c(C(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Product: CC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Reaction time: 4 h

Procedure:
General Procedure F. To a solution of 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid (Compound 28, 242 mg, 0.78 mmol) under argon was added methyllithium (3.0 M in diethoxymethane, 5.2 ml, 15.7 mmol) at room temperature. The reaction was stirred for 4 h and was quenched with 1 M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-50% EtOAc-hexanes to yield 1-(1-benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)ethanone (Compound 29) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccccn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (221 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=3:1 to give the title compound as colorless crystals (yield 175 mg, 92%).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+:53]>C(O)C>[Na+:53].[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:47])([F:49])[F:48])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O-:40])=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCN(CCCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CCCCCCC(=O)[O-])c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1

Procedure:
Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (250 mg) is dissolved in ethanol (4 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylamino]-heptanoic acid (131 mg). The resulting 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid (131 mg) is dissolved in ethanol (1 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (178 μl), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid sodium salt (133 mg). MS (m/z): 734 [M−Na]−
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CO>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH3:19])=[O:17])[C:7]=2[CH:8]=1
Reactant: Cc1cc2c(O)cccc2o1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccccc1COc1cccc2oc(C)cc12

Procedure:
4-Hydroxy-2-methylbenzofuran (2/3 g, 14.4 M), methyl 2-bromomethylbenzoate (3.29 g, 14.4 mM), anhydrous potassium carbonate (2.135 g), sodium iodide (87 mg) and methanol (20 ml) were reacted together in an analogous manner to that described in Example 5(A) to give methyl 2-(2-methyl-4-benzofuranyloxymethyl)benzoate, m.p. 93°-95° C. (Found: C, 72.74; H, 5.26. C18H16O4 required C, 72.96; H, 5.44%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[OH-].[Na+].[OH-].[K+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1.C(O)CCC.O>[CH2:13]([O:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH2:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCCCO
Product: NC1CCCCC1OCc1ccccc1

Procedure:
0.2 mol of trans-2-aminocyclohexanol are dissolved in 600 ml of xylene isomer mixture and 100 ml of n-butanol and heated to reflux. 0.2 mol of a 50% sodium hydroxide or potassium hydroxide solution in water is added dropwise to this solution over 15 minutes. In the course of this, the water which has been introduced and which forms is distilled off immediately. After the addition has ended, the water present in the reaction solution and then the n-butanol is distilled off until a transition temperature of 140-141° C. is attained. Thereafter, 0.2 mol of benzyl chloride is added dropwise over 30 minutes and the solution is stirred further under reflux for two hours. After aqueous workup, the desired 2-benzyloxycyclohexylamine is obtained in 93% (GC area%) yield in the case of sodium hydroxide, and in 92% (GC area%) yield in the case of potassium hydroxide.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>C(#N)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH3:1])[C:3]1=[O:11]
Reactant: CC1C(=O)Nc2ccccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1C(=O)N(CCCCl)c2ccccc21
Yield: 15.1 %

Procedure:
To a mixture of 3-methylindolin-2-one (1 g, 6.79 mmol, 1 equiv) in acetonitrile, potassium carbonate (1.877 g, 13.58 mmol, 2.5 equiv) followed by 1-bromo-3-chloropropane (2.01 ml, 20.38 mmol, 3 equiv) were added. The reaction was refluxed for 16 h. Upon cooling water was added and the mixture was extracted into ethyl acetate. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—2%-20% ethyl acetate in hexanes) to afford the title compound as a yellow oil (230 mg, 15%); 1H NMR (400 MHz, DMSO-d6): δ 1.31 (d, 3H, J=7.6 Hz); 1.99-2.05 (m, 2H); 3.47-3.53 (m, 1H); 3.66 (t, 2H, J=6.4 Hz); 3.74-3.82 (m, 2H); 7.04 (d, 2H; J=7.6 Hz); 7.24-7.27 (m, 1H); 7.3-7.32 (m, 1H); MS for C12H14ClNO m/z 211.06 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:19](=[O:34])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C@@H:21]([CH3:22])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[C:48](Cl)(=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59].C(N(CC)CC)C>C(OCC)(=O)C>[C:48]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:22])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:34])=[CH:37][CH:38]=1)(=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C[C@H]1C2N(C(=O)NCc3ccccc3)CCC(=O)N2[C@@H](Cc2ccc(O)cc2)C(=O)N1Cc1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in dry-THF (2 ml), dodecanoyl chloride 76 μl (0.319 mmol) and then triethylamine 45 μl (0.319 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml), saturated sodium bicarbonate (10 ml), water (10 ml), and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 61.6 mg (78%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]([O:45][CH2:46][CH2:47][CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][CH3:44])[CH2:47][CH3:48]
Reactant: CCCOc1ccc(OB([O-])[O-])cc1OCCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A mixture of 7-bromo-N-(4-((N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3,4-dipropoxyphenyl borate (0.17 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-(3,4-dipropoxyphenyl)-N-(4-((N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 155) (0.27 g) as colorless crystals.
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[F:1][C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1F)OCc1ccccc1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A mixture of spray-dried KF (200 mg, 3.48 mmol), intermediate 1 (250 mg, 0.696 mmol) and catalytic amount of 18-crown-6 in dry DMSO (5 mL) was stirred at 140-150° C. for 30 min. After completion (TLC), the reaction mixture was poured into ice cooled water (100 mL) and stirred for 5 min. The solution was extracted with EtOAc (3×50 mL). The combined solution was dried over anhyd Na2SO4. The solution was filtered and evaporated the solvents. The residue was chromatographed over silica gel column using hexane:acetone (80:20) as eluents to give the product as a pale yellow color solid (106 mg, 46%), mp 104-106° C. 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, t, J=8.0 Hz), 8.13 (1H, dd, J=8.6, 1.4 Hz), 8.04 (1H, dd, J=11.0, 1.8 Hz), 7.38 (5H, s), 5.25 (2H, s), 4.33 (2H, d, J=4.8 Hz); LC-MS (negative ion mode): m/z 331 (M−H)−.