Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[CH:44][C:45]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])=[N:46][CH:47]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([C:48]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:49])=[N:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C(c1ccc(Br)cn1)N1CCOCC1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCOCC4)nc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (81 mg) and (5-bromo-pyridin-2-yl)-morpholin-4-yl-methanone (45 mg) obtained in the same manner as Step A in Example 1-D-79 instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of [5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-85) as a colorless powder (37 mg, 50%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43](O)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30].[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1S(C)(=O)=O
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (105 mg, 0.59 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (118 mg, 1.18 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (150 mg, 61%) as a pale yellow foam: mp 104-107° C.; EI-HRMS m/e calcd for C19H24N2O5S3 (M+) 456.0847, found 456.0846.
Reaction SMILES: [C:1](=[O:16])([S:3][CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH3:8])[CH3:2].[ClH:17]>C(O)C.C1(C)C=CC=CC=1>[ClH:17].[C:1](=[O:16])([S:3][CH2:4][CH2:5][CH2:6][NH:7][CH3:8])[CH3:2]
Reactant: CC(=O)SCCCN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNCCCSC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
S-3-(tert-Butoxycarbonyl(methyl)amino)propyl ethanethioate (206 mg, 0.834 mmol) in 4 ml of EtAc was added 1.0 ml of HCl (conc.) at RT. The mixture was stirred at RT for 1 h, diluted with ethanol/toluene (6 ml, 1:1), evaporated and co-evaporated with ethanol/toluene (3×10 ml), crystallized with ethanol/EtAc/Hexane, filtered, and dried over a vacuum to afford 135 mg (88%) of the title compound. 1H NMR (CDCl3) 9.70 (br, 1H), 8.56 (br, 1H), 3.42 (m, 2H), 2.52 (m, 2H), 2.35 (s, 3H), 2.05 (s, 3H), 1.88 (m, 2H); 13C NMR 174.64, 40.57, 31.57, 27.69, 20.94, 15.62; MS m/z+170.0 (M+Na), 148.10 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][CH2:11][CH2:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: Clc1ccccc1CCCBr
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCCc1ccccc1Cl
Yield: 39.2 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.53 g (15.1 mmol) of 1-bromo-3-(2-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.62 g of the desired compound (yield: 39.1%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([CH2:29][O:30][CH2:31][CH2:32][Br:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC#N>C(Cl)(Cl)Cl>[Br-:33].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:32][CH2:31][O:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCOCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Yield: 23.1 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.020 g, 0.068 mmol) was diluted in CHCl3 (1.8 mL) and dispensed directly into a 1 dram vial containing 2-bromoethyl phenylmethyl ether (0.022 g, 0.102 mmol). CH3CN (1.2 mL) was added; the vial was fitted with a stirring bar and capped. The reaction was stirred and heated at 60° C. for 24 h. The contents of the vial were transferred (after removal of stirring bar) into a polypropylene tube and concentrated under Nitrogen. The crude product was collected on a polypropylene tube frit. Excess bromide was removed by washing the crude product with EtOAc (5×2 mL) and Hexane (5×2 mL). The product was then dried under vacuum to give the title compound (0.008 g, 23.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(F)cn1
Solvent: CC(=O)O
Product: Nc1ncc(F)cc1I
Yield: 57.5 %

Procedure:
But using 5 g of 5-fluoropyridin-2-ylamine and 11.04 g of N-iodosuccinimide in 250 ml of glacial acetic acid. 6.1 g of 5-fluoro-3-iodopyridin-2-ylamine are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]1>ClCCl.O>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[CH2:2][N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]2)=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: OC1CCCNC1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1N)N(C(=O)CN1CCCC(O)C1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and 3-piperidinol (1.54 g, 15.2 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, the reaction was stirred at RT overnight under balloon H2 pressure. The catalyst was removed via filtration and the solvent was removed under reduced pressure to yield 1-{2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-piperidinol as a white solid (3.0 g, 92%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 1.09 (m, 1 H), 1.44 (m, 1 H), 1.62 (m, 1 H), 1.74 (m, 1H), 2.14(br, 1H), 2.47(s, 1H), 2.74(br, 2H), 2.95 (m, 4H), 3.50(s, 2H), 3.68(s, 3H), 4.04 (t, J=6.13 Hz,2 H), 4.71 (s, 2H), 6.68 (s, 1 H), 7.51 (s, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([OH:15])[CH:14]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20](F)[CH:19]=1.Cl>CN(C=O)C.C(OCC)C.O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([O:15][C:13]2[CH:14]=[C:9]([CH2:8][OH:7])[CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:19]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: OCc1cc(O)cc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(CO)c1
Temperature: 120 °C
Yield: 9 %

Procedure:
To a stirred solution of cesium carbonate (11.62 g) in dry DMF (70 ml) was added 5-(hydroxymethyl)-1,3-benzenediol (5 g) followed by 4-chloro-2-fluorobenzonitrile (5 g). The mixture was then stirred and heated at 120° C. for 3 h. The cooled mixture was then poured into water (200 ml) and made acidic by the addition of 2M aqueous hydrochloric acid. The products were extracted into ethyl acetate (3×150 ml), and the combined extracts were washed with 10% aqueous potassium carbonate solution (100 ml). The organic extract was collected, dried (MgSO4) and concentrated to dryness. Diethyl ether was added to the residue and the mixture filtered. The filtrate was concentrated to dryness and the residue purified by chromatography (silica, 70% diethyl ether/isohexane) to afford, after trituration with diethyl ether, the sub-title compound (800 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])(O)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC)c(C(C)(O)COCCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(OC)c(C(C)COCCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of 2-(2,5-dimethoxyphenyl)-2-hydroxypropyl 2-phenylethyl ether (550 mg., 1.74 mM) in pyridine (2 ml.) is added dropwise phosphorous oxychloride (477 ml., 5.22 mM). The reaction is allowed to warm to 20° C. over a 1.5 hour period. It is then stirred for 1.5 hours at 20° C. and then added to ether (150 ml.) and 15% sodium carbonate (100 ml.). The organic phase is separated and washed with 15% sodium carbonate (3×50 ml.), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in absolute ethanol (15 ml.), 10% palladium-on-carbon (100 mg.) added and the mixture stirred under one atmosphere of hydrogen gas. When hydrogen uptake ceases, the reaction is filtered through diatomaceous earth and the filtrate evaporated to an oil. The oil is purified via preparative layer chromatography on silica gel plates, eluting with 6:1 pentane: ether to yield 2-(2,5-dimethoxyphenyl)propyl 2-phenylethyl ether.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[CH3:15][N:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C@@H:26]4[CH2:31][NH:30][CH2:29][CH2:28][C@@H:27]4[N:19]([C:20]=23)[CH2:18][CH2:17]1.N>>[ClH:1].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:30]3[CH2:29][CH2:28][C@@H:27]4[N:19]5[C:20]6[C:21]([C@@H:26]4[CH2:31]3)=[CH:22][CH:23]=[CH:24][C:25]=6[N:16]([CH3:15])[CH2:17][CH2:18]5)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: N
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCc3noc4cc(F)ccc34)CC[C@@H]12
Product: Cl

Procedure:
The title compound was prepared from addition of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole from Step D and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline following General procedure A, Example 197. 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J=8.8 Hz, 4.7 Hz, 1H), 7.20–7.24 (m, 1H), 7.03–7.10 (m, 1H), 6.65 (dd, J=7.7 Hz, 7.7 Hz, 1H), 6.50 (d, J=7.3 Hz, 1H), 6.41 (d, J=7.3 Hz), 3.73–3.77 (m, 1H), 3.55–3.62 (m, 1H), 3.21–3.32 (m, 3H), 2.91–3.10 (m, 3H), 2.86 (s, 3H), 2.75–2.82 (m, 2H), 2.54–2.63 (m, 1H), 2.41–2.48 (m, 1H), 1.95–2.11 (m, 6H) ppm. MS (CI, NH3) m/e 407 (base, M+H+).
Reaction SMILES: [CH2:1]([C:3]([OH:28])([CH2:26][CH3:27])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=[CH:10][CH:11]=1)[CH3:2].O.NN>>[NH2:15][CH2:14][CH2:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3]([OH:28])([CH2:26][CH3:27])[CH2:1][CH3:2]
Reactant: CCC(O)(CC)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Product: CCC(O)(CC)COc1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)propyl)isoindoline-1,3-dione using hydrazine hydrate following the method described in Example 18 gave Example 32. 1H NMR (400 MHz, DMSO-d6) δ 7.13 (t, J=6.8 Hz, 1H), 6.69-6.73 (m, 3H), 4.28 (brs, 1H), 3.66 (s, 2H), 2.99 (t, J=4.8 Hz, 2H), 2.47-2.55 (m, 4H), 1.45-1.51 (m, 4H), 0.80 (t, J=7.6 Hz, 6H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]=1[N:19]=[C:20]=[S:21])[CH3:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:19]([C:11]2[C:12]([CH:16]([CH3:17])[CH3:18])=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:8][CH3:9])[C:20]1=[S:21])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: CCc1cccc(C(C)C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C(C)C)c1N1C(=O)CN(CC)C1=S

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), 2-ethyl-6-isopropylphenyl-isothiocyanate, (20.5 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (5-10% ethyl acetate in hexane). Crystallization from diethyl ether/hexane afforded pure title compound (7.5 g) as a white solid, m.p. 77°-79° C. Anal. Calcd. for. C16H22N2OS: C, 66.17; H, 7.64; N, 9.65. Found: C, 66.12; H, 7.77; N, 9.69. Mass spectrum (EI, M.+) m/z 290.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1>[OH-].[Na+]>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]([NH2:9])=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (prepared according to Example 1) is hydrolysed by refluxing in 2N sodium hydroxide to give [1-(naphth-2-ylmethyl)piperid-4-yl]urea (m.p. 183°-5° C.). The product is acylated by reaction with 4-methoxybenzoyl chloride to give the title compound, m.p. of HCl, quarterhydrate=193°-193.5° C.).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([O:27][CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[H][H]>[Pd].O1CCCC1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[CH:35][CH:36]=1)([O:3][CH3:4])=[O:2]
Reactant: CCOC(=O)C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1

Procedure:
A solution of 4 g. 2-(ethoxycarbonyl)vinyl 4-(15-carbomethoxypentadecylamino)benzoate and 400 mg. 10% palladium-on-carbon in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-(ethoxycarbonyl)ethyl 4-(15-carbomethoxypentadecylamino)benzoate.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[O:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B>C1COCC1.C(OCC)C>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)c1cccc(OC)c1OC
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCNCc1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
N-Heptyl-2,3-dimethoxybenzamide (6.47 g, 23.2 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (29 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL) and washed with aqueous 2 M K2CO3 (3×100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (160 g) with ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol in ethyl acetate as the eluent yielded 3.40 g (55%) of a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][O:10][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1noc2cc([N+](=O)[O-])ccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1noc2cc(N)ccc12
Yield: 49.6 %

Procedure:
Ethyl 6-nitrobenzo[d]isoxazole-3-carboxylate (12.7 mmol), iron (53.6 mmol), and ammonium chloride (56.1 mmol) were combined and diluted with ethanol (150 mL) and water (20 mL). The resulting suspension was heated at reflux, with vigorous stirring, for 2 h. The reaction mixture was filtered through Celite, diluted with brine (200 mL), and the resulting solution was extracted with ethyl acetate (200 mL). The organic layer was washed with of brine (3×200 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (20/1 petroleum ether/ethyl acetate) to provide ethyl 6-aminobenzo[d]isoxazole-3-carboxylate 49.6% yield as a orange solid
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:48]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:45])[N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)[CH3:48])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester (1.05 g, 1.64 mmol) was dissolved in anhydrous DMF (10 mL) and cooled to 0° C. under argon. NaH (78.8 mg, 1.97 mmol, 60% dispersion in mineral oil) was added and the mixture stirred at 0° C. for 30 minutes. Methyl iodide (164 uL, 2.63 mmol) was added and the reaction was allowed to warm to room temperature at which point the solution was maintained for 18 hours. The reaction mixture was then poured into H2O and extracted twice with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to a yellow oil which was further purified by silica gel chromatography (10 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10% over 10 min; B: 10% for 10 min; B: 10% to 30% over 15 min; B: 30% for 10 min; detection at 214 nm) to give 1.05 g (1.63 mmol, 99%) of the title compound as a yellow oil. MS (ESI) 653.2
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C=O)C>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazol-2-one (2.3 g, 6 mmol) was dissolved in DMF (20 ml) and sodium hydride (300 mg, 60%) was added. The suspension was stirred at 50° C. for 30 min. After cooling to room temperature, ethyl bromoacetate (1.17 g, 7 mmol) was added and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (2.6 g) as pale-yellow crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13]
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Reactant: OCCCCBr
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCCCO)CC3)cc12
Yield: 22.6 %

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1 g) and 4-bromo-1-butanol (433 mg), 5-methyl-3-[1-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-1-one (201 mg) was obtained.