Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17](=[O:22])C(Cl)(Cl)Cl)[N:5]([CH2:7][C:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)=[O:9])[CH:6]=1.[OH-:23].[Na+].Cl.[CH3:26]O>O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:22][CH3:26])=[O:23])[N:5]([CH2:7][C:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)=[O:9])[CH:6]=1
Reactant: Cc1cnc(C(=O)Cn2cc(Br)cc2C(=O)C(Cl)(Cl)Cl)cn1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Br)cn1CC(=O)c1cnc(C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{4-bromo-1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrol-2-yl}-2,2,2-trichloroethanone (157 mg, 0.37 mmol) in methanol (7 mL) was treated with sodium hydroxide (15 mg, 0.37 mmol) in water (0.4 mL) at 0° C. and the mixture stirred at room temperature. After one hour the reaction was complete (monitored by LCMS). The mixture was acidified with a aqueous solution of HCl (1 M) and then extracted with CH2Cl2 (3 times). The organic were then dried (Na2SO4), filtrated and concentrated in vacuo to give methyl 4-bromo-1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (140 mg). The crude was used in the next step without purification. 1H-NMR (400 MHz, CDCl3): δ 2.69 (s, 3H), 3.71 (s, 3H), 5.86 (s, 2H), 6.83 (d, 1H, 1.9 Hz), 7.01 (d, 1H, J 1.9 Hz), 8.53 (s, 1H), 9.13 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:12][CH2:11][CH2:10][CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccc(O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCSc1ccc(O)cc1
Yield: 68.4 %

Procedure:
2-[3-(4-Hydroxy-phenylsulfanyl)-propyl]-isoindole-1,3-dione (10.5 g) was dissolved in ethanol (450 ml) and treated with hydrazine monohydrate (17 ml) at 100° C. for 2 h in argon gas. Filtration and evaporation then crystallization from ethanol gave 4-(3-amino-propylsulfanyl)-phenol (4.2 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].[C:15]([O-])([O-])=O.[K+].[K+].COS([O:26][CH3:27])(=O)=O>CC(C)=O>[CH3:15][O:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:26][CH3:27])=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)ccc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1C
Temperature: 60 °C
Yield: 33 %

Procedure:
To a solution of the crude 3-hydroxy-2-methyl-4-nitrobenzoic acid in acetone (300 mL) was added K2CO3 (15.8 g, 115 mmol) and Me2SO4 (8.7 g, 69 mmol). The mixture was refluxed at 60° C. for 2 h. After the solvent was evaporated in vacuo, the resulting residue was purified by silica gel-column (eluting with PE/EA=10:1) to afford methyl 3-methoxy-2-methyl-4-nitrobenzoate as a yellowish solid (2.7 g, 33% yield, two steps). m/z (ES+APCI)+: [M+H]+226.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (187 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol)) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (226 mg, 0.40 mmol, 64% yield) as a white foam: LCMS (ES) m/e 569, 571 (M, M+2)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(Cl)Cl>[C:30]1([CH2:36][C:37]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added phenylacetyl chloride (47.7 μL, 0.36 mmol). The resulting mixture was stirred at RT for 16 h. Then, H2O (3 mL) was added and the mixture was extracted with DCM (2×5 mL). The combined organic extracts were concentrated and the residue was dissolved in MeOH (1 mL). The solution mixture was purified by preparative HPLC (10-100% of MeCN (0.1% TFA)/H2O (0.1% TFA) to give the title compound as an off-white thick oil. MS (ESI, positive ion) m/z: 396 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:20]([O-])=O)=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[NH2:20][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])[CH:4]=1
Reactant: COc1cccc(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(Cl)c(N)cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 5-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-nitrophenol (5 g) and potassium carbonate (3.16 g) in N,N-dimethylformamide (15 mL) was added ethyl bromoacetate (2.2 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (75 mL). To the solution were added methanol (75 mL) and nickel(II) bromide (0.17 g). To the mixture was added sodium borohydride (1.73 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give the title compound (4.11 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16](Br)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(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>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:16]3[CH:15]=[C:14]([CH:10]4[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9]4)[N:22]4[C:17]=3[C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnn2c(C3CN(Cc4ccccc4)CCO3)cc(Br)c12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnn2c(C3CN(Cc4ccccc4)CCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A stirred, degassed mixture of 7-(4-benzylmorpholin-2-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (701 mg, 1.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (350 mg, 0.30 mmol) in DMF (2 mL) was stirred under N2 for 30 min at 80 C, then treated with 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (754 mg, 2.26 mmol), K3PO4 (765 mg, 3.61 mmol) and H2O (165 mg, 9 mmol). The reaction was heated (100° C.) for 1 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and MeOH (2.5 mL) and the mixture filtered through a long silica plug. After removal of the volatiles in vacuo, the residue was purified by ISCO® chromatography using a gradient of 1% to 10% MeOH in CH2Cl2 to afford 401 mg (43%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H, J=9 Hz), 7.57 (s, 1 H), 7.21-7.38 (m, 5 H), 7:12 (d, 1 H, J=9 Hz), 6.73 (s, 1 H), 5.65 (s, 2 H), 5.10 (dd, 1H, J=10, 2Hz), 3.88 (d, 1H, J=12 Hz), 3.69 (dd, 1H, J=10, 9 Hz), 3.57 (d, 1H, J=13 Hz), 3.51 (d, 1H, J=13 Hz), 2.97 (d, 1H, J=12 Hz), 2.17-2.28 (m, 1H), 2.67 (d, 1H, J=11 Hz), 2.36 (t, 1H, J=11 Hz); ES-MS m/z 516.3 [M+H]+, HPLC RT (min) 2.80.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].C1(C)C(C)=CC=CC=1.CO.O.[OH-].[Ca+2:17].[OH-]>>[B:1]([O-:4])([O-:3])[O-:2].[Ca+2:17].[B:1]([O-:4])([O-:3])[O-:2].[Ca+2:17].[Ca+2:17]
Reactant: OB(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CO
Solvent: O
Product: [O-]B([O-])[O-]
Temperature: 60 °C

Procedure:
Two hundred (200) grams of a neutral calcium alkylsalicylate (calcium content; 2.0 wt. %) (A), which had been diluted to an extent of effective concentration of 50% by weight with a lubricating oil fraction, 26 g of calcium hydroxide (B), 43.4 g (2.0 moles per mole of calcium hydroxide) of orthoboric acid (C) and 400 g of xylene (F) were put in a 1000-ml four-necked flask fitted with a condenser and heated to 60° C. while agitating. To this mixture were added 120 g of methanol (D) and 20 g of water (E), and the resulting mixture was heated up to a refluxing temperature (66° C.) under agitation and reacted for 4 hours. The reaction mixture was further heated to 140° C. for 1.5 hours to distill out the methanol, water and xylene. Finally the reaction product was diluted twofold with hexane and filtered to remove any residual solids present, and the hexane was distilled out to obtain a desired calcium borate overbased alkylsalicylate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:33][CH2:34]3)[CH:21]=1)[CH2:16][C:17]([NH2:38])=[O:19])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(N)=O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (100 mg, 0.22 mmol) in tetrahydrofurane was added carbonyldiimidazole (53 mg, 0.33 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added ammonium hydroxide (0.05 ml, 0.66 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionamide as a white solid (80 mg, 81%): mp 77-79° C.; 1HNMR (CDCl3): δ 0.32-0.38 (m, 2H), 0.60-0.67 (m, 2H), 1.20-1.31 (m, 1H), 2.27 (s, 3H), 3.03 (dd, J=5.5, 15.5 Hz, 1H), 3.70 (dd, J=8.4, 15.5 Hz, 1H), 5.28-5.40 (m, 1H), 5.74-5.80 (m, 1H), 5.79 (dd, J=5.8, 10.5 Hz, 1H), 6.60 (t, JH-F=75 Hz, 1H), 7.09-7.13 (m, 3H), 7.47 (d, J=7.3 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 8.75 (d, J=8.5 Hz, 1H), 9.49 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.74, 25.6, 38.1, 51.9, 474.5, 112.5, 114.8, 115.8, 116.7, 118.7, 120.8, 123.5, 125.6, 131.8, 136.7, 137.8, 138.1, 140.8, 151.2, 168.6, 169.9, 170.5, 172.1; Anal. Calcd. for C24H23F2N3O6+0.5H2O: C, 58.06%; H, 4.87; N, 8.46. Found: C, 57.77; H, 4.60; N, 8.33; 1% H2O.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]1=[O:15].[N:16]1([C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[S:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]3=[O:15])[CH2:20][CH2:21]2)=[N:23]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC1(C)CC(=O)N(CCCCBr)C(=O)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CC(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C(=O)C1
Yield: 64 %

Procedure:
A mixture of N-(4-bromobutyl)-3,3-dimethylglutarimide (4 g., 0.0145 mole) obtained according to the procedure of Example 9, 3-(1-piperazinyl)-1,2-benzisothiazole (3.18 g., 0.0145 mole), anhydrous potassium carbonate (20.04 g., 0.145 mole) and potassium iodide (0.25 g., 0.0015 mole) in 150 ml. of acetonitrile is stirred and refluxed for a period of 12 hr. The reaction mixture is filtered, concentrated in vacuo and residual material triturated with ether. Crystallization of the solid thus obtained from ether affords a 64% yield of analytically pure 1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-dimethyl-2,6-piperidinedione, m.p. 146°-147° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH3:15])[C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][C:20]([NH2:22])=[NH:21].C([O-])([O-])=O.[Cs+].[Cs+].O>CC1OCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[C:10]([CH:11]([CH3:13])[CH3:12])[N:22]=[C:20]([NH:19][CH3:18])[N:21]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C(C)C(=O)c1ccc(F)cc1
Reactant: CNC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC1CCCO1
Product: CNc1nc(-c2ccc(F)cc2)c(C)c(C(C)C)n1
Temperature: 40 °C
Reaction time: 10 h

Procedure:
A mixture of 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione (MDK, 1.00 g, 4.5 mmol), N-methyl guanidine hydrochloride salt (0.49 g, 4.5 mmol) and Cs2CO3 (2.61 g, 8.0 mmol) in MeTHF (10 mL) was stirred at 40° C. for 10 h. The resulting suspension was cooled down to room temperature. Water (10 mL) and MeTHF (10 mL) were added. Layers were separated and the water layer was back-extracted with MeTHF (10 mL). The combined MeTHF fractions were washed with brine (20 mL) and dried over magnesium sulphate. Then, approximately 90% of the solvent was evaporated under reduced pressure and methanol (5 mL) was added to the resulting oily residue. White crystalline precipitate was collected by filtration, washed with ice-cold methanol (5 mL) and dried to afford the pyrimidine derivative CMDK (1.1 g, 92%) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13]C(=O)C)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: CC(=O)Oc1ccc(Br)c2c1CCC(=O)N2
Agent: Cl
Product: O=C1CCc2c(O)ccc(Br)c2N1

Procedure:
Then 21 g of thus obtained 8-bromo-5-acetyloxy-3,4-dihydrocarbostyril was dispersed in 150 ml of 8N-hydrochloric acid and was heated under refluxing condition for 3 hours. After the reaction mixture was cooled, the insoluble matters were obtained by filtration, washed with water, dried and recrystallized from methanol-water. 14 Grams of 8-bromo-5-hydroxy-3,4-dihydrocarbostyril was obtained as in the form of colorless needle-like crystals. Melting point: 212°-213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13]([O:16][C:17](Cl)=[O:18])[CH:14]=[CH2:15].[OH-:20].[Na+]>>[CH2:13]([O:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:17]([O:16][CH2:13][CH:14]=[CH2:15])=[O:20])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ccc(NCC(=O)O)cc1
Reactant: [OH-]
Agent: [Na+]
Product: C=CCOC(=O)Nc1ccc(N(CC(=O)O)C(=O)OCC=C)cc1

Procedure:
Analogously to Example 6, 3.1 g of N-(4-aminophenyl)-glycine are converted with 4.97 ml of chloroformic acid allyl ester and sodium hydroxide solution into the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([O:16]CC)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1

Procedure:
Ethyl 1-(t-butoxycarbonyl)piperidine-3(S)-carboxylate (35.9 g, 0.099 mol) was dissolved in abs EtOH (70 mL), treated with 0.5N NaOH (418 mL, 0.209 mol), and heated at reflux for 0.75 h. The reaction mixture was cooled and extracted with EtOAc. The aqueous basic layer was cooled with ice, carefully acidified (pH 3) with 3N HCl and extracted with CH2Cl2 (3×100 mL). The organics were combined, dried (MgSO4), filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:29][C:30](OC(C)=O)=[O:31].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>>[C:30]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[C:7]1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)(=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(C(C)=O)c2ccccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
To a stirred solution of {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (0.300 g, 0.814 mmol) in Ac2O (3 mL, 3.18 mmol) at rt was added a catalytic amount of CSA (0.019 g, 0.0814 mmol). The reaction was heated to 70° C. for 18 h, and by TLC the reaction was about one half complete. Another 19 mg of CSA added and kept at 70° C. for an additional 24 h. After this time, the reaction mixture was quenched with 1 N HCl (˜2 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat. aq. NaHCO3 (10 mL), and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc:petroleum ether gradient) to afford the product (0.164 g, 49%) as a solid; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.2 Hz, 3H), 1.03-1.23 (m, 4H), 1.47-1.61 (m, 2H), 1.92 (s, 3H), 3.24-3.42 (m, 2H), 5.34 (s, 2H), 7.27-7.43 (m, 3H), 7.52-7.70 (m, 3H), 7.94-8.08 (m, 3H), 8.33 (d, J=8.8 Hz, 1H); mass spectrum [(+) ESI], m/z 411 (M+H)+, 433 (M+Na)+.
Reaction SMILES: C[O-].[Na+].CO.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.Cl[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(OCC)C.CN(C)C=O>[O:12]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC1CCNCC1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(OCC2CCNCC2)cc1
Yield: 32.4 %

Procedure:
To a mixture of 28 ml of 30% sodium methanolate solution and 50 ml methanol, there are added 14.1 g (0.15 mole) of phenol. The reaction mixture is evaporated, mixed with 50 ml of N,N-dimethyl formamide and 7.8 g (0.05 mole) of 4-chloromethylpiperidine hydrochloride and heated for 18 hours at 70°-80° C. After cooling, the reaction mixture is mixed with diethyl ether, washed with water and dilute aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated in a vacuum. There are obtained 3.1 g of 4-phenoxymethylpiperidine (32% of theory); m.p. 41°-42° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:31][S-:32].[Na+]>C1COCC1.CCOC(C)=O>[CH3:31][S:32][CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(CSC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
To a stirring solution of 3-(bromomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (8) (2.9 g, 6.32 mmol) in anhydrous THF (35 mL) under N2 was added sodium thiomethoxide (NaSMe, 880 mg, 12.64 mmol) and reaction stirred 1.5 h. It was then diluted with EtOAc; washed with aqueous 0.3 N NaOH, then H2O, then brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-15% EtOAc/CH2Cl2) to give the desired product (2.5 g, 90% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.10 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.72-7.60 (m, 3H), 7.53-7.25 (m, 9H), 6.68 (d, J=7.8 Hz, 1H), 5.29 (q, J=7.6 Hz, 1H), 3.79 (q, J=13.7 Hz, 2H), 2.19-1.90 (m, 2H), 1.77 (s, 3H), 1.03 (t, J=7.4 Hz, 3H); LCMS: m/z 427 (MH+).