Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C@H:19]([NH:18][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:12]=1)=[O:15])[C:20](=[O:21])[NH:22][CH3:23]
Reactant: O=C(O)c1cccc(Cc2ccc(F)cc2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1cccc(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-fluorobenzyl)picolinic acid (Example 277 a) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=372.0 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.B(F)(F)F.CCOCC.[N:24]1[O:25][CH2:26][C@@H:27]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29][C:28]=12>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][C:5]([C:28]23[CH2:29][N:30]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH:27]2[CH2:26][O:25][NH:24]3)=[CH:6][N:7]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: O=C(OCc1ccccc1)N1CC2=NOC[C@@H]2C1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)CC2CON3)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
A −78° C. solution of 2-trimethylsilylthiazole (383 mg, 2.44 mmol) in tetrahydrofuran (3 mL) is treated drop wise with a solution of n-butyl lithium (1.52 mL, 2.44 mmol, 1.6 M hexanes) and the reaction is stirred at −78° C. for 10 minutes to give a thick orange slurry. The slurry is treated with boron trifluoride etherate (205 μL, 1.62 mmol) to give a red mixture and then a solution of benzyl(3aR)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (200 mg, 812 μmol) is added immediately in toluene (2 mL) to this mixture. The resultant mixture is stirred at −78° C. for 20 minutes under nitrogen. The reaction is quenched with saturated ammonium chloride and warmed to room temperature. Water and saturated sodium bicarbonate is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel eluting with 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (245 mg, 75%). ES/MS (m/e): 404 (M+H).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[C:21]([O-:24])(=[O:23])[CH3:22].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:21]([O:24][CH2:2][C@@H:3]1[CH2:4][C@H:5]([CH2:11][C:12](=[O:13])[N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[O:6][C:7]([CH3:10])([CH3:9])[O:8]1)(=[O:23])[CH3:22]
Reactant: CC(C)N(C(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1)C(C)C
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CC(=O)OC[C@@H]1C[C@H](CC(=O)N(C(C)C)C(C)C)OC(C)(C)O1

Procedure:
Heated the reaction mixture of 250 grams of 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-diisopropylacetamide, 225 grams of sodium acetate and 290 grams of tetra butyl ammonium bromide to 110-115° C. Stirred the reaction for 12 hours at 110-115° C. Diluted the reaction mixture with petroleum ether and filtered the byproduct. Organic layer washed with water. Distilled the solvent completely under reduced pressure. Isolated the material in petroleum ether. Dried the material at 40-45° C. to get the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:43])[C:33]#[C:34][C:35]1[CH:40]=[CH:39][C:38](CO)=[CH:37][CH:36]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:25][C:38]1[CH:39]=[CH:40][C:35]([C:34]#[C:33][C:32]([OH:43])=[O:31])=[CH:36][CH:37]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C#Cc1ccc(CO)cc1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)C#Cc1ccc(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenyl]-methanol and (4-hydroxymethyl-phenyl)-propynoic acid methyl ester according to the procedure of Example 69. MS (ESI) m/z 538.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:8][C:9]1[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][C:14]=1[Cl:17]
Reactant: Oc1cccc(Cl)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(Cl)c(Cl)c1F
Reaction time: 24 h
Yield: 47.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 3-chloro-2-fluorophenol (750 mg, 5.12 mmol) and N-chlorosuccinimide (684 mg, 5.12 mmol) in acetonitrile (30 mL) and the reaction mixture stirred for 24 h. The mixture was concentrated in vacuo and purified by chromatography on silica gel with heptane:EtOAc (9:1, v/v) as eluent to afford the title compound (440 mg, 48%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11]C=O)[N:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:4].[CH:24]([O:29][CH3:30])([O:27][CH3:28])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:24]([O:27][CH3:28])[O:29][CH3:30])[N:6]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:4]
Reactant: COC(=O)C1CCCC(CC=O)N1C(=O)OCc1ccccc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)C1CCCC(CC(OC)OC)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
6-(2-Oxo-ethyl)-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Compound 236, 0.4 g, 1.25 mmol), trimethyl orthoformate (5 mL) and p-toluenesulfonic acid monohydrate (0.03 g) were combined, and the reaction mixture was stirred at room temperature for 12 hours. Aqueous NaHCO3 (25 mL) was added and the reaction was extracted with CHCl3 (3×100 mL). The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (1:2 EtOAc/hexanes) to afford Compound 237 (0.441 g, 96%). Rf=0.75 (1:1 EtOAc/hexanes).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>C(#N)C.O>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][O:23][CH3:24])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 75.4 %

Procedure:
A solution of N-Boc-piperazine (1.00 g, 5.31 mmol) in acetonitrile (30 ml) was treated with K2CO3 (2.20 g, 15.9 mmol) and (2-bromoethyl)methyl ether (812 μl, 5.84 mmol) and heated to 80° C. for 18 h. The cooled mixture was diluted with water and extracted with DCM. The combined organcs were dried over MgSO4, filtered and evaporated and the residue purified by column chromatography on SiO2, eluting with 5% EtOH in DCM to afford 1-Boc-4-(2-methoxy-ethyl)-piperazine as a clear oil (978 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 3.41 (t, J=5.8 Hz, 2H), 3.29-3.25 (m, 4H), 3.21 (s, 3H), 2.45 (t, J=5.8 Hz, 2H), 2.33 (t, J=5.0 Hz, 4H), 1.38 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([OH:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[C:25]2[C:20](=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:16][C:11]1[C:12](=[O:15])[N:13]([CH3:14])[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][NH:17]4)[CH:7]=2)=[N:9][CH:10]=1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Cn1c(-c2ccnc(Br)c2)ncc(O)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cn1c(-c2ccnc(-c3cccc4[nH]ccc34)c2)ncc(O)c1=O
Temperature: 160 °C
Yield: 78.5 %

Procedure:
A mixture of 2-(2-bromopyridin-4-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-one (30 mg, 0.106 mmol), 1H-indol-4-ylboronic acid (32 mg, 0.2 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichchloromethane complex (4 mg) in THF (2 mL) and 1 M aq Cs2CO3 (1 mL) was heated in a microwave at 160° C. for 10 min. After cooling to rt, the THF layer was separated and the aq. solution was extracted with THF (2 mL). The combined THF solution was treated with QuadraPure TU resin (Aldrich), filtered, and concentrated. The concentrated residue was purified by LCMS to give 5-hydroxy-2-[2-(1H-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3H)-one (26.5 mg, TPA salt). 1H-NMR (499 MHz, d6-DMSO): δ 11.31 (s, 1H); 9.77 (s, 1H); 8.85 (d, J=5.0 Hz, 1H); 8.08 (s, 1H); 7.61-7.56 (m, 2H); 7.56-7.50 (m, 2H); 7.46 (t, H=2.7 Hz, 1H); 7.22 (t, J=7.7 Hz, 1H); 6.99-6.96 (m, 1H); 3.44 (s, 3H); HRMS calculated for (C18H14N4O2+H)+ 319.1190 found 319.1188. Assays The activity of the compounds in accordance with the present invention as COMT inhibitors may be readily determined without undue experimentation using a fluorescence or fluorescence polarization (FP) methodology that is well known in the art (Kurkela M et al., Anal Biochem (331) 2004, 198-200 and Graves, T L et al., Anal Biochem (373) 2008, 296-306). Assays utilized purified human COMT enzyme of the Val158 variant (membrane-bound MB-COMT or soluble S-COMT) containing a C-terminal 6 or 10-histidine tag. Compounds of the following examples had activity in reference assays by exhibiting the ability to inhibit the methylation of esculetin and/or inhibit the production of S-adenosyl-homocysteine (SAH). Any compound exhibiting an IC50 below 1 μM would be considered a COMT inhibitor as defined herein.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:17]O>>[CH3:17][O:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Br:1]
Reactant: OC(c1ccccc1)c1ccccc1Br
Reactant: CO
Agent: Cl
Product: COC(c1ccccc1)c1ccccc1Br

Procedure:
A solution of 152 g. of 2-bromobenzhydrol, 1 liter of methanol, and 45 ml. of conc. hydrochloric acid is heated under reflux for 24 hours, cooled, stirred with 100 g. of potassium carbonate, filtered, and distilled to provide 2-bromobenzhydryl methyl ether, b.p. 126°-128° (0.7 mm.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C@H:22]([CH3:33])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27](SC)[N:26]=3)[CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].OO.C(=O)(O)[O-:37].[Na+]>C(O)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C@H:22]([CH3:33])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([OH:37])[N:26]=3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nccc(OC[C@@H](C)CN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)n1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@H](COc1ccnc(O)n1)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 g of (S)-2-tert-butyl-4-cyclobutyl-6-{4-[2-methyl-3-(2-methylsulfanyl-pyrimidin-4-yloxy)-propyl]-piperazin-1-yl}-pyrimidine (2.12 mmol) were dissolved in 10 ml of acetic acid. 2 g of aqueous hydrogen peroxide (17.6 mmol, 30% in water) were added at 0° C. The reaction mixture was stirred for 15 h at room temperature, poured onto water and the aqueous phase was adjusted to alkaline pH with saturated sodium bicarbonate solution. After extraction with ethyl acetate, the organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). Fractions containing the product were combined, the solvent was evaporated, and the residue treated with acetonitril, filtered and dried to yield 0.36 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH:41]=[CH2:42])=[N:9]2)=[CH:5][CH:4]=1.B1C2CCCC1CCC2.[OH:54]O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42][OH:54])=[N:9]2)=[CH:43][CH:44]=1
Reactant: OO
Reactant: C=Cc1nn(Cc2ccc(OC)cc2)c2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)c12
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(CCO)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of N-(4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.357 g, 0.60 mmol) in THF (5 mL) was added a 0.5 M solution of 9-BBN (3.60 mL, 1.80 mmol) in THF. The reaction was stirred for 18 hours at room temperature. The reaction was cooled in an ice bath, and then was quenched by addition of 2N aqueous NaOH (3 mL). After stirring for 10 minutes in the ice bath, 30% aqueous hydrogen peroxide (0.577 mL, 6.00 mmol) was added. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude was partially purified by Biotage Flash 40, eluting with 30% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, then neat EtOAc. The resulting solid was further purified by preparative TLC, eluting with 5% MeOH (containing 7N NH3) in DCM. The product was obtained as a waxy, white solid (179 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.49 (s, 1H), 8.28 (d, J=6 Hz, 1H), 7.75 (m, 1H), 7.46 (m, 2H), 7.32 (d, J=9 Hz, 2H), 7.27 (m, 1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H), 7.06 (t, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 6.17 (d, J=6 Hz, 1H), 5.57 (s, 2H), 4.09 (m, 2H), 3.76 (s, 3H), 3.36 (t, J=6 Hz, 2H), 2.76 (s, 1H), 1.80 (m, 2H), 1.63 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=4)=[S:35])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(Br)cc5)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 128 μl (2 molar equivalents) of 4-bromophenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 147 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=90%) which was characterized as follows:
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9](O)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.CN.[CH3:22][N:23](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([C@@H]1C[C@@H](O)C[C@H]1C(=O)N[C@]1(C(OCC)=O)C[C@H]1C=C)=O)(C)(C)C>>[C:15]([O:14][C:12](=[O:13])[NH:1][C@@H:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[C:9](=[O:10])[NH:23][CH3:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CN
Agent: Cl
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Yield: 76 %

Procedure:
Boc-Chg-OH (387 mg, 1.50 mmol) was coupled to methylamine hydrochloride (111 mg, 1.65 mmol) using the same HATU coupling conditions as in the synthesis of compound 34. The crude product was extracted with EtOAc, washed with brine and concentrated. Purification by flash column chromatography (EtOAc) provided compound 37 (307 mg, 76%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])(=O)=O.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([O:16][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[CH:14][CH:15]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxy-[1,1′-biphenyl]-2,4-diol (14.6 g) and 2,6-dimethylpyridine (10.2 mL) in toluene (100 mL) was added triisopropylsilyl trifluoromethanesulfonate (21.1 mL) at −15° C., and the mixture was stirred at −15° C. for 20 min. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a white amorphous solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl.CCOCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2noc3ccsc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Oc1ccc(-c2noc3ccsc23)cc1
Reaction time: 8 h

Procedure:
A solution of 6.94 g of 3-(4-methoxyphenyl)thieno[2,3-d]isoxazole in 40 ml of dichloromethane was treated dropwise with 1M solution of boron tribromide in dichloromethane. A precipitate appeared after a few minutes. The suspension was stirred overnight and thereafter quenched with 10% hydrochloric acid. Extraction with ether followed by washing and drying gave a solid which was found to be contaminated with 5% of the starting material. The crude product was fed to an alumina column packed in ether.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([C:10]2([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-]>>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([C:10]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)C2(C#N)CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(S(=O)(=O)C2(CN)CCCC2)cc1
Yield: 35.9 %

Procedure:
Similarly to Example 1(b), by reaction of 1.1 g (4.4 mmol) of 1-(toluene-4-sulfonyl)-cyclopentanecarbonitrile with 200 mg of aluminum lithium hydride. 400 mg of C-[1-(toluene-4-sulfonyl)-cyclopentyl]-methylamine is obtained in the form of an orange solid. (Yield=36%).
Reaction SMILES: [N:1]([CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[NH2:15][N:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]>O1CCOCC1>[O:22]=[C:17]1[NH:18][C:19](=[O:21])[CH2:20][N:16]1[NH:15][C:2]([NH:1][CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3]
Reactant: NN1CC(=O)NC1=O
Reactant: CCOC(=O)C(N=C=O)c1cccs1
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)NN1CC(=O)NC1=O)c1cccs1

Procedure:
By reacting 10.60 g. of DL-α-isocyanato-2-thiopheneacetic acid, ethyl ester with 5.75 g. of 1-amino-2,4-dioxoimidazolidine in 250 ml. of dioxane according to the procedure of Example 5, 15.6 g. of DL-α-[[[(2,4-dioxo-1-imidazolidinyl)-amino]carbonyl]amino]-2-thiopheneacetic acid, ethyl ester is obtained, m.p. 151°-155°.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][C:13]([CH3:17])([C:15]#[CH:16])C.[F-].[Cs+].Cl.[CH2:22](N(CC)C1C=CC=CC=1)C>>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]2[C:5]=1[O:12][C:13]([CH:15]([CH3:16])[CH3:22])=[CH:17]2
Reactant: CCN(CC)c1ccccc1
Reactant: C#CC(C)(C)Oc1cc(C=O)ccc1OC(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: CC(C)c1cc2c(C=O)ccc(OC(F)F)c2o1

Procedure:
5.5 g of 4-difluoromethoxy-3-(2-methyl-3-butyn-2-yloxy) benzaldehyde are heated to reflux with 7.2 g of cesium fluoride with nitrogen aeration for 12 h in 30 ml of N,N-diethylaniline. The mixture is stirred into 300 ml of 4 N hydrochloric acid after cooling, the resulting emulsion is extracted three times with 50 ml of ethyl acetate, and the organic extracts are combined, dried over ignited potassium carbonate and evaporated in vacuo. The residue is chromatographed on silica gel using toluene. After the evaporation of the appropriate fractions, the title compound is obtained as an oil.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[CH2:28]([N:26]([CH3:27])[C:24]1[C:23]([CH3:32])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CN3CCCC3)c1)CC(=O)N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (200 mg, 0.46 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (50 mg, 22%).