Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([OH:27])[CH:26]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]O)=[CH:33][CH:32]=1)#[N:30].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][O:20][C:21]2[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([CH3:28])[CH:22]=2)=[CH:33][CH:32]=1)#[N:30]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: Cc1cc(O)cc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(O)cc(OCCc2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Triphenylphoshine (7.86 g; 30 mmol), 3,5-dihydroxytoluene (2.5 g; 20 mmol) and 2-(4-cyanophenyl)ethanol (4.41 g; 30 mmol) were dissolved in THF (50 mL). Diethylazodicarboxylate (5.22 g; 30 mmol; dissolved in THF (10 mL)), was added and the solution was stirred at room temperature overnight. The solvent was removed in vacuo and the white solid residue extracted with Et2O. Purification by flash chromatography (SiO2; toluene:EtOAc (10:1)) afforded 1.85 g (37%) of the sub-title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)=[N:24][C:25]=4[O:26][CH3:27])[CH:18]=3)[N:13]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:12]=2)[CH:8]=[N:7]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:25]([O:26][CH3:27])=[N:24][C:23]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1nc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Yield: 90.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (67 mg, 0.090 mmol) was deprotected in methanol/HCl in dioxane (2/5 ml) to afford 52 mg (89% yield) of the titled compound. MS: m/z=638.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].O.C(=O)(O)[O-].[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>CC(C)=O>[O:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH2:18]1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-amino-4-hydroxybenzonitrile (g, 10 mmol was dissolved in acetone (20 mL) and water (20 mL) containing sodium bicarbonate (4 g). 2-chloroacetyl chloride was added slowly and the mixture heated to reflux for 4 h and then allowed to stir overnight at 25 ° C. The layers were separated, and the water layer was extracted with ethyl acetate. The organic layers were combined and evaporated to give 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carbonitrile as an oil (1.3 g): 1H NMR (400 M ; DMSO-D6): 7.4 (d, 1H); 7.2 (s, 1H); 7.1 (d, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18])[CH3:5].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH:4]([N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH3:5])[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: CC(CCBr)N1c2cccc3cccc(c23)S1(=O)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCN1CCN(c2ccc(F)cc2)CC1)N1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Yield: 17.9 %

Procedure:
The experiment is carried out as in Example 56, starting with 2-(4-bromo-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.2 g), triethylamine (2.1 cc) and 4-(4-fluorophenyl)piperazine (2.8 g) in toluene (200 cc). The mixture is heated at boiling point for 8 hours and then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (90-10 vol) as eluant, crystallization from isopropyl oxide (30 cc) and recrystallization from boiling acetonitrile (10 cc), 2-{4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g) is obtained, m.p. 116° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[CH:4][C:3]=1[CH3:15].[C-:16]#[N:17].[K+].CC(C)=O>O>[NH2:1][C:2]1[C:7]([C:16]#[N:17])=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[CH:4][C:3]=1[CH3:15]
Reactant: [C-]#N
Reactant: Cc1cn(-c2cc(C)c(N)c(I)c2)cn1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cn(-c2cc(C)c(N)c(C#N)c2)cn1
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of 2-amino-3-iodo-5-(4-methylimidazol-1-yl)toluene (391 mg), potassium cyanide (130 mg), PD(OCA) (catalytic amount) and dimethylformaldehyde (4.01 ml) was heated under stirring under nitrogen atmosphere for 3 days. Solvent was removed to give a residue. To the residue was added water and the solution was extracted with chloroform. The extract was dried with MgSO and solvent was removed to give 175 mg (66%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11]([O:13]CC)=[O:12])=[N:2]1.CO.O.[OH-].[Li+]>O>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11]([OH:13])=[O:12])=[N:2]1
Reactant: CCOC(=O)C1=NOC2(CCCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NOC2(CCCCC2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
Ethyl 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylate (8.12 g, 38.5 mmol, as prepared in the previous step) was placed in a 200 mL round-bottom flask equipped with a magnetic stir bar, and MeOH (75 mL) and water (25 mL) were added. Lithium hydroxide monohydrate (1.77 g, 42.3 mmol) was added as a solid. The reaction was stirred at RT for 20 h, and the solvents were removed under reduced pressure. The resulting solid was triturated with ether and collected by filtration. The solid was then dissolved in water (200 mL) and acidified to pH 2 with 3 M aq HCl. The precipitate was isolated by filtration, washed well with water, air dried, and dried under vacuum. The filtrate was extracted three times with DCM (50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The initial precipitate and the material from the extraction were combined, giving 5.81 g (83%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 2.93 (s, 2H), 1.72-1.89 (m, 4H), 1.60-1.72 (m, 2H), 1.37-1.54 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:20][CH2:19][OH:18])[C:6]=2[CH:16]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Reactant: CCOC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cnccc2c2ccc(Cl)cc2n1CCO
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a stirred solution of 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (80 mg, 0.347 mmol) in anhydrous DMF (5 mL) under a nitrogen atmosphere was added ethyl carbonate (122 mg, 1.387 mmol), K2CO3 (96 mg, 0.694 mmol), and 18-crown-6 (18.31 mg, 0.069 mmol). The reaction mixture was heated to 80° C. for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate layers were dried over sodium sulphate and concentrated under reduced pressure to afford 8-chloro-6-(2-hydroxyethyl)benzo[c][2,7]naphthyridin-5(6H)-one (80 mg, 0.291 mmol, 84% crude yield) The material was carried on without further purification. LC/MS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12ClN2O2, 275.1]; 1H NMR (400 MHz, MeOD) δ 9.55 (s, 1H), 8.87 (d, J=5.6 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.34 (d, J=5.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.44 (dd, J=8.4, 2.0 Hz, 1H), 4.57 (t, J=6.0 Hz, 2H), 3.96 (t, J=6.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH3:22])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1oc(-n2ccnc2C)nc1-c1ccc(F)cc1

Procedure:
Ethyl 2-chloro-4-(4-fluorophenyl)-5-oxazolebutanoate (3.11 g), 2-methylimidazole (2.46 g), potassium carbonate (4.15 g) and N,N-dimethylformamide (25 ml) was stirred at 120-130° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoate was obtained as an oil (3.47 g, 57%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Conversion to the hydrochloride and the subsequent recrystallization from hexane-ethylacetate gave pale yellow prisms. Melting point 140-145° C.
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[NH2:11][N:12]1[C:16]([NH2:17])=[N:15][N:14]=[C:13]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[C:5]1([C:2]2[CH:3]=[N:11][N:12]3[C:13]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)=[N:14][N:15]=[C:16]3[N:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: O=CC(=O)c1ccccc1
Product: Oc1ccc(Cc2nnc3nc(-c4ccccc4)cnn23)cc1

Procedure:
General procedure A was followed with the reaction of oxo-phenyl-acetaldehyde and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol to provide 4-(7-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol and the desired product 4-(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (example 3).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4(3,4-methylenedioxybenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:12](=[O:15])[NH:13]Cl)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43](N)[CH3:44])=[CH:39][CH:38]=1>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:12]([NH:13][C@H:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH3:44])=[O:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CN(C(=O)NCl)c2ccc(C3CCCCC3)cc2)cc1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 2 h

Procedure:
A 2 L reaction flask equipped with mechanical stirring was charged with N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mol), N-methyl-2-pyrrolidinone (1.0 L) and triethylamine (68 mL, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL), before drying with anhydrous sodium sulphate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])[CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCCC(Cn2ccccc2=O)C1
Agent: [Pd]
Solvent: CCO
Product: O=c1ccccn1CC1CCCNC1
Yield: 84.9 %

Procedure:
A mixture of 3-(2-oxo-2H-pyridin-1-ylmethyl)piperidine-1-carboxylic acid benzyl ester (100 mg) and 5% Pd—C (20 mg) in EtOH (15 mL) was stirred under H2 (1 atm). The reaction was traced by TLC. The catalyst was filtered and the filtration was concentrated and purified by chromatography with CH2Cl2-MeOH—NH3.H2O (10:1:0.1) to give a syrup (50 mg, 85%). 1H NMR (CDCl3) δ 7.31 (m, 1H), 7.21 (dd, 1H, J=6.9, 2.1 Hz), 6.56 (d, 1H, J=9.0 Hz), 6.14 (td, 1H, J=6.6, 1.5 Hz), 3.90 (dd, 1H, J=13.0, 8.1 Hz) 3.76 (dd, 1H, J=13.0, 6.7 Hz), 2.98 (m, 2H), 2.62 (t, 1H, J=9.8 Hz), 2.44 (t, 1H, J=11.2 Hz), 2.10-1.10 (m, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(NC(C)C)(C)C.[Li].[CH3:21][CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1>O1CCCC1>[CH3:21][C:22]1([F:43])[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32]
Reactant: CC1CCc2ccccc2C1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(F)CCc2ccccc2C1=O
Reaction time: 1.67 h
Yield: 50 %

Procedure:
0.16 milliliter diisopropylamine in 10 milliliters tetrahydrofuran were allowed to stand with 1.15 equivalents butyllithium at -25° C. The resulting solution of lithium diisopropylamine was cooled to -78° C. and 1 equivalent 2-methyl-1-tetralone in 5 milliliters tetrahydrofuran solution was dropped in. The mixture was allowed to stand at -70° C. for 100 minutes. 1.5 equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 11 milliliters tetrahydrofuran were mixed rapidly with the mixture at -95° C. The mixture was quenched with 30 milliliters ammonium chloride solution and extracted with dichloromethane. The organic phase was dried with magnesium sulfate, filtered, and evaporated. 2-methyl-2-fluoro-tetralone was obtained in 50% yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=C(C(C3N=CC4CCCCC=4C=3)=O)[NH:21]2)=[CH:17][CH:16]=1>>[O:9]1[C:8]2[CH:12]=[CH:13][C:5]([C:3]([C:2]3[NH:21][C:22]4[C:18]([C:19]=3[CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:17][CH:16]=[C:15]([Cl:14])[CH:23]=4)=[O:4])=[CH:6][C:7]=2[O:11][CH2:10]1
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Product: COC(=O)Cc1c(C(=O)c2ccc3c(c2)OCO3)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-bromoacetyl-1,3-benzodioxole (J.Med. Chem., 1977, 20, 394) and methyl trans-4-chloro-2-[(phenylsulfonyl)amino]cinnamate (Example 1, step 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1Br.[Mg].[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:23]1([OH:26])[CH2:22][CH2:21][CH:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]2)[CH2:25][CH2:24]1
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Reactant: Fc1ccc(F)c(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CCC(O)(c3cc(F)ccc3F)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 2,5-difluorobromobenzene (1.33 mmol) in THF (10 ml) is added dropwise to magnesium (1.44 mmol). After the addition is completed, the reaction mixture is stirred at 50° C. for 2 hrs. To the reaction mixture, a solution of 4-(trans-4-propylcyclohexyl)cyclohexanone (1.03 mmol) in THF (10 ml) is added dropwise. After the addition is completed, the reaction mixture is stirred for 2 hrs at 50° C. A saturated aqueous solution of ammonium chloride (10 ml) is added in small portions and the aqueous layer is extracted with ethyl acetate (100 ml) twice. The extract is washed with water, and then dried over anhydrous magnesium sulfate. The titled compound is obtained by evaporation of the solvent under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[O-:15][C:16]#N.[K+]>O>[Cl:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:16](=[O:15])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)c1NCCCO
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cccc(Cl)c2n1CCCO
Reaction time: 8 h
Yield: 41 %

Procedure:
To a stirred and cooled (10° C.) mixture of 20 parts of 3-[(2-amino-6-chlorophenyl)amino]-1-propanol, 12 parts of a hydrochloric acid solution and 100 parts of water is added dropwise a solution of 9 parts of potassium cyanate in 30 parts of water. Upon completion, stirring is continued first for 2 hours at room temperature and further overnight at reflux temperature. After cooling, the product is extracted with trichloromethane. The extract is washed with a diluted hydrochloric acid solution, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 9 parts (41%) of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18]I)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[C:23]([CH2:30][OH:31])[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:21]1[CH:22]=[C:23]([CH2:30][OH:31])[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1Br
Reactant: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OC(C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: CC(C)(C)OC(=O)C[C@@H](Cc1cc(CO)ccc1[N+](=O)[O-])NC(=O)OC(C)(C)C

Procedure:
Following the General Procedure of Description 15 (Part A), the zinc insertion product of (6c) is used in situ to cross couple with commercial (3-bromo-4-nitro-phenyl)methanol (232 mg, 1.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (23 mg, 0.025 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (30 mg, 0.10 mmol, 10 mol-%) in anhydrous degassed DMF (3 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography furnish the title compound (20a).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:6]=1[C:12](=[O:14])[CH3:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>C(Cl)Cl.CO>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(I)ccc1OCCO
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
The product was prepared analogously to Example 7.1e starting from 1-[2-(2-hydroxyethoxy)-5-iodophenyl]ethanone and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.90 g (70% of theoretical); C23H18ClNO3 (M=391.847); calc.: molpeak (M+H)+: 392/394 (Cl); found: molpeak (M+H)+: 392/394 (Cl); Rf value: 0.55 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[ClH:17].[Cl:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cl)c(N2CCNCC2)c1
Reaction time: 5 h

Procedure:
To a solution of 5.3 g (20 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride in 120 mL of acetic acid and 30 mL of water at 0° C. was added 3.3 g (20 mmol) of N-chlorosuccinimide. After 5 hours, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.28 (d, 1H), 6.66 (m, 3H), 3.70 (s, 3H), 3.32 (m, 4H), 3.20 (m, 4H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:30])[C:17]([CH3:29])([CH3:28])[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:30])[C:17]([CH3:28])([CH3:29])[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)C(=O)C(C)(C)O2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
5% Palladium on carbon (7.0 g) was added to a solution 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (19 g, 42.1 mmol) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was changed to an atmosphere of hydrogen. The reaction mixture was stirred under an atmosphere of hydrogen at RT for 4 h (the reaction was monitored by TLC). The reaction mixtures was filtered over through a pad of Celite®, washed with methanol, concentrated in vacuo and the resultant residue was slurried with heptane. The solid was filtered & dried under vacuum to afford 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (14.0 g, 95%,) as light yellow solid. 1H NMR, 500 MHz, DMSO-d6: δ 9.5 (bs, 1H), 7.55 (d, 2H), 7.05 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]: m/z=311.2. HPLC: (98.8%, Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).