Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCN1CCOCC1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCN3CCOCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(morpholin-4-yl)-ethyl-amine to afford the title compound. MS: m/e=371 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>C(#N)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:14][CH2:13]3)[CH2:11]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCNCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
A mixture of 1-[1-(diphenylmethyl)azetidin-3-yl]piperazine (250 mg, 0.81 mmol), K2CO3 (146 mg, 1.1 mmol), propionyl chloride (98 mg, 1.1 mmol) and acetonitrile (6 mL) was stirred at RT for 16 h. The mixture was filtered through a phase separator column and the solvent was removed by evaporation. The residue was dissolved in methylene chloride and the solution washed with aqueous NaHCO3. The organic phase was separated by using a phase separator column and then the solvent was removed by evaporation. There was obtained 216 mg (73%) of 1-[1-(diphenylmethyl)azetidin-3-yl]-4-propionylpiperazine as an oil. 1H NMR (500 MHz, CDCl3): 1.1-1.2 (t, 3H), 2.2-2.4 (m, 6H), 2.9 (t, 2H), 3.0 (m, 1H), 3.4-3.5 (m, 4H), 3.6 (b, 2H), 4.4 (s, 1H), 7.2 (m, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 364 (M+1)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].Cl>O.CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
To a mixture of 5-fluoro-2-nitrotoluene (7.0 grams, 45 mmol), 4-methoxyphenol (6.2 grams, 50 mmol) and dimethylformamide (45 mL) was added potassium tert-butoxide (5.1 grams, 45 mmol). After stirring at room temperature for 24 hours, the mixture was diluted with water, acidified with 1 M aqueous hydrochloric acid, and the aqueous phase was extracted 3 times with ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-20% ethyl acetate-hexane afforded 3.5 grams of 4-(4-methoxy-phenoxy)-2-methylnitrobenzene as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)=[C:31]([CH:34]=1)[C:32]#[N:33].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:40][CH2:39][N:38]([C:17](=[O:18])[CH2:16][C@H:14]3[C:13](=[O:20])[N:12]([CH2:21][C:22]([F:23])([F:25])[F:24])[CH2:11][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[C:2]([Cl:1])=[CH:3][C:4]=4[CH2:15]3)[CH2:37][CH:36]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]
Reactant: N#Cc1cc(Cl)ccc1C1=CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1C1=CCN(C(=O)C[C@@H]2Cc3cc(Cl)c4[nH]ncc4c3CN(CC(F)(F)F)C2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
In an oven-dried round bottom flask, (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (44.1 mg, 0.173 mmol) were dissolved in DMF (2 ml). To this solution was added DIEA (0.093 ml, 0.532 mmol) followed by PyBOP (69.3 mg, 0.133 mmol). The reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere for 3 hours during which time it became dark red in color. The DMF was evaporated under high vacuum. The residue was subjected to column chromatography (silica, 20:1 CH2Cl2/2M NH3 in MeOH). The most pure fractions were collected, evaporated and again subjected to column chromatography (silica, 40:1 CH2Cl2/2M NH3 in MeOH). The fractions were collected, evaporated and dried overnight under vacuum to give (S)-5-chloro-2-(1-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (40 mg, 0.069 mmol, 52.1% yield) as a light tan solid. 1H NMR (500 MHz, MeOD) δ ppm 1.24-1.34 (m, 1H) 2.50-2.60 (m, 3H) 2.60-2.76 (m, 2H) 2.95-3.05 (m, 1H) 3.14-3.23 (m, 2H) 3.82-3.91 (m, 1H) 3.90-4.02 (m, 1H) 4.05-4.14 (m, 1H) 4.53-4.62 (m, 2H) 5.54 (d, J=17.4 Hz, 1H) 6.07 (d, J=13.7 Hz, 1H) 7.21 (s, 1H) 7.46 (d, J=8.3 Hz, 1H) 7.64 (d, J =8.5 Hz, 1H) 7.78 (s, 1H) 8.24 (s, 1H); MS (ESI): 575 (M-1H); Rf=1.90 (4 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:12]([C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCCCCc1ccc(N)cc1
Product: CCCCCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-pentylaniline to yield 2-[(4-pentylphenyl)amino]phenylacetic acid.
Reaction SMILES: NC1C=C(C([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)=CC#N)C=CC=1OC.[Mg].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[CH:30]=[O:31]>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:30]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[OH:31])[CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36]
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Agent: [Mg]
Product: COc1ccc(C(O)c2ccc([N+](=O)[O-])c(OC)c2)cc1OC
Yield: 72 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using 3,4-bromoveratrole (2.5 g, 11.5 mmol), magnesium turning (0.3 g, 11.5 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.5 g, 8.2 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford (3-methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (1.9 g, 72%): 1H NMR (CDCl3) δ 7.80 (d, J=8 Hz, 1H), 7.22 (s, 1H), 6.98-6.85 (m, 4H), 5.79 (d, J=2 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O=S(Cl)Cl.C[N:22](C=O)C>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:7]([C:8](=[O:9])[NH2:22])[CH:6]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A mixture of 3-methoxycarbonyl-5-nitrobenzoic acid (44 mmol), SOCl2 (40 mL) and DMF (1 mL) was heated to reflux for 2 hours. Then the excessive SOCl2 was removed under reduced pressure. The residue was dissolved in DCM (80 mL), and added with NH3.H2O (15 mL) dropwise after cooling by ice-water. After addition, it was continued to stir 5 min. The resulting mixture was filtrated to give methyl-3-carbamoyl-5-nitrobenzoate in 85% yield.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=C[C:35]=2[N:34]=N1.CC1CCCN1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:34]3[CH2:35][CH2:36][CH2:37][CH:38]3[CH3:39])=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CC1CCCN1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCN1C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-methyl-pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12](N)=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].C(O)(=[O:25])C>Cl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12]([OH:25])=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: CC(=O)O
Reactant: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Agent: Cl
Product: O=C(O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21

Procedure:
2 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide in 20 ml of acetic acid and 20 ml of concentrated hydrochloric acid are stirred for 4 hours at 95°-100°. The mixture is left to cool, filtered with suction, washed with water and recrystallised from trichloromethane/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 202°-203°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:28]([O:31][CH2:32][C:33]([CH2:35]Cl)=[O:34])(=[O:30])[CH3:29]>CN(C)C=O.O>[C:28]([O:31][CH2:32][C:33](=[O:34])[CH2:35][N:13]([S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:30])[CH3:29]
Reactant: CC(=O)OCC(=O)CCl
Reactant: CCOC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)COC(C)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a suspension of the compound obtained in Step 1 (10.0 g), potassium carbonate (7.20 g) and sodium iodide (5.2 g) in N,N-dimethylformamide (100 ml) was added a solution (20 ml) of 1-acetoxy-3-chloroacetone (7.84 g) in N,N-dimethylformamide under cooling with ice and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture under cooling with ice, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To the resulting residue was added hexane and the mixture was stirred. The supernatant was removed by decantation and crystallized by addition of diethyl ether. The crystals were collected by filtration and air-dried to thereby obtain the title compound (9.36 g). NMR spectrum (*CDCl3) δppm: 8.10–8.02 (1H, m), 7.76–7.62 (3H, m), 4.73 (2H, s), 4.53 (2H, s), 4.24 (2H, s), 4.15 (2H, q, J=7 Hz), 2.16 (3H, s), 1.24 (3H, t, J=7 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:31][Mg]Br>C1COCC1.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:31])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:30])([F:28])[F:29])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Reaction time: 18 h
Yield: 48.3 %

Procedure:
To a solution of 1-(4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-phenyl)-ethanone (50 mg, 0.12 mmol) in dry THF (2 mL) was added methylmagnesium bromide (3 M, 44 μL, 0.13 mmol) under nitrogen at room temperature and the resulting mixture stirred for 18 h, after which time methylmagnesium bromide (3 M, 40 μL, 0.12 mmol) was added and the resulting mixture stirred for 19 h. The mixture was then diluted with HCl (0.1 N) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:3 to 0:100) afforded the title compound (25 mg, 48%) which was obtained as a white solid. MS: m/e=432.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([O:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([N-]C(C)C)(C)C.[Li+].[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][CH:34]=1>O1CCCC1.[Cl-].[Na+].O>[CH3:21][C:13]1[CH:12]=[C:11]([CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH2:1][C:39]([C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)([OH:41])[CH3:40])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Cc1cc(COc2ccc(S(C)(=O)=O)cc2)c2ccccc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(C)(O)CS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)cc1
Reaction time: 0.67 h
Yield: 66 %

Procedure:
Under an atmosphere of argon, a solution of 473 mg (1.44 mmol) of 4-(4-methanesulfonylphenoxymethyl)-2-methylquinoline in tetrahydrofuran was cooled to −78° C. and then, 1.44 mL (1.44 mmol) of 2 M lithium diisopropylamide was added thereto and stirred for 40 minutes. Into this solution was dropped a solution of 194 mg (1.59 mmol) of p-methylacetophenone in tetrahydrofuran, followed by stirring for 2.5 hours. The reaction was stopped by the addition of saturated brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under a reduced pressure. The obtained residue was purified by column chromatography on silica gel (developing solvent; hexane:ethyl acetate=1:1 to 1:2) to obtain 440 mg (0.95 mmol) of 1-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]-2-p-tolylpropan-2-ol (VIII-57). Its physical property is shown below.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[N:5](=[C:7]([C:11](=[O:13])[CH3:12])[C:8](=O)[CH3:9])O>C(#N)C>[C:11]([C:7]1[NH:5][C:1]([CH:2]=[CH2:3])=[N:4][C:8]=1[CH3:9])(=[O:13])[CH3:12]
Reactant: C=CCN
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: C=Cc1nc(C)c(C(C)=O)[nH]1
Yield: 76.8 %

Procedure:
An acetonitrile solution of allylamine (0.4 g, 7.8 mmol) and 3-oximino-2,4-pentanedione (1 g, 7.8 mmol) was refluxed for 6 hours. The acetonitrile was evaporated to give 0.9 g of 5-acetyl-4-methyl-2-vinylimidazole.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:4]=1)[NH2:2].[CH3:22][C:23](=O)[CH2:24][C:25](=O)[CH3:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH3:26])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:4]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(NCCc3ccccc3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(NCCc3ccccc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-phenethyl-amine and 2,4-pentanedione.
Reaction SMILES: [CH3:1][N:2]([CH:15](Cl)[CH:16]([CH3:18])C)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.O>C(#N)C>[CH3:1][N:2]([CH:15]([CH2:16][CH3:18])[C:20]#[N:21])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1ccc(CCN(C)C(Cl)C(C)C)cc1OC
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(C#N)N(C)CCc1ccc(OC)c(OC)c1
Yield: 87 %

Procedure:
4.67 g of 3-((N-methyl-N-(2-(3,4 -dimethoxyphenyl)ethyl)-amino)-2-methylpropyl chloride was dissolved in 40 ml of acetonitrile, followed by the addition of 2.13 g of potassium cyanide and 0.1 g of 18-crown-6. The obtained mixture was heated under reflux for 40 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] to obtain 3.93 g of the title compound as a pale yellow oil (yield: 87%).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[C:22]2[CH:23]=[C:24]([CH3:26])[O:25][C:21]=2[C:20]([F:27])=[C:19]([F:28])[CH:18]=1.B(OC)(OC)[O:30]C.OO.Cl>C1COCC1.O.C(O)(=O)C>[Br:16][C:17]1[C:22]2[CH:23]=[C:24]([CH3:26])[O:25][C:21]=2[C:20]([F:27])=[C:19]([F:28])[C:18]=1[OH:30]
Reactant: COB(OC)OC
Reactant: Cc1cc2c(Br)cc(F)c(F)c2o1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: OO
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(Br)c(O)c(F)c(F)c2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
107.1 ml (0.17 mol) of n-BuLi (15% soln. in hexane) are initially introduced at −70° C. in 150 ml of THF, and 29.0 ml (0.17 mol) of 2,2,6,6-tetramethylpiperidine are added. After 30 min at this temperature, a solution of 38.3 g (0.16 mol) of 4-bromo-6,7-difluoro-2-methylbenzofuran in 100 ml of THF is metered in. After 3 h at this temperature, 19.1 ml (0.17 mol) of trimethyl borate are added dropwise, and the batch is warmed to room temperature. 40 ml of dilute acetic acid (about 30%) are added, and 40 ml of aqueous hydrogen peroxide soln. (35%) are carefully added to the batch. When the addition is complete, the mixture is stirred at 20° C. for 18 h. Water is added, and the batch is acidified using HCl. The solution is extracted a number of times with MTBE, and the combined organic phases are washed successively with water, sat. sodium chloride soln. and ammonium iron(II) sulfate soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=2:1), giving 4-bromo-6,7-difluoro-2-methylbenzofuran-5-ol as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:23]#[C:24][CH2:25]CC)=[CH:4][CH2:3]1.CC1(C)C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(C#CC)=CC1>>[CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=3)=[CH:7][C:6]=2[C:5]([C:23]#[C:24][CH3:25])=[CH:4][CH2:3]1
Reactant: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Product: CC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoic acid (Compound 84), 75.0 mg (0.204 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-3-yl)ethynyl]benzoate (Compound 77) was converted into the title compound (colorless solid) using 21.4 mg (0.51 mmol) of LiOH in H2O.
Reaction SMILES: N([O-])=O.[Na+].Cl.[C-]#N.[Na+].C([Cu])#N.[OH-].[Na+].N(OS(=O)(=O)O)=O.CI.[C:23]([O-:26])([O-])=[O:24].[K+].[K+].C1C(=O)N(Br)C(=O)C1.Br[C:38]1[CH:44]=[CH:43][C:41](N)=[CH:40][CH:39]=1.[Cu](C#N)C#N>>[C:23]([OH:26])(=[O:24])[C:38]1[CH:44]=[CH:43][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: N#C[Cu]
Agent: N#C[Cu]C#N
Agent: Cl
Solvent: CI
Product: O=C(O)c1ccccc1

Procedure:
Scheme 1 illustrates a representative synthesis of a 6-substituted 4-bromo-2-bromomethyl-benzoic acid methyl ester from commercially available precursors wherein the respective reaction steps comprise as follows: (a) NaNO2, aq. HCl; (b) NaCN, CuCN and HCl; (c) NaOH; (d) nitrososulphuric acid; (e) MeI and K2CO3, and (f) NBS and (PhCO2)2. Briefly, a 4-bromo-aniline may be diazotized under Sandmeyer reaction conditions, followed by conversion to the nitrile using sodium cyanide and copper cyanide. The nitrile may then be hydrolyzed to an amide by basic hydrolysis. The amide can then be hydrolyzed with nitrososulphuric acid to provide a benzoic acid, which may be converted to a methyl ester under standard conditions. The benzylic methyl group may be monobrominated with N-bromosuccinimide using benzoyl peroxide as a radical initiator to yield a desired 6-substituted 4-bromo-2-bromomethyl-benzoic acid methyl ester.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>CO>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:3]2[C:4](=[O:10])[C:5](=[O:9])[C:6]=2[O:7][CH3:8])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1c(Nc2ccc(Cl)cc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.5 %

Procedure:
To a stirred mixture of 3,4-dimethoxycyclobut-3-ene-1,2-dione (O1, 1.00 g, 7.04 mmol) in methanol (7 mL) at 0° C. under nitrogen was added a solution of 4-chloroaniline (0.898 g, 7.04 mmol) in methanol (8 mL) dropwise over 0.5 h. After addition, the reaction mixture was slowly warmed to room temperature and stirred at room temperature for another 2 days. The reaction mixture was filtered. The filter cake was washed with cold methanol (5 mL) and dried under reduced pressure to afford compound O2 as a yellow solid (1.48 g, 89%): 1H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.44-7.35 (m, 4H), 4.38 (s, 3H). MS (M+H) 238.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCN(CC2CCCCN2)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2CN2CCCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[(1-piperidinyl)methyl]piperidine to give colorless crystals, mp. 220°-221° C. (acetonitrile).