Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[N:10][OH:11].C(OC(=O)C)(=O)C.CCN(CC)CC.O.[Cl-].[Na+].O>>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:11][N:10]=2)=[CH:2][CH:7]=1
Reactant: ON=C(c1ccc(O)cc1)c1ccc(O)cc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1ccc(-c2noc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
A mixture of (2,4-dihydroxyphenyl)(4-hydroxyphenyl)methanone oxime (0.46 g, 1.87 mmol), acetic anhydride (0.19 g, 1.87 mmol) and Et3N (0.25 g, 2.44 mmol) was stirred at room temperature for 24 h. The mixture was pored into water/brine and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/EtOAc/MeOH 5/3.5/1/0.05) gave an off-white solid (0.19 g, 42% yield, m.p. 192-194° C.); MS m/e 226 (M−H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.Cl[Si](CC)(CC)CC.C([Li])(CC)C.[F:25][C:26]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>C1COCC1>[F:25][C:26]1[CH:33]=[C:32]([CH:34]([OH:35])[C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: Cn1ccnc1
Reactant: N#Cc1ccc(C=O)cc1F
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1-Methylimidazole (15.88 mL, 0.199 mol), dissolved in anhydrous THF (500 mL) in flame-dried glassware under Ar, was cooled to −78° C. and treated with n-butyl lithium (1.6M in hexane)(124 mL, 0.199 mol) via syringe. After stirring for 1 hr chlorotriethylsilane (33.4 mL, 0.199 mol) was added and the reaction mixture was left to warm to ambient temperature overnight. The THF was removed in vacuo with gentle warming, and the residue was redissolved in dry THF (500 mL), cooled to −78° C., and treated with sec-butyl lithium (1.3M in cyclohexane) (153 mL, 0.199 mol) dropwise. After 1 hr this solution was cannulated into a solution of 2-fluoro-4-formylbenzonitrile (27 g, 0.181 mol) in THF (200 mL). After 15 min the cooling bath was removed, the mixture was stirred for 2 hr at ambient temperature, then was quenched with saturated NH4Cl solution. After 15 min 10% HCl was added to pH=3. After 0.5 hr the THF was removed in vacuo, the mixture was made basic with solid Na2CO3 and extracted with EtOAc (3×200 mL). The organics were combined, washed with 10% HCl (3×), the aqueous acidic layers combined, made basic with solid Na2CO3, extracted with EtOAc (3×), the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([Br:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:18]([NH:17][C:10]1[C:11]([Br:16])=[CH:12][C:13]([Br:15])=[CH:14][C:9]=1[Br:8])=[O:19]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1c(Br)cc(Br)cc1Br
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1c(Br)cc(Br)cc1Br
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) is converted to free base (4.0 g.; 0.05 mole - assuming 100% conversion) by adding 5 ml. of 50% NaOH to an aqueous slurry (minimal amount of water) of the salt and benzene extraction. After drying over K2CO3, the benzene solution is stirred at room temperature and 16.79 g. (0.0472 mole) of 2,4,6-tribromophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene, is added with stirring. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo to give a solid residue of 1-(1-methyl-2-pyrrolidylidene)-3-(2,4,6-tribromophenyl)urea. Recrystallizations from acetone yields the pure product, m.p. = 165°-167.5° C. EXAMPLE XXXVII
Reaction SMILES: C([Mg]Br)(C)C.[CH3:6][N:7]1[C:12]2=[CH:13][N:14]([CH2:22][CH2:23][C:24](OC)=[O:25])[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]2[C:10](=[O:28])[N:9]([CH3:29])[C:8]1=[O:30].Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1>[CH3:6][N:7]1[C:12]2=[CH:13][N:14]([CH2:22][CH2:23][C:24]([N:33]([O:34][CH3:35])[CH3:32])=[O:25])[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]2[C:10](=[O:28])[N:9]([CH3:29])[C:8]1=[O:30]
Reactant: CNOC
Reactant: COC(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropylmagnesium bromide solution (2.9M, 3.03 mL, 8.79 mmol) was added slowly to a suspension of methyl 3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propanoate (Example 11.0 step 1) (1.5 g, 4.39 mmol) and commercially available N,O-dimethylhydroxylamine hydrochloride (0.514 g, 5.27 mmol) in THF (50 mL) at 0° C. The mixture was warmed to room temperature and stirred for 30 mins. A further portion of isopropylmagnesium bromide solution (2.9M, 3.03 mL, 8.79 mmol) was added slowly and the mixture stirred for a further 60 mins. The reaction was quenched with saturated NH4Cl(aq) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 50-100% EtOAc/hexane, then 1-8% MeOH/EtOAc afforded the title compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)[O:9][C:8]=1[C:28]1[CH:33]=[C:32]([O:34]C)[C:31]([O:36]C)=[CH:30][C:29]=1[O:38]C.CO>C(Cl)Cl>[OH:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)[O:9][C:8]=1[C:28]1[CH:33]=[C:32]([OH:34])[C:31]([OH:36])=[CH:30][C:29]=1[OH:38]
Reactant: CCCCCCCCCCc1ccc2c(=O)c(OC)c(-c3cc(OC)c(OC)cc3OC)oc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)cc3O)oc2c1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Boron tribromide (1.0 M solution in DCM) (4.0 ml, 4.06 mmol, 5.0 eq) was added slowly to a solution of 69 (392 mg, 0.81 mmol) in dry DCM (3 ml) at 0° C. under argon. The solution was then stirred overnight and then methanol (5 ml) added slowly. The solution was heated under reflux for 30 min. then concentrated under vacuum. Water (20 ml) was added to the residue and the flask placed in a sonic bath for 5 min. The resulting fine precipitate was filtered off and washed with water (10 ml) then freeze dried to give the flavonol as a red/brown amorphous solid (338 mg, 98%). m.p. decomp >90° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.B1C2CCCC1CCC2.[O:22]1CCCC1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:22])=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(C(=O)OC)cc1
Agent: B1C2CCCC1CCC2
Product: COC(=O)c1ccc(CCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Methyl-4-vinylbenzoate 70 (2.270 g, 14.00 mmol) was dissolved in 50 ml of tetrahydrofuran and cooled to 0° C. 9-BBN (0.5M in THF)(28.00 ml, 14.00 mmol) was added and the mixture was stirred for 2 hours. The solution was allowed to warm to room temperature and stirred for an additional 2 hours. The reaction was cooled to 0° C. and quenched with alkaline hydrogen peroxide. The mixture was then extracted with diethyl ether. The extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by flash chromatography on silica eluted with 4:1 hexane/acetone to give 1.632g (64.7%) of 4-(2-hydroxyethyl)benzoic acid methyl ester 71 as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.[OH-].[K+].Cl>CS(C)=O.O>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of the product from Example 10A (3.55g, 10 mmol), 4-aminophenol (1.09 g, 10 mmol), and potassium hydroxide (1.12 g, 20 mmol) were dissolved in dimethyl sulfoxide (15 mL) and heated at 100° C. in a CEM Discover microwave for 25 minutes. The mixture was then cooled to room temperature, poured into water (300 mL), the pH of the solution adjusted to 6 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried to provide the title compound as a yellow solid (4.2 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[C:16](S(C)(=O)=O)[N:15]=[C:14]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:13]=2[O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])=[N:6][CH:7]=1.[CH2:45]([CH2:47][NH2:48])[OH:46].[Cl-].[NH4+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[C:16]([NH:48][CH2:47][CH2:45][OH:46])[N:15]=[C:14]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][CH:31]=3)(=[O:24])=[O:25])[C:13]=2[O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCOc1ncc(Br)cn1
Reactant: NCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NCCO)nc1OCCOc1ncc(Br)cn1
Reaction time: 20 h
Yield: 11.7 %

Procedure:
A mixture of N-{6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(2-methoxy-phenoxy)-2-methylsulfonylpyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (500 mg), ethanolamine (172 mg) and dimethylacetamide (4 ml) is heated with stirring at 110°-120° C. for 20 hours. After cooling, to the mixture is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=3:1) to give the title compound (57 mg) as a powder.
Reaction SMILES: NC1C=CC=CC=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:23][S:24][CH2:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1)=[O:27].C([N:44](CC)CC)C>C(Cl)Cl>[NH2:44][CH:25]([S:24][CH3:23])[C:26]([NH:28][CH2:29][CH2:30][CH:31]([C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1)=[O:27]
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: COc1ccc(CCCNC(=O)CSC)cc1OC
Reactant: CCN(CC)CC
Agent: CC(C)(C)OCl
Solvent: ClCCl
Product: COc1ccc(C(CCNC(=O)C(N)SC)C(=O)c2ccc(F)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 21.5 g (0.1 mole) of 2-amino- 4'-fluoro-benzophenone in 400 mL of methylene chloride, cooled to -70° C. is added 11.5 g (0.1 mole) of 95% t-butylhypochlorite over 15 min, keeping the temperature below -66° C. To this solution is added a solution of α-(methylthio)-N-3-(3,4-dimethoxyphenyl)propylacetamide (0.1 mole) in 50 mL of methylene chloride over a ten minute period. The solution is stirred for 1 h at -65° to -70° C. and then is allowed to warm to 0° C. Triethylamine (0.1 mole) is added and the resulting solution is washed with water. The organic solution is dried with magnesium sulfate, and concentrated in vacuo. The product is isolated using standard conditions.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH:8]1([C:14](Cl)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(OC)(OC)(=O)=O.C(N(CC)CC)C.[CH3:31][NH:32][NH2:33]>O1CCCC1>[NH2:4][C:3]1[N:32]([CH3:31])[N:33]=[C:14]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:2]=1[C:1]#[N:5]
Reactant: O=C(Cl)C1CCCCC1
Reactant: N#CCC#N
Reactant: CNN
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc(C2CCCCC2)c(C#N)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39 %

Procedure:
To a solution of 17.2 g (260 mmol) of malononitrile in 260 mL of tetrahydrofuran was added slowly to 20.8 g (60% dispersion in mineral oil; 520 mmol) of sodium hydride at 0° C., then, to this mixture was added by dripping 35 mL (260 mmol) of cyclohexanecarbonyl chloride at the same temperature and the mixture was stirred for 1.5 hours at room temperature. Then, 30 mL (312 mmol) of dimethyl sulfate was added to the reaction mixture and the mixture was refluxed for 3 hours. Then, 17.4 mL (125 mmol) of triethylamine and 13.8 mL (260 mmol) of methylhydrazine were added to the reaction mixture under ice cooling and the mixture was refluxed for 1 hour. After the mixture was cooled to the room temperature, the solvent was removed under reduce pressure. Water was added to the residue and the mixture was extracted with ethyl acetate and the organic layer was washed with water, and saturated saline solution, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1 to 20/1). The obtained crude crystalline was further purified by recrystallization (hexane-ethyl acetate) to give 20.7 g (39%) of the title compound. The filtrate was further purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2: 1) to give 11.3 g (21%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1)=[O:5].[BH4-].[Na+].C(OC(=O)C)C>CO>[NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 2-amino-3′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (7 g) in methanol (70 ml) was added sodium borohydride (1.1 g), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added acetic acid ethyl ester (100 ml). The mixture was washed with water and dried over anhydrous MgSO4, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography to give the object 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (6.9 g) as a colorless oily compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[NH:12][CH2:11]3)[C:9](=[O:16])[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]2=[CH:6][CH:7]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:12]1[C:13](=[O:15])[CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:16])[CH2:11]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CNC(=O)C2)c2cc(Cl)ccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2)c2cc(Cl)ccc21
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (5-chloro-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate, intermediate 32 (175.00 mg; 0.50 mmol) in dry THF (5 mL), sodium hydride (24 mg; 0.60 mmol) was added. The reaction mixture was stirred 15 minutes then benzyl bromide (71.10 μl; 0.60 mmol) was added. After stirring for 10 min, the solvent was evaporated and the residue redissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and removed in vacuo to give a residue which was purified by chromatography (silica) eluting with cyclohexane containing increasing amounts of ethyl acetate (20 to 50%) to give the title compound was obtained (220 g, 52.1%, HPLC purity 96.7%). MS (ESI+): 441.4; MS (ESI−): 439.2
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:13])[CH3:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccs1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)=O)s1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 40 g of 2-acetylaminomethylthiophene and 30.3 g of acetylchloride in 600 ml of dichloroethane is added a small portion of 76.3 g of anhydrous aluminum chloride under cooling at 5°-10° C. After the mixture is stirred at 10° C. for 30 minutes and poured into ice-cold water, the precipitated crystals are collected by filtration to give 2-acetylaminomethyl-5-acetylthiophene, melting F- at 129°-130° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.[CH2:16]([O:23][C:24]1[CH:29]=[C:28](Br)[CH:27]=[CH:26][C:25]=1[F:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:27]=[CH:26][C:25]=1[F:31])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Br)cc1OCc1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cn1nccc1-c1ccc(F)c(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1058.42 mg, 5.09 mmol) in MeCN (40 mL) and water (10 mL) was added 2-benzyloxy-4-bromo-1-fluoro-benzene [CAS: 1036724-54-5](1300 mg, 4.62 mmol), sodium carbonate (1470.8 mg, 13.88 mmol) and bis(triphenylphosphine)palladium (II) dichloride (164.24 mg, 0.2300 mmol). The reaction was then heated at 100° C. for 4 hours. The cooled reaction mixture was poured into EtOAc (70 mL) and water (100 mL). The organics were separated, and washed with brine (75 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified over silica (25 g, SNAP cartridge), eluting with EtOAc in isohexane from 0% to 40%. Fractions containing desired product were combined and concentrated in vacuo to give 5-(3-benzyloxy-4-fluoro-phenyl)-1-methyl-pyrazole (D82) (1026.5 mg, 3.4543 mmol, 74.7% yield) as a colourless oil;
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:26]=[C:27]3[C:36](=[CH:37][CH:38]=2)[C:35](C(O)=O)=[CH:34][C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]2.N#N.CO.O>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]([C:25]2[CH:26]=[C:27]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[CH:34][C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=2)=[C:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: O=C(O)c1cc2ccccc2c2cc(-c3c4ccccc4c(-c4ccc5ccccc5c4)c4ccccc34)ccc12
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: N#N
Solvent: O
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: c1ccc2cc(-c3c4ccccc4c(-c4ccc5ccc6ccccc6c5c4)c4ccccc34)ccc2c1

Procedure:
49 g (94 mmol) of 6-(10-naphth-2-ylanthracen-9-yl)phenanthrene-9-carboxylic acid are suspended in 250 ml of quinoline, the suspension is saturated with N2, 11.8 g (38 mmol) of copper chromite are added, and the mixture is heated at the boil for 8 h. The mixture is subsequently poured into 1 l of MeOH/water, and the black solid is filtered off with suction, washed with MeOH and subjected to Soxhlet extraction with CHCl3. Removal of the solvent leaves a greyish solid, which is recrystallised four times from chlorobenzene and sublimed twice in vacuo (p=1×10−5 mbar, T=360° C.). The yield is 32 g (71%) with a purity>99.9%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]2)(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
tert-Butyl piperidin-4-ylmethylcarbamate (0.100 g) in dichloromethane (2.3 mL) was treated with 5-(pyridin-2-yl)thiophene-2-sulfonyl chloride (0.133 g), followed by triethylamine (0.325 mL) at room temperature. After stirring the mixture at room temperature overnight, it was washed with 1N hydrochloric acid, the organic layer was separated and filtered. Evaporation of the solvent and purification by column chromatography on silica gel (1-4% methanol in dichloromethane) provide the title compound (0.088 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:20]([C:18]1[S:19][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[CH:16][CH:17]=1)(=[O:21])=[O:22]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)c1Br
Yield: 40 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4- bromo-3-methylisoxazole and 5-(2-pyridyl)thiophene-2-sulphonyl chloride in 40% yield. Purification was achieved by recrystallization from ethyl acetate to give a crystalline solid, m.p. 186°-188° C.