Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][CH:10]([CH3:13])[C:11]#[CH:12]>CCN(CC)CC.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][CH:10]([CH3:13])[C:11]#[C:12][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C#CC(C)C
Reactant: Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodoaniline (Aldrich, 5.0 g, 22.8 mmol) in Et3N (50 ml) in a re-sealable pressure tube was added copper (I) iodide (22 mg, 0.114 mmol), Pd(PPh3)2Cl2 (80 mg, 0.114 mmol), and 3-methylbut-1-yne (Alfa Aesar, 3.1 g, 45.7 mmol). The mixture was stirred at room temperature for 20 h and was diluted with Et2O, filtered through Celite, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 30% Et2O-hexanes to yield 2-(3-methylbut-1-ynyl)aniline (Compound 37) as orange oil.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=O)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH2:6])=[O:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(-c3cccc([N+](=O)[O-])c3)c2)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of trimethylaluminium in toluene (10 mL of 2.0 M) is added over 30 minutes to a stirred suspension of ammonium choride (1.07 g 20 mmol) in toluene (20 mL) at 5° C. under an argon atmosphere. The mixture is stirred at 20° C. for 2 h, treated with a solution of 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (1.65 g, 4.3 mmol) in toluene (40 mL) and stirred at 60° C. for 18 h. The cooled mixture is washed with hydrochloric acid (50 mL of 0.5 M) followed by saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by crystallisation from ethyl acetate-t-butylethyl ether to give 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxamide as a colourless crystalline solid, m.p. 201-205° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH3:20])[O:17][N:16]=3)[N:4]2[N:3]=1.[CH3:21][N:22]1[C:26]([CH2:27][OH:28])=[N:25][CH:24]=[N:23]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CN(C)C=O>[CH3:20][C:18]1[O:17][N:16]=[C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:28][CH2:27][C:26]4[N:22]([CH3:21])[N:23]=[CH:24][N:25]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][N:10]=4)[CH:19]=1
Reactant: Cn1ncnc1CO
Reactant: Cc1cc(-c2nnc3c4cccnc4c(Cl)nn23)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc3c4cccnc4c(OCc4ncnn4C)nn23)no1
Temperature: -78 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A solution of 5-chloro-3-(5-methylisoxazol-3-yl)-1,2,3a,4,6-pentaaza-cyclopenta[a]naphthalene (100 mg, 0.35 mmol) in N,N-dimethyl formamide (7 ml) was added to a solution of 2-methyl-1,2,4-triazole-3-methanol (43 mg, 0.38 mmol) (prepared using the conditions of Itoh and Okongi, EP-A-421210) under nitrogen, and the mixture cooled to −78° C. Lithium bis(trimethylsilyl)amide (0.42 ml, 1.0 M in tetrahydrofuran, 0.42 mmol) was added, and the reaction stirred at −78° C. for 2 h, then allowed to warm to room temperature and stirred for 3 h. The solvents were evaporated by azeotroping with xylene and the residue pre-absorbed onto silica (1 g) from methanol/dichloromethane. Flash chromatography on a silica bond elute cartridge (10 g) eluting with a 0%→5% methanol/dichloromethane gradient, followed by recrystallisation (dichloromethane/ethyl acetate) gave the title-product (52 mg, 41%), mp 255-257° C.; 1H NMR (360 MHz, CDCl3) δ 9.16 (1H, dd, J=4.4 Hz and 1.7 Hz, Ar—H), 9.01 (1H, dd, J=8.2 Hz and 1.7 Hz, Ar—H), 7.92 (1H, m, Ar—H), 7.90 (1H, s, Ar—H), 6.93 (1H, s, Ar—H), 5.88 (2H, s, CH2), 4.12 (3H, s, CH3), 2.60 (3H, s, CH3); MS (ES+) m/e 364 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH2:22][CH3:23].S(=O)(=O)(O)[OH:25].OO>CO.C(O)(C)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH2:22][CH3:23])=[O:25]
Reactant: O=S(=O)(O)O
Reactant: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: OO
Solvent: CO
Solvent: CC(C)O
Product: CCS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 302.9 %

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylthiopyrazole (22.25 g) in methanol was added a solution of sulfuric acid (1.5 g) in isopropanol. Hydrogen peroxide (6.95 g of 30% aqueous solution) was added and the temperature raised to 60° C. After two hours, the reaction was filtered and the solid washed with methanol. The filtrate was washed (water), dried and recrystallized (methanol) to give 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylsulfinylpyrazole (18.4 g), m.p. 173-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CN(C=O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:10](=[O:13])[CH2:11][CH3:12])=[C:2]([O:1][CH2:21][CH2:22][O:23][CH3:24])[CH:7]=1
Reactant: COCCBr
Reactant: CCC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(OC)cc1OCCOC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(2-hydroxy-4-methoxyphenyl)propan-1-one (1 g, 5.55 mmol) in DMF (50 ml) is treated with potassium carbonate (0.920 g, 6.66 mmol) and stirred at RT for approximately 10 mins. 1-Bromo-2-methoxyethane (0.771 g, 5.55 mmol) is added and the mixture is stirred at RT overnight. The solvent is removed in vacuo and the residue is partitioned between in EtOAc/H2O. The organic phase is separated and washed with sat Na2CO3, 1M HCl, brine, dried (MgSO4) and concentrated in vacuo to afford a dark green/brown oil. Purification by chromatography on silica gel (50 g+70 g) eluting with 20% EtOAc/iso-hexane affords the title compound; MS m/z 239.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][N:11]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](Cl)[N:14]=3)[CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)CO>[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:24]=1[NH:25][C:15]1[N:14]=[C:13]([N:11]2[CH2:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH2:9][CH2:10]2)[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: Cc1cc(N2CCC=C(c3ccccc3)C2)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: Cc1cc(N2CCC=C(c3ccccc3)C2)nc(Nc2ccc(C(C)C)cc2Br)n1
Yield: 74 %

Procedure:
4-(5-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-chloro-6-methylpyrimidine (1.10 g), 2-bromo-4-isopropylaniline hydrochloride (0.97 g), and diisopropylethylamine (0.50 g) were heated at reflux in 5 ml of ethylene glycol for 1 hour. The reaction solution was poured into a saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The extract was washed with water and then with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give 1.32 g of 2-[N-(2-bromo-4-isopropylphenyl)amino]-4-(5-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine as an amorphous substance.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].Cl.O1CCOCC1>O>[Cl:25][C:5]1[CH:6]=[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([C:29]([C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:37])=[N:3][CH:4]=1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(OC(C)C)cc1
Reactant: CON(C)C(=O)c1cccnc1C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-bromo-5-chloro-pyridin-3-yl)-4-isopropoxy-N-methoxymethyl-benzenesulfonamide (592 mg, 1.32 mmol) was placed in a dry 25 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (5 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (1.72 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 60 minutes, followed by the addition of N-methoxy-2,N-dimethyl-nicotinamide (379 mg, 2.11 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (6 mL, 24.0 mmol) and H2O (6.0 mL), and then stirred at 80° C. for two hours. The resultant solution was concentrated in vacuo and saturated sodium bicarbonate was added to adjust to neutral pH. The solution was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude sulfonamide was finally purified via automated flash chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 8.58 (d, 1H), 8.17 (m, 2H), 7.80 (d, 2H), 7.49 (d, 1H), 7.16 (m, 1H), 6.89 (d, 2H), 4.57 (sep, 1H), 2.34 (s, 3H), 1.33 (d, 6H); MS (ES) M+H expect 445.9. found 446.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][CH2:15][N:14]=[C:13]2[C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[CH:18]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:52][N:53]1[CH2:58][CH2:57][CH2:56][N:55]([CH2:59][C:60]([F:63])([F:62])[F:61])[C:54]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:28])([F:29])[F:30])[O:16][CH2:15][N:14]=[C:13]2[C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:52][N:53]3[CH2:58][CH2:57][CH2:56][N:55]([CH2:59][C:60]([F:61])([F:63])[F:62])[C:54]3=[O:64])=[O:22])=[C:19]([CH3:26])[CH:18]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: NN1CCCN(CC(F)(F)F)C1=O
Reactant: Cc1cc(C2=NCOC2(c2cc(Cl)cc(C(F)(F)F)c2)C(F)(F)F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C2=NCOC2(c2cc(Cl)cc(C(F)(F)F)c2)C(F)(F)F)ccc1C(=O)NN1CCCN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,5-dihydro-1,3-oxazol-4-yl]-2-methylbenzoic acid (50 mg, 0.11 mmol, 1.00 equiv), dichloromethane (20 mL), EDCI (25 mg, 0.13 mmol, 1.20 equiv), HOBt (18 mg, 0.13 mmol, 1.20 equiv), TEA (30 mg, 0.30 mmol, 3.00 equiv), 1-amino-3-(2,2,2-trifluoroethyl)-1,3-diazinan-2-one (22 mg, 0.11 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 40 mL of DCM. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 12 mg (17.2%) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,5-dihydro-1,3-oxazol-4-yl]-2-methyl-N-[2-oxo-3-(2,2,2-trifluoroethyl)-1,3-diazinan-1-yl]benzamide as a white solid. (ES, m/z): 631 [M+H]+ 1H-NMR (CDCl3, ppm): 7.82 (s, 1H), 7.76-7.73 (m, 2H), 7.69 (s, 1H), 7.61-7.50 (m, 3H), 4.14 (d, J=18.6 Hz, 1H), 4.07-3.98 (m, 2H), 3.80-3.69 (m, 3H), 3.58-3.52 (m, 2H), 2.51 (s, 3H), 2.25-2.17 (m, 2H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)=[C:8]([C:18]([O:20][CH3:21])=[O:19])[NH:7][C:6]1=[O:22])=[O:4].[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][C:32]([C:41]([O:43][CH3:44])=[O:42])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[N:5]([C:3]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][C:32]([C:41]([O:43][CH3:44])=[O:42])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:33][CH2:34]3)=[O:4])[C:6](=[O:22])[NH:7][C:8]=2[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: COC(=O)c1[nH]c(=O)n(C(=O)C(Cl)(Cl)Cl)c1-c1ccc(F)c(F)c1
Reactant: COC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1[nH]c(=O)n(C(=O)NCCCN2CCC(C(=O)OC)(c3ccccc3)CC2)c1-c1ccc(F)c(F)c1
Yield: 1.8 %

Procedure:
A mixture of 1-trichloroacetyl-5-(3,4-difluorophenyl)-2,3-dihydro-4-methoxycarbonyl-2(1H)-imidazolone (583 mg, 1.46 mmol), 1-(3-aminopropyl)-4-methoxycarbonyl-4-phenylpiperidine (808 mg, 2.92 mmol) and potassium carbonate (809 mg, 5.85 mmol) in dioxane (15 mL) was heated at reflux for 24 hours and then concentrated. The residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was flash chromatographed over silica gel to give the product (15 mg, 2% yield). Hydrochloride salt: light brown solid; m.p. 134-136° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12]C(OCC)=O>O.FC(F)(F)C(O)=O.O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH3:12]
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of ethyl 2-methyl-3-nitro-β-oxobenzenepropanoate (10.0 g, 39.7 mmol) in 100 mL of 30% water/trifluoroacetic acid is heated at reflux for 5 hours. The reaction mixture is cooled to room temperature, diluted with water (100 mL), and extracted with ether. The organic layer is washed with water, saturated aqueous sodium bicarbonate, and brine. Evaporation of the organic layer, followed by recrystallization of the residue gives 1-(2-methyl-3-nitrophenyl)ethanone (4.8 g, 67%), mp=49-51° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][CH2:35][CH2:36][Mg]Br.O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:33])[CH:35]([CH3:36])[CH3:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in tetrahydrofuran (3 mL) was added (2-methylethyl)magnesium bromide (1M tetrahydrofuran solution, 650 μL), and the mixture was stirred at −20° C. for 30 min and then overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (40.0 mg, yield 37%) as a pale-yellow amorphous solid. MS: 509 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C=O.Cl.[C:15](O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:15][O:7][C:6]2=[O:8])=[CH:10][CH:11]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 20 g (131 mmol) of 3-methoxybenzoic acid, 13 ml (160 mmol) of 37% strength formalin soln., 16 ml (162 mmol) of 37% strength HCl and 150 ml of 100% strength acetic acid is heated to 90° C., while stirring. After a clear solution has formed, the stirrer is switched off and the mixture is left at this temperature for 14 hours. The acetic acid is stripped off at 80° C. in vacuo, the residue is taken up in 150 ml of toluene and the mixture is concentrated to 80 ml. The 80° C. hot solution is washed with 40 ml portions of 20% strength Na2SO4 solution until the pH of the aqueous solution is alkaline, and is then washed with 40 ml of H2O. After addition of 6 ml of morpholine, the organic phase is stirred at 80° C. for 2 h and then washed with 50 ml portions of 10% strength H2SO4 until the aqueous phase is acidic, and twice with 50 ml of H2O each time. For crystallization of the product, the mixture is concentrated to 50 ml, a seed crystal is added if necessary, and the mixture is stirred until it has cooled to room temperature. The product is obtained by filtering off in the form of white crystals.
Reaction SMILES: [N+](=[C:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH3:17][OH:18]>C1C=CC=CC=1.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:3]([O:18][CH3:17])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)=[N+]=[N-]
Reactant: CO
Agent: [Rh]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC
Temperature: 25 °C

Procedure:
A solution of ethyl 2-diazo-3-(4hydroxyphenyl)propanoate (c.f. N. Takamura and T. Mizoguchi, Tetrahedron Lett., 1971, 4495) (8.8 g) in benzene (40 mL) was added over 30 minutes to a stirred, refluxing mixture of rhodium (II) acetate dimer (10 mg), methanol (7.9 mL) and benzene (50 mL). The mixture was heated at reflux for a further 30 minutes, then allowed to cool to room temperature overnight and washed with water (2×200 mL). The benzene solution was dried (MgSO4) and evaporated and the residual oil chromatographed twice on silica gel, firstly with 20% ethyl acetate in hexane as eluent and subsequently with 4% ethyl acetate in dichloromethane as eluent to afford the title compound as an oil.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:14])[C:7]([O:12][CH3:13])=[CH:8][C:9]=2[OH:11])[C:4](=[O:15])[O:3]1.CN(C)C(N(C)C)=N.[CH2:24](Br)[CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([O:3][C:4](=[O:15])[C:5]1[C:6]([CH3:14])=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([OH:11])[C:10]=1[CH:2]=[O:1])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: COc1cc(O)c2c(c1C)C(=O)OC2O
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 42.0 g of (RS)-3,4-dihydroxy-6-methoxy-7-methyl-1,3-dihydro-isobenzofuran-1-one in 1 l of N,N-dimethylformamide were added 23.0 g of 1,1,3,3-tetramethylguanidine. The solution was stirred for 30 min and then, 48.4 g of allyl bromide were added and stirring was continued for 3 h. The mixture was evaporated in vacuo and the residue was dissolved in 0.7 l of ethyl acetate. The solution was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was crystallized from tert-butyl methyl ether to give 37.3 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester as white crystals of m.p. 73°-74° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].OO.NC(N)=[O:20].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N+:6]([O-:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=[N+]([O-])c1cccnc1-c1ccccc1
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc[n+]([O-])c1-c1ccccc1
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
In a 250 mL three-necked round-bottomed flask equipped with a thermometer, droppingbfunnel and a condensor, 11.62 g of 3-nitro-2-phenyl-pyridine is dissolved in 58.0 ml of dichloromethane. Then, 13.65 g of H2O2 urea adduct is added. Under cooling with an ice/water bath, 16.40 ml trifluoroacetic acid anhydride is added dropwise over 25 minutes (temperature below 12° C.). After stirring at 10° C. for 45 minutes, the cooling bath is removed and the mixture is stirred at an ambient temperature for 18 hours. Afterwards, 150 ml of water is added (pH about 1) and extraction is carried out with dichloromethane (3×100 ml). After washing the organic phase with 10% aqueous sodium sulfite solution, it is dried over Na2SO4. After purification by chromatography on a pad of silica gel (eluent: first dichloromethane, then ethyl acetate), 9.45 g of the title compound is obtained as a yellow-green solid (MP: 116-117° C.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In DMF (166 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (19.5 g). To the mixture was added under ice-cooling 65% sodium hydride (5.3 g), and the mixture was stirred at room temperature for 1.5 hours. To the mixture was added dropwise iodopentane (17.7 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-(2-pentyloxyethoxy)benzene (12.0 g).
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)(Cl)Cl.[Ag]=O>[CH2:1]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=2)[CH2:16]1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: COc1ccc(C2CCCNC2)cc1OC
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCCN1CCCC(c2ccc(OC)c(OC)c2)C1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
2 g of silver oxide and then 2 ml of propyl iodide were added to a solution of 4 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 20 ml of chloroform and the mixture was stirred for 8 hours at 20° C under an inert atmosphere. Another 1 g of silver oxide and 1 ml of propyl iodide were added and the mixture was stirred for 15 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 3.2 g of N-propyl-3-(3',4'-dimethoxyphenyl)-piperidine.