Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][C:4]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[N:14]1.[BrH:20].C(O)(=O)C>C(O)(=O)C>[Br:20][CH2:3][C:4]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[N:14]1
Reactant: COCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reactant: Br
Solvent: CC(=O)O
Product: Cn1nnn(-c2cccc(C3CC3)c2CBr)c1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-methoxymethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 7) 26.0 g, acetic acid 40 ml and 25% hydrogen bromide-acetic acid solution 40 ml was stirred at 65° C. for two hours. To the reaction mixture was added saturated saline, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give 1-(2-bromomethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 30.8 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9](OC)=[O:10])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=2)[N:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]=2)[N:5]=1
Reactant: COCc1nn(-c2cccc(C(F)(F)F)n2)cc1C(=O)OC
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCc1nn(-c2cccc(C(F)(F)F)n2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution (10 mL) of methyl 3-(methoxymethyl)-1-[6-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylate (6.5 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (25 mL) of lithium aluminum hydride (0.79 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (2.0 mL), 1N aqueous sodium hydroxide solution (10.0 mL) and water (2.0 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (6.0 g) of 3-(methoxymethyl)-1-[6-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (100 mL), manganese dioxide (3.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (5.3 g, 90%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1[CH2:9][CH2:10][OH:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1[CH2:9][CH:10]=[O:11]
Reactant: CC1=C(CCO)C2CCC1C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1=C(CC=O)C2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
2-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-ethanol (16.37 g, 107.53 mmol) was dissolved in dichloromethane (150 ml) and Dess-Martin periodinane in solution in dichloromethane (15%, 536.2 g, 189.7 mmol) was added at room temperature over a 110 minutes period under nitrogen. The mixture was further stirred at room temperature for 30 minutes and was hydrolyzed with aqueous NaOH 5% in an ice-bath, and extracted 3 times with Et2O. The combined organic layers were washed with H2O, brine, dried over Na2SO4, and filtered off. Solvents were removed under reduced pressure to give a crude which was further purified by bulb to bulb distillation under reduced pressure to afford the desired compound (13.468 g, 88% purity) in 83% yield.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24]([O:26]C)=O)=[CH:6][CH:5]=2.[ClH:28].[NH2:29][CH2:30][CH2:31][S:32]([NH2:35])(=[O:34])=[O:33].C[Al](C)C>C(=O)([O-])O.[Na+]>[ClH:28].[NH2:35][S:32]([CH2:31][CH2:30][NH:29][C:24]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([OH:1])=[C:10]2[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:13][N:12]=1)=[O:26])(=[O:34])=[O:33]
Reactant: NCCS(N)(=O)=O
Reactant: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])O
Product: NS(=O)(=O)CCNC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Yield: 40 %

Procedure:
Starting materials: methyl 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxylate and 2-aminoethanesulfonamide hydrochloride, but the reaction mixture was heated at 80° C. for 22 h. After the first 2 h, an additional 6 eqv. of trimethylaluminium was added to the reaction mixture. The mixture was cooled, diluted with a saturated sodium hydrogen carbonate solution (10 mL) and concentrated in vacuo. The residue was suspended in methanol/dichloromethane, (1:1), silica gel (˜2 g) was added and the mixture was re-concentrated in vacuo, resulting in a fine yellow powder that was purified on a silica gel column using dichloromethane/methanol/aqueous NH3, (first 100:10:1, then 70:10:1), as the eluent to afford the title compound as a base in 40% yield: 1H NMR (DMSO-d6, 300 MHz) δ 14.5 (br s, 1H), 11.29 (br s, 1H), 10.69 (s, 1H), 8.61 (br s, 1H), 8.22 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 6.96-6.90 (m, 3H), 4.25 (s, 2H), 3.98-3.64 (m, 14H), 3.36-3.22 (m, 4H), 3.12-3.04 (m, 2H); MS (ES) m/z 460 (M++1). The base was converted to the hydrochloride
Reaction SMILES: COC(=O)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:40])[CH2:14][N:15]2[N:21]=[C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:16]2=[O:39])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH:22]1([C:20]2[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:16](=[O:39])[N:15]([CH2:14][C:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=3)=[O:40])[N:21]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)OCc1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(CO)c2)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Carbonic acid 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzyl ester methyl ester (Example 48, step a) was dissolved in THF-MeOH (1:1/40 ml) and 1% K2CO3 solution (30 ml) was added. The mixture was stirred at room temperature for 2 h. After concentration of the organic solvents, a precipitate formed, which was collected by filtration and dried in vacuo to afford the title compound as a yellow solid (790 mg, 89%). 1H NMR (CDCl3) 8.31 (1H, s), 7.51-7.45 (3H, m), 7.31-7.28 (3H, m), 7.26-7.10 (2H, m), 4.70 (1H, d), 4.67 (2H, s), 4.64 (1H, d), 4.26 (1H, d), 4.22 (1H, d), 2.89 (1H, m), 1.85-1.55 (6H, m), 1.30-1.24 (13H, m). Found: C, 67.70; H, 7.40; N, 10.79%; C29H36N4O4.0.5H2O requires: C, 67.81; H, 7.26; N, 10.91%.
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@@H:6]([CH3:27])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[CH:17][C:8]=3[O:7][C@H:6]([CH3:27])[CH2:5][NH:4][CH3:1])[N:13]=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Temperature: 130 °C
Yield: 102.6 %

Procedure:
Chlorotris(triphenylphosphine)rhodium(I) (40 mg) was added to a solution of 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-chlorophenol (841 mg) in acetonitrile/water (5:1, 4 ml), and the mixture heated to 130° C. for 10 minutes by microwave irradiation. The cooled mixture was subjected to ion exchange chromatography and product eluted with methanol/2M ammonia yielding 2-chloro-4-({5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol as a brown solid (776 mg, 100%); NMR spectrum (DMSO-d6) 1.40 (d, 3H), 2.33 (s, 3H), 2.87 (m, 2H), 3.29 (1H obscured by water), 4.88 (m, 1H), 6.97 (d, 1H), 7.14 (d, 1H), 7.28 (d, 1H), 7.55 (dd, 1H), 7.68 (t, 1H), 7.95 (d, 1H), 8.45 (s, 1H), 10.51 (bs, 1H); Mass spectrum MH+ 359.
Reaction SMILES: [Mg].[C:2]12([C:12]3[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:13]=3[O:14][CH2:15][CH:16]3[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.BrC(Br)C.Br[C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[C:38]([C:43]([O:45][CH3:46])=[O:44])[CH:37]=[CH:36]2.[Cl-].[NH4+]>[Cl-].[Zn+2].[Cl-].C1COCC1>[C:2]12([C:12]3[CH:26]=[C:25]([C:33]4[CH:34]=[C:35]5[C:40](=[CH:41][CH:42]=4)[CH:39]=[C:38]([C:43]([O:45][CH3:46])=[O:44])[CH:37]=[CH:36]5)[CH:24]=[CH:23][C:13]=3[O:14][CH2:15][CH:16]3[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC1(C)OCC(COc2ccc(Br)cc2C23CC4CC(CC(C4)C2)C3)O1
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(-c3ccc(OCC4COC(C)(C)O4)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
962 mg (39.6 mmol) of magnesium granules are wetted with a minimum of THF. A solution of 7.4 g (17.6 mmol) of 4-(2-adamantan-1-yl-4-bromophenoxymethyl)-2,2-dimethyl[1,3]dioxolane, 50 ml of THF and 300 μl (3.5 mmol) of dibromoethane is run dropwise into the suspension of magnesium. The reaction medium is heated at the reflux of the THF for 1 h 30 min and then brought back to 20° C. 5.1 g (37.6 mmol) of zinc chloride, dried and melted under vacuum beforehand, are added while keeping the temperature of the medium at 20° C., and then 50 ml of THF are added and the medium is stirred at 20° C. for 1 h 30 min. 10 g (37.6 mmol) of methyl 6-bromonaphthalene-2-carboxylate are added in small fractions while maintaining the temperature of the medium at 20° C., and then 300 mg of NiCl2/dppe complex and 50 ml of THF are added and the reaction medium is stirred at ambient temperature for 15 h. The reaction medium is then treated with a saturated ammonium chloride solution and extracted with ether. The organic phase is filtered, washed with water, and then dried and concentrated under reduced pressure. The residue obtained is then purified by chromatography on a silica column (elution being carried out with 70 heptane/30 dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])S[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1.O[O:30][S:31]([O-:33])=O.[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:18](=[O:28])[C:19]([CH3:27])([CH3:26])[S:31](=[O:33])(=[O:30])[C:21]([CH3:25])([CH3:24])[C:22]2=[O:23])[CH:10]=1
Reactant: O=S([O-])OO
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)S(=O)(=O)C(C)(C)C1=O
Yield: 29 %

Procedure:
A mixture of 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylthiopyran-3,5-dione (79 mg, 0.1816 mmol) and oxone (446 mg, 0.726 mmol) is stirred at ambient temperature for 20 hours as a solution in methanol/water (1 ml, 1:1 ratio). The reaction mixture is then partitioned between water and dichloromethane, the organic phase is separated and concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC to give 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-1,1-dioxo-thiopyran-3,5-dione (24.6 mg) as a clear gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)cc1

Procedure:
128.2 mg of the target compound (0.36 mmol, 65.0%) was obtained using 1-(4-methoxyphenyl)piperazine (212 mg, 1.10 mmol), biphenyl-3-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[CH:63]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)([CH3:65])[CH3:64]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:64][CH:63]([N:66]1[CH2:71][CH2:70][N:69]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH2:68][CH2:67]1)[CH3:65]
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C(C)C)CC2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 54.8 %

Procedure:
To an N2 degassed solution of 1,4-dioxane (50 mL, Aldrich) was added 4-bromo-1-(methyloxy)-2-nitrobenzene (1.0 g, 4.31 mmol, Aldrich), XANTPHOS (0.74 g, 1.28 mmol, Aldrich), Pd2(dba)3(0.79 g, 0.86 mmol, Aldrich), Cs2CO3 (2.8 g, 8.63 mmol, Aldrich), and 1-isopropylpiperazine (1.10 g, 8.6 mmol, Oakwood Chemicals). After heating overnight at 90° C., the reaction was diluted with ethyl acetate (50 mL), washed with water (50 mL), organic layer adsorbed to silica gel and purified by column chromatography (dichloromethane to 5% methanol/dichloromethane) to afford 1-(1-methylethyl)-4-[4-(methyloxy)-3-nitrophenyl]piperazine (0.66 g, 55%). ESIMS (M+H)+=280.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH:12]=[C:13]1[NH:17][C:16](=[O:18])[NH:15][C:14]1=O.[H][H].CO.II>CN(C)C=O.[Pd].O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]=[C:14]3[NH:15][C:16](=[O:18])[NH:17][C:13]3=[CH:12][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: II
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc2nc3[nH]c(=O)[nH]c3cc2c1C
Yield: 329.5 %

Procedure:
5-[(2,3-Dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione (19.95 g, 76 mmol) in dimethylformamide (350 mL) was hydrogenated over 10% palladium on charcoal (3 g) at 60 p.s.i. in a Parr hydrogenation apparatus. After hydrogen uptake ceased, the mixture was filtered through kieselgehr and the solvent evaporated to leave a solid which was suspended in a refluxing methanol (1 L). Iodine (19.4 g, 76 mmol) was added portionwise over 5 minutes and the mixture refluxed for 15 minutes before being concentrated in vacuo to about 100 mL. A solution of sodium thiosulfate (21 g) and sodium carbonate (11 g) in water (300 mL) was added with vigorous stirring to afford a beige precipitate which was collected, washed with water and dried in air to give 15.7 g. This was combined with crude material from experiments performed on 40 g and 4.16 g of starting material, suspended in hot (80° C.) water, filtered, suspended in refluxing methanol and filtered. Crystallization from dimethylacetamide afforded 1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one (53.4 g, 65%), m.p. >300° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CN(C)CCN(C)C.[CH3:21][C:22]1[CH:31]=[CH:30][C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1.[C:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35].[Cl-].[NH4+]>O.C1COCC1>[N:23]1[C:24]2[CH2:25][CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=[CH:31][C:22]=1[CH2:21][C:32]([O:33][CH2:34][CH3:35])=[O:36]
Reactant: Cc1ccc2c(n1)CCCC2
Reactant: CCOC(=O)Cl
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1ccc2c(n1)CCCC2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A solution of 7.56 g (74.7 mmol) of diisopropylamine in 100 mL of water-free THF was cooled to −30° C. and n-BuLi (31.9 g, 15% solution in n-hexane, 74.7 mmol mmol) was added via a syringe. The mixture was allowed to stir for 30 min. After cooling to −70° C., 8.68 g (74.7 mmol) tetramethylethylenediamine in 20 mL of THF were added and the mixture was allowed at −70° C. for 1 h. Then, 5 g (34.00 mmol) of 2-methyl-5,6,7,8-tetrahydroquinoline and 3.87 g (35.7 mmol) of ethyl carbonochloridate were added. The mixture was allowed to warm to room temperature within 2 h while being stirring. The reaction mixture was poured onto conc. cold aqueous ammonium chloride solution and extracted with EA (3 times). The combined organic phase was once extracted with a saturated ammonium chloride solution, washed with a saturated sodium bicarbonate solution and dried (magnesium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography (eluent: heptane/EA 1/2) to provide 2.16 g (29%) of the title compound).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-].CCOCC>ClCCl>[CH3:10][O:9][C:5]1[C:4]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:20](=[O:22])[CH3:21]
Reactant: COc1cccc(OC)c1CCCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(OC)c1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 15.28 g (59.6 mmol) of 1,3-dimethoxy-2-(3-phenylpropyl)benzene from the preceding example, and 4.68 g (59.6 mmol) of acetyl chloride, in 306 mL of dichloromethane was stirred at -5° to 0° C. and 7.95 g (59.6 mmol) of aluminum chloride was added. The resulting mixture was stirred at -5° to 0° C. for 2 hr and then allowed to warm to room temperature before being poured onto ice. Work-up with ether in the usual manner gave a product which was chromatographed on silica gel. Elution with 7:3 hexane-ether afforded 10.0 g (56.3%) of the title compound as a pale-yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([NH2:33])[N:30]([CH3:34])[N:29]=2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:32]=[C:31]([NH:33][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)[N:30]([CH3:34])[N:29]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ccc(Cl)cc2)cc1NCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-(4-chlorophenyl)-1-methyl-1H-pyrazole-5-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:22][NH:21][CH2:20]1)([O-:3])=[O:2].[CH2:24](Cl)Cl.C=O.C([BH3-])#N.[Na+]>CC#N>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:20][N:21]([CH3:24])[CH2:22]1)([O-:3])=[O:2]
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CNC1
Reactant: ClCCl
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CN1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred solution of azetidin-3-ylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.09 g, 0.26 mmol, 1.0 eq.) in CH3CN:CH2Cl2 was added aq. formaldehyde (0.77 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 30 min then cooled to 0° C. Sodium cyanoborohydride (0.03 g, 0.46 mmol, 1.8 eq.) was added slowly. The reaction was quenched with an aqueous saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to obtain (1-methylazetidin-3-yl)methyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.07 g, 75% yield).
Reaction SMILES: CCOCC.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:25]=[CH:24][C:16]([CH:17]=[CH:18][C:19](OCC)=[O:20])=[CH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[CH:18][CH2:19][OH:20])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C=Cc1ccc(OC2CCCCO2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: OCC=Cc1ccc(OC2CCCCO2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
50 Milliliters of anhydrous ether solution containing 6.8 g of ethyl 4-(2-tetrahydropyranyloxy)cinnamate was added dropwise to an anhydrous ether solution containing 0.47 g of lithium aluminium hydride being cooled at -30° C. After the addition was finished, the reaction mixture was stirred for 1 hour at the same temperature, then the temperature of the reaction mixture was gradually elevated up to -10° C., then a saturated aqueous solution of sodium sulfate was gradually added to the reaction mixture, and the precipitates formed were removed by filtration. The filtrate was dried with anhydrous sodium sulfate, then concentrated to dryness, the residue thus obtained was treated by means of silica gel column chromatography (eluent:chloroform) to yield 3.2 g of 4-(2-tetrahydropyranyloxy)cinnamyl alcohol in the form of colorless oily substance. Refractive index: nD22 1.5520.