Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7](Br)[CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4].C([O-])(=O)C.[Na+]>C(O)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4]
Reactant: Cc1cc(Br)c(Cl)c(Cl)c1N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(Cl)c1N
Yield: 89.1 %

Procedure:
A slurry of 6.50 g (25.5 mmol) of 2,3-dichloro-4-bromo-6-methyl aniline and 8.37 g (102 mmol) of sodium acetate in 120 ml of acetic acid-ethanol (1:1, v/v) was treated with 0.65 g of 5% palladium on carbon. The mixture was hydrogenated in a Parr hydrogenation apparatus at an initial pressure of 50 psi for 10 minutes. The reaction mixture was filtered, and the filtrate was concentrated by evaporation at reduced pressure. The residue was partitioned between ether and water, and the organic layer was washed with 5% aqueous sodium hydroxide, dried and evaporated at reduced pressure. The residue was purified by Kugelrohr distillation to afford 4.00 g (89%) of the desired product as a colorless oil, b.p. 60°-70° C. (0.15 mm). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(OCC)C.ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCc1ccc(OCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 5-phenylpentanol (3.7 mL), methyl 3-(4-hydroxyphenyl)propanoate (3.6 g), triphenylphosphine (5.77 g) and dichloromethane (200 mL) was added 1,1′-(azodicarbonyl)dipiperidine (5.55 g). The reaction mixture was stirred at room temperature for 4 days. Diethyl ether was added to the reaction mixture, which was filtered and the filtrate was concentrated. Hexane-diethyl ether (1:1) (200 mL) was added to the residue, which was filtered and the filtrate was concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1→4:1) to give the title compound (6.16 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([C:19](OC)=[O:20])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([CH2:19][OH:20])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
Methyl 5-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxythieno[2,3-b]pyridine-2-carboxylate (0.506 g) from Example No. 33 is dissolved in THF (100 mL) with heating and then the reaction is cooled in an ice bath. To this solution is added a 1.0 M solution of LiAlH4 in THF (2.4 mL). The reaction is allowed to warm to room temperature and is stirred for 2.5 h. The reaction is quenched with water (1 mL), 10% NaOH (1 mL), and H2O (1 mL). The aluminum salts are filtered off and the filtrate is concentrated in vacuo. The resulting yellow oil is purified by column chromatography (CH2Cl2/methanol, 98/2; 95/5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.254 g (54%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[C:7]([F:11])[CH:8]=2)[C:3]1=[O:13].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C([O-])(O)=O.[Na+]>[CH2:18]([O:17][C:15](=[O:16])[NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[C:7]([F:11])[CH:8]=2)[C:3]1=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1Cc2cc(F)c(F)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NC1Cc2cc(F)c(F)cc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-amino-5,6-difluoroindan-1-one (Preparation 78) (165 mg, 0.90 mmol) in saturated NaHCO3 (15 mL) was added benzyl chloroformate (0.15 mL, 1.08 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was extracted with EtOAc (25 mL) and the organic phase washed with water (20 mL), brine (20 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (MeOH:DCM 1:99) to give the title compound: RT=3.50 min; m/z (ES+)=318.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.OO>O1CCCC1.COC(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]([OH:18])([CH3:20])[CH3:19])[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC(CC2CC2)(CC2(C)CO2)OC1=O
Agent: OO
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
LiBHEt3 solution (1 mol/L, 34 mL) was added dropwise to a solution of 3-[(S)-1-(4-bromophenyl)ethyl]-6-(cyclopropylmethyl)-6-[(2-methyloxiran-2-yl)methyl]-1,3-oxazinan-2-one (1.40 g) in tetrahydrofuran (200 mL) at 0° C. The resulting solution was stirred at 2-3° C. for 1.5 h and then at room temperature for another 3 h. 30% aqueous H2O2 solution (30 mL) was added dropwise at 0° C. and the mixture was diluted with tert-butyl methyl ether (200 mL). The mixture was washed with 3% aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution (4×100 mL) and dried (Na2SO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 1:1→3:1) to afford the title compound; besides, the diastereomer, 3-[(S)-1-(4-bromophenyl)ethyl]-(R)-6-(cyclopropylmethyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one was also isolated (0.40 g, 29% yield). Yield: 0.55 g (40% of theory).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([O:15][CH3:16])[NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:17]>CO>[CH3:16][O:15][C:13]1[NH:14][C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:17])[C:11]=2[N:12]=1
Reactant: N
Reactant: COc1nc2c(Cl)nc3ccccc3c2[nH]1
Solvent: CO
Product: COc1nc2c(N)nc3ccccc3c2[nH]1
Temperature: 150 °C

Procedure:
4-Chloro-2-methoxy-1H-imidazo[4,5-c]quinoline (700 mg) was added to a high-pressure vessel with ammonia (40 mL of a 7 N solution in methanol), and the vessel was sealed and heated at 150° C. for 24 hours, and then allowed to cool. The contents were concentrated under reduced pressure. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane first in a gradient from 0:0:100 to 0.3:4.7:95 and secondly in a gradient from 0:0:100 to 0.2:3.8:96) to provide 20 mg of 2-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as a white solid. The compound was further purified by prep HPLC according to the method described in Examples 8-55. The observed accurate mass (M+H) for the isolated trifluoroacetate salt was 215.0931.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13]>C1COCC1>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CCOC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Sodium hydroxide (2M, 349 mL, 697.58 mmol) was added to a solution of methyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (67.68 g, 359.58 mmol) in THF (680 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The THF was removed in vacuo, the aqueous layer was then washed with ethyl acetate (260 mL), before cooling to 0° C. and careful acidification to pH 5 by the addition of hydrochloric acid (2M). The product was extracted with ethyl acetate (3×250 mL) before drying (MgSO4) and evaporation to give 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (57.0 g, 91%) as a clear oil. This material was dissolved in ethyl acetate (750 mL) then washed with water (3×250 mL) and brine (250 mL) to remove remaining acetic acid. The organic solution was dried (MgSO4) and evaporated to give 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (45.67 g 72.9%) as a colourless oil: 1H NMR Spectrum: 1H NMR (CDCl3) 1.43-1.67 (4H, m), 1.65-1.95 (2H, m), 2.68 (2H, t), 3.48-3.58 (1H, m), 3.73 (1H, dt), 3.88 (1H, ddd), 4.02 (1H, dt), 4.59-4.7 (1H, m); Mass Spectrum [M−H]−=173.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8](CC)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].Br[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Reactant: Brc1cccc2[nH]ccc12
Product: CCOC(=O)c1c(-c2ccc(-c3cccc4[nH]ccc34)cc2)c(C#N)cn1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-222 using 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or 97b) and 4-bromo-indole. Purify the material by silica gel chromatography eluting with eluting with hexanes/ethyl acetate 4:1 to provide the title compound which is triturated with methylene chloride and hexanes to provide the title compound as a white solid. Mass spectrum (m/e): 398.2 (M*+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]1[CH:13]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:12]1.Cl>CS(C)=O.O1CCCC1>[CH2:3]([O:10][CH2:12][CH:13]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C(CCCCCCC1CCCCC1)CCCCCOCC1CO1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: OC(COCCCCCCCCCCCCC1CCCCC1)COCc1ccccc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
In 100 ml of dimethylsulfoxide is suspended 1.4 g of sodium hydride, to which 9.73 g of benzyl alcohol is added dropwise at room temperature with stirring. After the addition is over, the mixture is gradually heated to 60° C. and stirred at that temperature for 40 minutes. Then, a solution of 9.7 g of 1,2-epoxy-3-(12-cyclohexyldodecyloxy)propane in 50 ml of tetrahydrofuran is added dropwise to the mixture and the resulting mixture is stirred at 60° C. for 2 hours. The thus obtaind reaction mixture is then neutralized with dilute hydrochloric acid and extracted with hexane-ethyl acetate (1:1). The extract layer is washed with water, dried and concentrated. The residue is purified by silica gel column chromatography to yield 10.2 g of the captioned compound as an oily substance.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:21]([N:24]([CH2:29][CH2:30][CH3:31])[C:25](=[O:28])[CH2:26]Cl)[CH2:22][CH3:23].O>CC(C)=O>[Br:7][C:8]1[C:18]([O:19][CH2:26][C:25]([N:24]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][CH3:23])=[O:28])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)OCC)c1Br

Procedure:
0.853 g of K2CO3, 0.154 g of KI and 1.000 g of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced in 10 ml of acetone. At RT 0.783 g of N,N-di-n-propylchloroacetamide was added. The mixture was then heated at reflux for 4 hours. It was subsequently poured into water and extracted with diisopropyl ether. The organic phases were washed with water, dried over Na2SO4 and concentrated. Chromatography on silica gel (eluent: n-heptane/ethyl acetate) gave ethyl 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoate as brown oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[C:23]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])[CH:22]=[N:21][CH:20]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:23]1[CH:24]=[N:19][CH:20]=[N:21][CH:22]=1)[OH:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1-c1cncnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-c1cncnc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
Tetrabutylammonium fluoride (TBAF, 0.1 ml of 1M in THF) was added to a solution of 2-pyrimidin-5-yl-benzaldehyde (184 mg, 1 mmol) and trifluoromethyl trimethylsilane (TMSCF3, 0.2 ml, 1.2 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The mixture was then treated with 3 ml of 1M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.21 g of 2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethanol (yield: 84%), which was directly used in next step without purification.
Reaction SMILES: C(O)(=O)CC(O)=[O:4].[CH2:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:17]1([NH:16][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][CH2:8][CH2:13][CH2:12]2)=[O:4])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
104 mg (1 mmol) of malonic acid and 1.23 g (2.2 mmol) of alcohol 7 were dissolved in dry CH2Cl2 under N2 protection and the solution cooled in an ice bath. 41.0 mg (0.20 mmol) DMAP (10 mol %) and 454 mg (2.20 mmol) DCC were added subsequently. After stirring under N2-protection for 15 min at 0° C. and 2 h at RT, TLC control showed complete conversion of the starting material. Dicyclohexyl urea formed during the reaction precipitated and was filtered off. Traces of urea were subsequently removed by repeated precipitation from ethyl acetate. After evaporation of the solvent and purification by FC on silica (CH2Cl2:EtOH=94:6) 714 mg of a white solid was obtained (yield 60%).—1H NMR (400 MHz, RT, CDCl3): δ=6.22, 4.97 (2br, 4H), 4.11 (t, 3J=6.8 Hz, 4H), 3.66-3.48 (3m, 12H), 3.34 (s, 2H), 3.33 (dt, 4H), 3.20 (dt, 4H), 2.11 (t, 3J=7.6 Hz, 4H), 1.74 (m, 4H), 1.60 (m, 4H), 1.41 (s, 18H), 1.35-1.19 (m, 40H).—13C NMR (100.5 MHz, RT, CDCl3): δ=172.9 (2C), 166.4 (2C), 155.8 (2C), 78.9 (2C), 70.5, 70.5, 70.2, 70.1, 70.1, 69.5 (12C), 65.6 (2C), 41.7 (1C), 38.6, 37.9 (4C), 36.9 (2C), 29.7, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.1 (20C), 28.5 (6C), 25.9, 25.8 (4C).—IR (Film/KBr): ν=3312, 3082, 2919, 2851, 1747, 1719, 1685, 1640, 1543, 1468, 1390, 1366, 1347, 1251, 1182, 1127, 1021, 997, 867, 720, 694, 603 cm−1.—MS (FAB): m/z=1322 [M+Cs]+, 1212 [M+Na]+, 1190 [M]+, 1190, 990, 443.
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(OC)=O.[CH2:21]([C:23]1[CH2:24][C@H:25]2[C@@H:28]([CH:29]=1)[C:27](=O)[CH2:26]2)[CH3:22]>O1CCCC1.CC(C)([O-])C.[K+].C(OC(=O)CP(OC)(OC)=O)(C)(C)C>[CH2:21]([C:23]1[CH2:29][C@H:28]2[C@@H:25]([CH:24]=1)[C:26](=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:27]2)[CH3:22]
Reactant: CCC1=C[C@H]2C(=O)C[C@H]2C1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1=C[C@H]2C(=CC(=O)OC(C)(C)C)C[C@H]2C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 134.2 %

Procedure:
Potassium t-butoxide (8.66 g) was dissolved in tetrahydrofuran (50 mL) under a nitrogen atmosphere, and the solution was then cooled to approximately 5° C. Tert-butyl (dimethoxyphosphoryl)acetate (17.30 g) was added thereto at 15° C. or lower, and the mixture was stirred at 5 to 15° C. for 1 hour. (1R,5S)-3-Ethylbicyclo[3.2.0]hept-3-en-6-one (10.00 g) and tetrahydrofuran (25 mL) were further added thereto, and the mixture was stirred at 5 to 15° C. for 1.5 hours. Potassium t-butoxide (0.90 g) and tert-butyl(dimethoxyphosphoryl)acetate (1.73 g) were further added thereto, and the mixture was stirred for approximately 1 hour. Then, the reaction mixture was separated into aqueous and organic layers by the addition of toluene (85 mL) and water (40 mL). The organic layer was washed twice with water (20 mL) and then concentrated under reduced pressure to obtain tert-butyl [(1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (23.09 g) as a yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16](F)=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl.[CH3:36][O:37][CH2:38][CH2:39][OH:40]>O1CCCC1>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCO
Reactant: COC(=O)c1ccc(NC(c2cc(-c3ccc(F)nc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccc(-c2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)o2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Methyl 4-({cyclohexyl[5-(6-fluoropyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoate (1.9 g) was dissolved in 2-methoxyethanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (5 mL) was added, and the mixture was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give the title compound (0.9 g, 42%) as an amorphous compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][C:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27](O)=[O:28])=[CH:20][CH:19]=1>>[C:18]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:22][C:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:28])=[CH:20][CH:19]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Product: O=C(CCC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 4-biphenyl-4-yl-4-oxo-butyric acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.80 (m, 2 H), 1.97 (m, 2 H), 2.83 (t, J=6.10 Hz, 2 H), 3.02 (m, 2 H), 3.41 (t, J=6.26 Hz, 2 H), 3.50 (m, 2 H), 3.69 (m, 2 H), 4.66 (t, J=6.26 Hz, 2 H), 7.11 (m, 1 H), 7.45 (m, 1 H), 7.52 (m, 2 H), 7.72 (m, 1 H), 7.77 (m, 2 H), 7.86 (m, 2 H), 8.10 (m, 3 H), 8.29 (s, 1 H), 9.56 (br s, N H); MS (DCI/NH3) m/z 467 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:39][CH3:40])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[O:39][CH3:40]
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cc(C)nn5C)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.240 mmol) and THF (1.5 mL). To the resulting solution was added 5-amino-2-methoxyphenol (39 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was filtered and washed with 1 mL of ice cold THF yielding 61% (34 mg, 0.065 mmol) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.[I-].[Na+]>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Yield: 36.1 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g), triethylamine (2.6 cc), 4-(4-chlorophenyl) piperazine (5 g) and sodium iodide (2.8 g) in toluene (50 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After recrystallization, firstly from boiling acetonitrile 6 hours and secondly from boiling methyl ethyl ketone (15 cc), 2-{3-[4-(4-chlorophenyl)-1-piperazinyl ]propyl}naptho[1,8-cd]isothiazole 1,1-dioxide (3 g) is obtained, m.p. 120° C.