Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)CNCc1ccccc1
Yield: 66 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine and 5.2 g (51 mmol) of triethylamine are heated in 20 g of water in an autoclave at an internal temperature of 120° C. for 6 hours. The two-phase solution is twice extracted with 50 ml of dichloromethane each time and the combined organic phases are washed with 50 ml of water and subsequently distilled. An amount of 5.2 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 66%, based on benzylamine.
Reaction SMILES: [O:1]=[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].[Cl:18][C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([Cl:26])[C:20]=1[OH:27].C(N(CC)CC)C>CO>[Cl:18][C:19]1[CH:24]=[C:23]([S:25][CH2:4][CH2:3][C:2]([N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)=[O:1])[CH:22]=[C:21]([Cl:26])[C:20]=1[OH:27]
Reactant: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: Oc1c(Cl)cc(S)cc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCSc1cc(Cl)c(O)c(Cl)c1)N1CCN(Cc2ccccc2)CC1
Reaction time: 12 h

Procedure:
1-(1-Oxo-2-propenyl)-4-(phenylmethyl)piperazine (2.53 g, 0.011 mole) and 2,6-dichloro-4-mercaptophenol (2.15 g, 0.011 mole) were dissolved in methanol (75 ml). Triethylamine (1 ml) was added and the reaction stirred for 12 hours. The solvent was removed, and the product purified by chromatography on silica, eluting with ethyl acetate/hexane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:9][C:4]1[CH:5]=[C:6]([O:8][CH3:10])[CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)cc(O)c1
Yield: 80 %

Procedure:
1 mmol of 3,5-Dihydroxy-toluene was taken in 3 mL of acetone, and then 3 mmol of K2CO3 was added and stirred for several minutes. Then, a solution of CH3I (3 mmol) in 10 ml of acetone was added from a pressure-equalizing dropping funnel, and the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered to remove K2CO3, and evaporated by a rotatory evaporator to remove acetone. The mixture was then purified by column chromatography to give 5-methyl-3-methoxy-phenol (80%).
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.CO[C:10](=[O:30])[CH2:11][CH:12]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>C1C=CC=CC=1>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH2:11][C:10]([NH:2][CH3:1])=[O:30])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CN
Reactant: COC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Temperature: 5 °C
Yield: 94.3 %

Procedure:
To a 5° C. stirring suspension of MeNH2—HCl (160 mg, 2.4 mmol) in benzene (2 ml) under N2, in a sealed tube was added dropwise Me3Al (2M in toluene, 1.2 ml, 2.4 mmol). The mixture was stirred at room temperature for 1 hour and a solution of 3-(1H-Indol-6-yl)-3-(2-methoxy-phenyl)-propionic acid methyl ester XXXVII (340 mg, 1.1 mmol) in benzene (10 ml) was added. The resulting mixture was stirred at 90° C. for about 4.5 hours, cooled to room temperature, and the reaction was quenched by slowly adding HCl (1M, 25 ml). The resulting mixture was stirred for 10 minutes, diluted with H2O, and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and evaporated to provide 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide XXXVIII (320 mg, 94% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[C:42]1C=C(COS(C)(=O)=O)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=1.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:19]2[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:50])[CH3:51])[N:47]=[C:42]([C:36]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=3[F:34])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O

Procedure:
Following the procedure of Example 1 (10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a slightly yellow oil (yield: 97.5%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>CN(C)C=O>[CH2:30]([O:29][CH2:28][C:17]1[N:18]([CH2:19][C:20]([CH3:22])([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH3:21])[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[C:15]=2[N:16]=1)[CH3:31]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCOCc1nc2c(NC(C)=O)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C

Procedure:
Acetyl chloride (150 μL, 1.1 equivalents (eq)) was added to N-{2-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (750 mg, 1 eq) in a mixture of triethylamine (401 μL, 1.5 eq) and N,N-dimethylformamide (DMF) (5 mL) and the resulting solution was stirred at ambient temperature. After 2 hours acetic anhydride (1 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a gradient of 0-10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide 278 mg of N-(2-ethoxymethyl-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-4-yl)acetamide as a white powder, mp 75-76° C. Anal. calcd for C20H27N5O4S.0.40H2O: C, 54.50; H, 6.36; N, 15.89. Found: C, 54.70; H, 6.10; N, 15.58.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].N1C=CC=CC=1.[C:23]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32](Cl)=[O:33])([CH3:26])([CH3:25])[CH3:24]>CCOCC.O.CCCCC>[C:23]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32]([O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5])=[O:33])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(c1ccccc1O)c1ccccc1O
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCCCC
Product: CC(C)(C)N=NC(C)(C#N)CCC(=O)Oc1ccccc1C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of 4.68 g. (0.0218 m) of 2,2'-dihydroxybenzophenone and 2.5 ml of pyridine in 30 ml of ether in a 4 neck 100 ml round bottom flask equipped with a thermometer, condenser and magnetic stirring bar was added 5.0 g. (0.0218 m) of 4-t-butylazo-4-cyanovaleryl chloride dropwise with cooling so the temperature did not rise above 25° C. After completion of the addition the reaction mixture was stirred 1/2 hour at room temperature and then diluted with 100 ml of water. The ether layer was separated, washed consecutively with 5% HCl, water, 10% NaHCO3 solution and saturated sodium chloride solution. The ether was evaporated off leaving a yellow solid. The solid was slurried in pentane, filtered and air dried. The product weighed 6.3 g. (71.2% yield) and decomposed slowly on heating above 80° C. The infrared spectrum of the product was in agreement with the structure of the desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([CH2:14]O)=[N:8][C:7]=2[N:6]([CH2:16][CH3:17])[C:4]1=[O:5])[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([CH2:14][Cl:20])=[N:8][C:7]=2[N:6]([CH2:16][CH3:17])[C:4]1=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCn1c(=O)c2[nH]c(CO)nc2n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(CCl)nc2n(CC)c1=O
Yield: 74.3 %

Procedure:
1 gram of 1,3-diethyl-8-hydroxymethylxanthine was added to an excess (3 grams) of thionyl chloride and the mixture was refluxed for 1 hour. The excess thionyl chloride was evaporated and the resulting residue was crystallized from hexane, to yield 1,3-diethyl-8-chloromethylxanthine (0.8 gram).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:16])=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]2.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]2
Reactant: COC(=O)c1cc(O)c2c(Cl)cccc2n1
Reactant: COC(=O)CBr
Product: COC(=O)COc1cc(C(=O)OC)nc2cccc(Cl)c12

Procedure:
The purified methyl 5-chloro-4-hydroxy-2-quinoline-carboxylate is alkylated with methyl bromoacetate as described in example 2 to produce methyl 5-chloro-4-methoxycarbonylmethyloxy-2-quinolinecarboxylate.
Reaction SMILES: C[O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.ClCC(O)=O.[O-:23][C:24]#[N:25].[Na+]>C1(C)C=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:24]([NH2:25])=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:3](=[O:2])[CH2:4][C:5]=2[CH:6]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 40 °C
Yield: 24.8 %

Procedure:
A mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 106 gms of monochloro-acetic acid and 73 gms of sodium cyanate were heated to 40° C. under stirring and maintained for 4 hours. After completion of the reaction (monitored by HPLC and/or TLC), the mixture was cooled to room temperature, filtered and washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid, and the mixture was heated to 75-80° C. and maintained for 2 hours under good agitation. It was then cooled to 0-5° C. and maintained for 2 hours, and the product oxcarbazepine was separated by filtration. This was then purified twice in toluene:methanol followed by methanol:dichloromethane solvent mixture to furnish 28 gms of pure oxcarbazepine.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[NH:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[NH:3]1
Reactant: CC1(C)NC(=O)c2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)NC(=O)c2c(N)cccc21
Reaction time: 16 h

Procedure:
67 mg (0.325 mmol) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The mixture is hydrogenated for 16 h at 4 bar H2 pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]1(OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:13][C:14](=[O:27])[CH:15]([CH2:25][CH3:26])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])(C)C)=[O:19])(C)(C)C>FC(F)(F)C(O)=O>[C:18]([NH:17][CH2:16][CH:15]([CH2:25][CH3:26])[C:14]([OH:13])=[O:27])([O:20][CH2:21][CH:24]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:6]2[C:1]1=[CH:2][CH:3]=[CH:4][CH:5]=2)=[O:19]
Reactant: CCC(CNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
Anisole (0.5 ml) and trifluoroacetic acid (10 ml) were added to N-t-butyloxycarbonyl-α-ethyl-β-alanine-t-butyl ester (0.98 g) and the mixture was stirred at room temperature for 12 hours. After trifluoroacetic acid was distilled off, the residue was dissolved in water (5 ml) and neutralized with a 10% aqueous solution of sodium carbonate. The product was protected with Fmoc by the same procedure as in Example 2-(3). A crystal of N-Fmoc-α-ethyl-β-alanine (437 mg, 36%) was obtained upon recrystallization from hexane.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:15][CH2:16][F:17].C(N(CC)C(C)C)(C)C>C(#N)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][F:17])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Yield: 98.5 %

Procedure:
Heat a mixture of 1-boc-piperazine (4.08 g, 21.9 mmol), 1-bromo-2-fluoroethane (16.68 g, 0.131 mol) and N,N-diisopropyl ethyl amine (17.0 g, 0.131 mol) in acetonitrile (40 mL) to 50° C. for 16 hours and then heat to reflux for 7 additional hours. Cool the reaction to room temperature and remove the solvent in vacuo. Treat the residue with 1 N NaOH (25 mL) and extract twice with ethyl acetate. Dry the organic layer with Na2SO4 and purify the crude product on silica with a 0 to 10% Methanol in CH2Cl2 gradient to afford 5.01 g (99%) of 4-(2-fluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (Rf 0.36 (9/1 CH2Cl2/Methanol, I2 stain).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C2CC2)cc1
Reaction time: 12 h
Yield: 92.3 %

Procedure:
To a solution of 4-cyclopropyl-phenol (1.00 g, 7.46 mmol) in acetone (20 mL) was added potassium iodide (2.47 g, 16.4 mmol), sodium carbonate (2.34 g, 16.4 mmol), and methyl bromoacetate (0.63 mL, 6.78 mmol), and the reaction mixture was stirred 12 hours. After filtering off the solid, the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: EtOAc=4:1) to afford the title compound as a yellow oil (1.29 g, 84%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCCC3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cc2c(cc1N1CCCC1)CNC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 0.12 mmol 5-chloro-6-pyrrolidin-1-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 1 ml dioxane was added 1.86 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 2 h. The reaction mixture was then concentrated in vacuo to yield the title compound as a brown solid which was used in the next step without further purification. MS (m/e): 325.2 ({37Cl}M+H+, 35%), 323.2 ({35Cl}M+H+, 100%).
Reaction SMILES: [C:1]1([C:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:15])O)=[CH:4][C:5](=[CH:7][CH:8]=1)O)[OH:2].C1C=CC=CC=1.C1(C)C=CC=CC=1>C1CCCCC1>[O:2]1[C:1]2[C:3](=[CH:4][CH:5]=[CH:7][CH:8]=2)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][OH:15]
Reactant: Oc1ccc(O)c(CCCCC(O)O)c1
Solvent: c1ccccc1
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: OCCC1CCc2ccccc2O1

Procedure:
The hydroquinonepentanediol compound (19) is refluxed in a nonpolar organic solvent (for example, benzene, toluene, or cyclohexane) in the presence of an alkyl or phenylsulfonic acid (for example, p-toluenesulfonic acid) to cause an intramolecular dehydrocondensation, and then cyclization, whereby the chroman ethanol compound (110) is obtained while retaining the chirality. Accordingly, the configuration of the chiral central carbon atom stemming from the starting mevalonolactone (12) is introduced into the 2-position of the chroman ring. The purification is carried out by silica gel column chromatography.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:44]3[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H40N6O3Cl2 [(M+H)+] 651.2612, observed 651.2615.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C@H:7]([O:30][C@H:31]2[C@H:36]([O:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:35]([CH2:46][O:47][C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:34][C@H:33]([O:56][C@H:57]3[C@@H:70]([O:71][CH2:72][C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C@H:69]([O:79][CH2:80][C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=4)[C@@H:68]([CH2:87][O:88][CH2:89][C:90]4[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=4)[O:67][C@@H:58]3[O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:32]2[O:96][C:97](=[O:104])[C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C@H:6]1[O:105][C:106](=[O:113])[C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)C=C>CO.ClCCCl.Cl[Pd]Cl>[C:106]([O:105][C@H:6]1[C@@H:5]([OH:4])[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][C@@H:7]1[O:30][C@H:31]1[C@H:36]([O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@@H:35]([CH2:46][O:47][C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:34][C@H:33]([O:56][C@H:57]2[C@@H:70]([O:71][CH2:72][C:73]3[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=3)[C@H:69]([O:79][CH2:80][C:81]3[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=3)[C@@H:68]([CH2:87][O:88][CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[O:67][C@@H:58]2[O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C@H:32]1[O:96][C:97](=[O:104])[C:98]1[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=1)(=[O:113])[C:107]1[CH:108]=[CH:109][CH:110]=[CH:111][CH:112]=1
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@@H]3[C@@H](OCc4ccccc4)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@@H]3[C@@H](OCc4ccccc4)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 88.3 %

Procedure:
PdCl2 (40 mg) was added to a solution of the allyl ether (26) (394 mg, 241 μmol) in MeOH (10 mL) and 1,2-DCE (10 mL) and the combined mixture was heated (70°, 60 min). After the time, the solvents were evaporated and the residue subjected to FC (20-30% EtOAc/hexanes) to yield the alcohol (27) as a colourless oil (317 mg, 84%). 1H NMR (CDCl3) δ 3.67-3.82, 3.91-3.99, 4.01-4.21, 4.29-4.71 (4 m, 21H; H-2I,-3I,-4I,-5I,-6aI,-6bI,-3II,-5II,-6aII,-6bII,-3III,-5III,-6aIII,-6bIIICH2Ph), 4.83 (d, 1H, JA,B 10.9 Hz; A of AB quartet), 5.03-5.05 (m, 2H; H-1I,-2II), 5.25-5.28 (m, 2H; H-1II,-1III), 5.63 (dd, 1H, J3,4=J4,5 9.9 Hz; H-4II), 5.77 (dd, 1H, J1,2 2.0, J2,3 3.1 Hz; H-2III), 5.92 (dd, 1H, J3,4 9.7, J4,5 9.9 Hz; H-4III), 6.99-7.62, 7.80-8.16 (2 m, 50H; Ar).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([F:21])[C:12]=2[F:22])=[N:8][C:7]=1[CH3:23])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:22][C:12]1[C:13]([F:21])=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=1[C:9]1[S:10][C:6]([CH2:4][OH:3])=[C:7]([CH3:23])[N:8]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)c(F)c2F)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO

Procedure:
In analogy to the procedure described for example 8 c], 2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester was reduced with lithium aluminum hydride to give [2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol as white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.O1CCCCC1[O:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40]>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:37]3/[C:38](=[O:39])[N:34]([OH:33])[C:35](=[O:40])[S:36]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: O=C1CSC(=O)N1OC1CCCCO1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1O

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-hydroxy-1,3-thiazolidine-2,4-dione was prepared from [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) and 3-(tetrahydropyran-2-yl)oxy-1,3-thiazolidine-2,4-dione (from Example 288) following General Procedure F.