Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:4]=1[C:5]([C:7]#[C:8][C:9]([O:11]C)=[O:10])=[O:6].[OH-].[K+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:4]=1[C:5]([C:7]#[C:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: COC(=O)C#CC(=O)c1cc(OC)ccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c(C(=O)C#CC(=O)O)c1
Reaction time: 1 h

Procedure:
A solution of 5 g (20 mmol) of methyl 3-(2,5-dimethoxybenzoyl)propiolate in 50 ml of tetrahydrofuran was treated slowly at 0° with 56 ml of 3% potassium hydroxide solution and stirred at 0° for a further 1 hour. The reaction mixture was treated with water and extracted once with ether. The ether phase was discarded. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid and extracted twice with ether. The combined organic phases were dried over sodium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded 3-(2,5-dimethoxybenzoyl)propiolic acid of melting point 91°-93°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:19]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH3:19])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1C

Procedure:
The preparation is carried out as in Example 1.1, from 8.0 g (35.8 mmol) of ethyl 6-chloro-1H-indole-2-carboxylate, from 1.8 g of 60% sodium hydride and from 2.8 ml of iodomethane.
Reaction SMILES: C(OC([NH:11][N:12]([C@@H:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:24][CH:25]=[CH2:26])[C:13](=[O:22])[C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1)=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH:27]1([C@H:23]([N:12]([C:13](=[O:22])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)[NH2:11])[CH2:24][CH2:25][CH3:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C=CC[C@H](C1CCCCC1)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC[C@H](C1CCCCC1)N(N)C(=O)c1cc(C)cc(C)c1
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
(R)—N′-(1-Cyclohexyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazine carboxylic acid benzyl ester (2.91 g, 6.7 mmoles) was suspended in ca. 50 mL glacial acetic acid. 102 mg 10% palladium on charcoal was added as a slurry in several mL of acetic acid. The mixture was diluted with acetic acid to 75 mL, and shaken on a Parr hydrogenator for 90 minutes at 20-30 psi. The suspension was allowed to stand for two days to allow the carbon to settle out. The supernatant was filtered through a 0.45 micron syringe filter into a recrystallizing dish and solvent was evaporated to leave 2.06 g (102% mass balance) of (R)-3,5-dimethyl-benzoic acid N-(1-cyclohexyl-butyl)-hydrazide as a reddish brown viscous oil. Rf=0.24 (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 7.05 (1H, s), 7.0 (2H, s), 4.55+3.35 (1H, 2t), 2.4 (6H, s), 0.8-1.9 (15H, m), 0.9 (3H, t); HRMS (ESI) m/z calcd for C19H31N2O [M+H]+ 303.2436. found 303.2441, calcd for C19H30N2NaO [M+Na]+ 325.2256. found 325.2262.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:20]3[C:21]([CH3:37])=[C:22]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=4)[C:23]([CH3:26])=[C:24]([CH3:25])[C:19]=3[O:18][C:17]2([CH3:39])[CH3:38])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].O.C(OCC)(=[O:43])C>C(O)C>[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:20]3[C:21]([CH3:37])=[C:22]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([S:35]([CH3:36])=[O:43])=[CH:33][CH:34]=4)[C:23]([CH3:26])=[C:24]([CH3:25])[C:19]=3[O:18][C:17]2([CH3:39])[CH3:38])=[CH:14][CH:15]=1)([CH3:9])[CH3:8]
Reactant: CSc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OCc1ccc(S(C)=O)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 79 %

Procedure:
Sodium periodate (0.766 g, 3.58 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-5-(4-methylthiobenzyloxy)-2,3-dihydrobenzofuran (1.50 g, 3.26 mmol) in a mixture of ethanol (80 mL) and water (8 mol), and the mixture was heated under reflux for 2 hours. To the reaction mixture were added ethyl acetate and water to separate it into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the title compound (1.23 g, yield 79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:12][C:10](=[O:11])[C:6](=[CH:7][O:8]C)[C:4](=[O:5])[O:3]1.Cl.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:3][C:4](=[O:5])[C:6](=[CH:7][OH:8])[C:10](=[O:11])[O:12]1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC1(C)OC(=O)C(=CO)C(=O)O1
Temperature: 25 °C

Procedure:
Next, this methoxy methylene Meldrum's acid (25 g, 0.13 mol) was dissolved in chloroform (200 ml), followed by adding 2N-HCl (50 ml), agitating the mixture at room temperature, allowing it to still standing, separating the chloroform layer, saturating the aqueous layer with sodium chloride, extracting the solution with chloroform, combining the extract solution with the previously obtained chloroform solution, drying over anhydrous magnesium sulfate, filtering off the drying agent, and distilling off chloroform under reduced pressure to obtain raw formyl Meldrum's acid as residue, adding ether thereto, filtering off, further washing with ether, vaporizing the remaining ether and recrystallizing the resulting crystals from a mixed solvent of dichloromethanehexane to obtain formyl Meldrum's acid in the form of colorless crystals (20.5 g, yield 89%) having a m.p. of 95°-96° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[Cl:24][C:25]1[CH:33]=[C:32]([CH:31]=[CH:30][C:26]=1[C:27]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:28])[C:34]#[N:35]
Reactant: N#Cc1ccc(C(=O)Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (7.32 g) and diisopropylethylamine (13.6 ml) in dichloromethane (35 ml) was added under nitrogen the cloudy solution of 2-chloro-4-cyanobenzoyl chloride. After one hour at room temperature, the mixture was diluted with dichloromethane and washed sequentially with water, 5% sodium bicarbonate, and 50% saturated brine, After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to afford a crude product (18.0 g). Purification by column chromatography on silica gel (250 g), eluting with 20% ethyl acetate/hexane, followed by 25% ethyl acetate/hexane, yielded the title compound (13.56 g) as a straw yellow foam, MS (EI), m/z: 347 (M)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].[Br:20][C:21]([Br:25])=[CH:22][CH2:23]Br>CN(C)C=O>[Br:20][C:21]([Br:25])=[CH:22][CH2:23][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: BrCC=C(Br)Br
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Br)Br)Cc1ccc(OC(F)(F)F)cc1
Yield: 43.9 %

Procedure:
Using 0.20 g of (4-(trifluoromethoxy)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 50 mg of sodium hydride (60% in oil), and 0.46 g of 1,1,3-tribromopropene, and according to the process described in the Production Example 1, there was obtained 0.16 g of 2-(3,3-dibromo-2-propenyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (29)).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:20])[NH:12][C@H:13]([CH2:18][OH:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[N:10]=2)[CH2:3]1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[Si:21]([O:19][CH2:18][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:20])[CH2:14][CH:15]([CH3:17])[CH3:16])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)C[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (820 mg, 2.74 mmol) (obtained as described in Reference Example 37(3)) in dimethylformamide (41 ml) were added t-butyldimethylsilyl chloride (495 mg, 3.29 mmol) and imidazole (224 mg, 3.29 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (731 mg, yield 65%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(OCC)(=O)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:1][C:2]2([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(S(=O)(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Yield: 54 %

Procedure:
8.1 g (20 mmol) of phenylmethyl 1-aminocyclohexanecarboxylate ·p-toluenesulfonate was added to 50 nm of water, and then 4.1 g (20 mmol) of 4-methoxybenzenesulfonylchloride and 50 ml of ethyl acetate was added to the mixture with stirring. After stirring at room temperature, the reaction mixture was put into a separatory funnel and water layer was removed therefrom. Subsequently, organic layer was washed with successive, 10% potassium hydrogensulfate solution, and saturated brine, and then, was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystal was stirred overnight in ether, whereby 4.36 g of phenylmethyl 1-[N-(4-methoxybenzenesulfonyl)amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:11]3[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][C:3]=2[O:2]1>CCO.[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of ethyl (RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.00 g, 2.60 mmol) in EtOH (25 ml) was added 10% palladium on activated carbon (30 mg). The resulting suspension was stirred under an atmosphere of H2 overnight. Thin layer chromatographic analysis indicated that the reaction was incomplete, so additional 10% palladium on activated carbon (30 mg) was added, and the mixture was shaken on a Parr hydrogenator at 30 psi H2 for 2 d. At this time, thin layer chromatographic analysis again indicated that the reaction was incomplete. The reaction mixture was filtered through a pad of Celite, and 10% palladium on activated carbon (250 mg) was added. The reaction mixture was shaken on a Parr hydrogenator at 60 psi H2 overnight. Filtration and repetition of the latter hydrogenation conditions led to complete consumption of starting material. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (650 mg, 65%), which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][NH:14][CH2:13][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:15]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: c1ccc(-c2cccc3c2CNCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C

Procedure:
A solution of 4.2 parts of 8-phenyl-1,2,3,4-tetrahydroisoquinoline and 4 parts of triethylamine in 90 parts by volume of methylene chloride is cooled in an ice bath with stirring and 1.7 part of acetyl chloride in 10 parts by volume of methylene chloride is added slowly. The mixture is allowed to warm to ambient temperature and stirred for about 2 hours. The reaction solution is washed four times with 20 parts by volume portions of water and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to afford 2-acetyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[N:17]=[C:18]=[S:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[C:11]=1[NH:17][C:18](=[S:19])[N:3]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:1][CH3:2]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: CCNCCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCC(=O)O)C(=S)Nc1c(C)cccc1C
Yield: 39.3 %

Procedure:
A mixture of 3-ethylaminopropionic acid (19.8 g), 2,6-dimethylphenyl-isothiocyanate (16.3 g), triethylamine (20 g) and methylene chloride (200 mL) was heated at reflux for 3 hours. The cooled reaction mixture was extracted with 1N NaOH (150 mL). The aqueous layer was separated and acidified with 2N HCl. The solid formed was collected by filtration. Recrystallization from ethanol afforded the title compound (11 g) as a white solid, m.p. 115°-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21].C[O-].[Na+].C(O)(C)C>O>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=2)[N:1]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[N:21]=1
Reactant: N#Cc1ccccn1
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc2nc(-c3ccccn3)nc(N)c2cc1OC

Procedure:
8.9 g. (0.05 mol) of 6-aminoveratronitrile, 5.2 g. (0.05 mol) of 2-pyridine carbonitrile and 5.4 g. (0.1 mol) of sodium methoxide in 250 ml. of isopropanol are refluxed for 48 hours under a nitrogen atmosphere. The reaction mixture is then decomposed with water and the isopropanol is distilled off. 80 ml. of diethyl ether and 80 ml. of water are added and the layers are separated. The water is distilled off from the aqueous layer and the residue is dissolved in 100 ml. of chloroform. The solution is filtered and the chloroform is distilled off. The residue is crystallized from toluene to give 4-amino-6,7-dimethoxy-2-(2-pyridyl)quinazoline, m.p. 248° - 251°C. The base is converted into the monohydrochloride, and the salt after crystallization from a mixture of water and isopropanol, melts above 310°C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:8][CH2:9]Cl)[CH2:5][CH2:6]Cl.[CH3:11][O:12][CH2:13][CH2:14][OH:15]>>[CH2:3]([N:4]([CH2:8][CH2:9][O:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:5][CH2:6][O:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:2][O:15][CH2:14][CH2:13][O:12][CH3:11]
Reactant: ClCCN(CCCl)CCCl
Reactant: COCCO
Product: COCCOCCN(CCOCCOC)CCOCCOC

Procedure:
To the aforesaid reaction mixture (i), 51.6 g tris(2-chloroethyl)amine chlorhydrate (0.215 moles) were added. The mixture was then heated with reflux of 2-methoxyethanol (125° C.) for 12 hours, followed by the distillation of the solvent under reduced pressure. The excess sodium 2-methoxyethanolate was then neutralized by addition of 11.6 cm3 aqueous HCl (10 N). The sodium chloride was filtered off and the solution distilled.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C.C(O)(=O)C>CO>[O:8]([CH:9]([C:22]1[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(C(=O)O)o1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole-5-carboxylic acid (281 mg, 6.673 mmol) was dissolved in a mixture of MeOH:toluene (4 mL: 10 mL), cooled to 0° C. and TMSCHN2 (2 M in hexanes, 3 equiv) was added dropwise under Ar. The reaction mixture was stirred at room temperature for 0.5 h before it was cooled to 0° C. and acetic acid was added dropwise until the solution turned from yellow to clear. The mixture was evaporated in vacuo and the resulting solid was dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude ester which was purified by flash chromatography (10-30% EtOAc/hexanes) to afford the pure ester as a clear oil (225 mg, 78%): 1H NMR (CDCl3, 500 MHz) δ 7.78 (s, 1H), 7.36-7.33 (m, 2H), 725-7.23 (m, 3H), 4.92 (t, 1H, J=7.0 Hz), 3.98 (s, 3H), 2.67 (t, 2H, J=7.5 Hz), 2.12-1.94 (m, 2H), 1.72-1.67 (m, 2H), 1.53-1.43 (m, 6H), 0.98 (s, 9H), 0.17 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 169.0, 158.5, 143.1, 142.6, 134.5, 128.8, 128.6, 126.0, 69.1, 52.5, 36.7, 36.3, 31.8, 29.5, 26.1, 26.1, 25.4, 18.6, −4.6, −4.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH:9](O)([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)O
Reactant: Oc1cncc(Br)c1
Product: CC(C)Oc1cncc(Br)c1

Procedure:
The title compound was synthesized in a similar manner as described for Stage 29.1.1 using 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland) and isopropanol (Merck, Dietikon, Switzerland) to give the title compound as a colorless oil. (HPLC: tR 2.92 min (Method A); M+H=216, 218 MS-ES).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[CH2:14](Cl)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: ClCC=Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OC/C=C/c2ccccc2)c(C)c(C)c1NC=O
Yield: 44 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and cinnamyl chloride, the title compound was synthesized according to Reference Example 17b. Yield: 44%. Melting point: 197-199° C. (Ethyl acetate-hexane)
Reaction SMILES: [CH3:1][N:2]1[N:11]=[N:10][C:9]2[N:5]([CH:6]=[N:7][C:8]=2[C:12]([NH2:14])=O)[C:3]1=[O:4].C1C=CC(OC2C=CC(P3(SP(C4C=CC(OC5C=CC=CC=5)=CC=4)(=S)S3)=[S:29])=CC=2)=CC=1>C(Cl)Cl>[CH3:1][N:2]1[C:3](=[O:4])[N:5]2[CH:6]=[N:7][C:8]([C:12](=[S:29])[NH2:14])=[C:9]2[N:10]=[N:11]1
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Solvent: ClCCl
Product: Cn1nnc2c(C(N)=S)ncn2c1=O

Procedure:
A mixture of temozolomide (3 g, 15.5 mmol) and Belleau's reagent (4.49 g, 8.5 mmol) was refluxed in DCM (80 mL) overnight. The reaction was quenched with water and the precipitate was filtered and washed with diethyl ether to give the pure title compound as an orange solid. (2.75 g, 84%). δH, (DMSO-d6): 9.92 (1H, s), 9.45 (1H, s), 8.81 (1H, s), 3.85 (3H, s).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC(=O)Cl
Reactant: CCC1CNC(c2cccc(C(F)(F)F)c2)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)N1CC(CC)OC1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Four and seven-tenths grams of 2-(m-trifluoromethylphenyl)-5-ethyl-1,3-oxazolidine was combined with 1.6 g of pyridine in 25 ml of methylene chloride and 2.0 g of butyroyl chloride was added dropwise. The mixture was allowed to stir overnight. The mixture was washed with 50 ml of 5% NaOH and 200 ml of water, dried and stripped on the rotary evaporator. Yield was 6.3 g, nD30 1.5015. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[N:14]=[C:13]([CH3:22])[C:12]=2[CH3:23])=[C:4]([O:24][CH3:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1>>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[C:5](=[C:4]([O:24][CH3:25])[CH:3]=[C:2]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1cc(Br)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12
Product: COc1cc(-c2cn[nH]c2)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12

Procedure:
Prepared according to procedure W using 4-(6-bromo-4-methoxy-1H-indol-1-yl)-6-chloro-2,3-dimethylquinoline (0.4 g, 0.962 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.3734 g, 1.92 mmol) to give 6-chloro-4-(4-methoxy-6-(1H-pyrazol-4-yl)-1H-indol-1-yl)-2,3-dimethylquinoline as a white solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (2H, d, J=9.0 Hz), 7.81 (1H, s), 7.73 (1H, dd, J=8.9, 2.3 Hz), 7.39 (1H, d, J=3.2 Hz), 6.90-6.94 (2H, m), 6.80 (1H, dd, J=3.2, 0.5 Hz), 6.63 (1H, s), 4.00-4.06 (4H, m), 2.77 (3H, s), 2.06 (3H, s); Mass Spectrum (ESI) m/e=403.0 (M+1).