Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:2]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:3][C:4]1[CH:11]=[CH:10][CH:8]=[CH:6][CH:5]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
1 g of caffeic acid was dissolved in 20 mL of ethanol and 2 mL water. 0.5 g of sodium bicarbonate was added while stirring. Stirring continued for 3 hr. Solvent and water were distilled off under vacuum. The residual solid was dissolved in 25 mL dimethylformamide and heated to 150° C. To this hot reaction mixture 0.8 mL of phenethyl bromide was added. The resulting reaction mixture was stirred for 40 hrs. Next, the reaction mixture was poured into 75 mL of cold water and extracted with ether (3×70 mL). The combined organic extract was washed with 50 mL of 5% HCl and water (60 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from toluene by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 304 mg and the purity was greater than 90%.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2>S(=O)(=O)(O)O>[Br:6][C:7]1[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2
Reactant: Brc1cccc2cnccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Potassium nitrate (1.17 g, 11.59 mmol) was added portion-wise to a solution of 5-bromo-isoquinoline (2.0 g, 9.66 mmol) in concentrated sulphuric acid (10 mL) and stirred at ambient temperature for 1 h. The reaction mixture was quenched with water and basified with aqueous ammonia. The aqueous layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 5-bromo-8-nitro-isoquinoline (2.0 g, 82%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:13]=[C:14]([C:15](OC)=[O:16])[C:7]=2[N:6]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:13]=[C:14]([CH2:15][OH:16])[C:7]=2[N:6]=1
Reactant: CCC(CC)c1ccc(C(=O)OC)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(CO)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 55 °C
Yield: 98.3 %

Procedure:
A mixture of methyl 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate (1.00 g, 2.30 mmol), lithium borohydride (100 mg, 4.60 mmol) and tetrahydrofuran (20 ml) was heated at 55° C. for 1 h. The reaction mixture was concentrated in vacuo. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 30% ethyl acetate/n-hexane to give 920 mg (2.26 mmol, 98%) of the title compound as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1.[CH2:16]([C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C@H:23]1[CH2:27][N:26]([C:13](=[O:15])[CH2:12][N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][O:3][CH3:2])[CH2:11][CH2:10]2)[C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCN1CCN(CC(=O)O)CC1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: COCCN1CCN(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 26.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-methoxyethyl)piperazin-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 100, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(4-(2-methoxyethyl)piperazin-1-yl)acetyl)pyrrolidine-2-carboxamide (10.6 mg, 26.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.28 (m, 2H), 7.22-7.13 (m, 5H), 6.99-6.92 (m, 4H), 4.45 (m, 1H), 3.73 (m, 1H), 3.39 (m, 2H), 3.23 (t, 1H), 3.20 (s, 2H), 3.13 (s, 2H), 3.07 (m, 1H), 2.63 (m, 2H), 2.48 (m, 8H), 2.43 (t, 2H), 2.09 (t, 1H), 1.91 (m, 2H). MS (EI) for C33H39FN4O4. found 575.7 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][C:12]([CH:14]([CH3:16])[CH3:15])=O>C(O)(=O)C.C(O)C>[CH3:11][C:12]1[C:14]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[N:9]=1
Reactant: CC(=O)C(C)C
Reactant: COc1ccc(NN)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2

Procedure:
A mixture of 0.18 mole of 4-methoxy-phenylhydrazine, 0.27 mole of methyl-isopropyl ketone, five drops of acetic acid and 300 ml of ethanol was refluxed for 3 hours and then the solvent was evaporated. The dark residue (28 g of hydrazone) was dissolved in 125 ml of ethanol. After adding 54 ml of a 15 % by weight solution of concentrated sulphuric acid in ethanol the mixture was refluxed for 2.5 hours. The white precipitate (ammonium sulphate was filtered and the filtrate was diluted with 750 ml of water, neutralized with a few ml of aqueous 5N NaOH and extracted with ether. The dried extract was distilled in vacuo.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Cl:8][SiH:9]([Cl:11])[Cl:10]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][Si:9]([Cl:11])([Cl:10])[Cl:8]
Reactant: FC(F)(F)CCCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: FC(F)(F)CC[Si](Cl)(Cl)Cl
Yield: 79.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.68 mmol) of tetrabutylphosphonium chloride, 0.89 g (6.72 mmol) of 1-chloro-3,3,3-trifluoropropane, and 2.71 g (20.0 mmol) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 1.24 g of (3,3,3-trifluoropropyl)trichlorosilane (yield; 80%).
Reaction SMILES: [NH2:1][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]=[C:8]([Cl:12])[CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.Cl>>[Cl:12][C:8]1[CH:7]=[C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])[CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1C(=O)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Product: O=C(c1cccc(Cl)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 125 °C
Yield: 29.9 %

Procedure:
To a stirred melt of 10.0 g (0.043 mole) of 2-amino-3'-chlorobenzophenone under an atmosphere of nitrogen gas was added at 115°-120° C. in two portions at 20 min intervals, 6.3 g (0.040 mole) of 2-chloro-3-nitropyridine. The reaction mixture was heated at 125° C. for 4 hr and then poured into 250 ml of hot 3N hydrochloric acid under vigorous agitation. The mixture was cooled, the aqueous portion decanted and the residue was dissolved in 150 ml of methylene chloride. The methylene chloride solution was washed in sequence five times with 30 ml portions of 3N hydrochloric acid, once with 30 ml of 5% aqueous sodium hydroxide, once with 30 ml of saturated aqueous sodium chloride solution. The washed methylene chloride solution was dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropyl ether, yielding 4.23 g (28%) of dark yellow solid, m.p. 124°-125° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH:12]=2)=[CH:5][C:4]([NH2:14])=[N:3]1>[Pd].C(O)C>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[CH:5][C:4]([NH2:14])=[N:3]1
Reactant: CN1CC=C(c2cc(N)nn2C)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(c2cc(N)nn2C)CC1
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a mixture of 1-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-3-amine (574 mg) and ethanol (10 mL) was added 10% palladium-supported carbon (50% wet product) (318 mg), followed by stirring for 5 hours under a hydrogen gas atmosphere (4 atm). The reaction mixture was filtered through celite and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type, eluent; chloroform:methanol=100:0-95:5), and the obtained solid was washed with diisopropyl ether:ethyl acetate (10:1) to obtain 1-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrazol-3-amine (367 mg) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([O-])=O.[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24].O>C1COCC1>[SH:24][C:23]1[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(S)nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
In a test tube equipped with a septum, tert-butyl (2-nitro-4-trifluoromethyl-phenylamino)-acetate (Starting material 5-VIII, 80 mg, 0.25 mmol) is dissolved in dry THF (0.5 ml). Argon is allowed to bubble through this solution for 10 min. Then dry palladium on carbon (10% w/w, 26 mg, 10% mol) is added and the flask is set under H2 atmosphere. The resulting mixture is shaken vigorously at rt overnight. If necessary, another 8% mol of palladium on charcoal 10% w/w is added and the resulting suspension is stirred for another hour under H2 atmosphere. The crude mixture is then filtered over celite to remove any solid particle. The celite is rinsed once with dry THF. To the resulting light yellow solution is added, under argon, 1,1′-thiocarbonyldiimidazole (89 mg, 0.5 mmol, 2 eq.). The resulting orange solution is allowed to stir at rt for 5 h. Water is then added. The yellow solid formed is filtered over a fritted funnel, rinsed thoroughly with water and dried under high vacuum. This yields the title compound (60 mg) in 73% as a yellow solid: tR=1.10 min (LC-3), ESI-MS (pos.): m/z 332.99 [M+H]+, 331.13 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.41 (s, 9H, tBu), 5.06 (s, 2H, NHCH2CO2), 7.44 (s, 1H, Harom), 7.57 (s, 2H, Harom), 13.25 (br. s, 1H, SH).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:3][CH2:2]1.[Li+].[OH-].CO>O>[CH:1]1([C:4]#[C:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#CC2CC2)c(OCC2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C#CC2CC2)c(OCC2CC2)c1
Yield: 104 %

Procedure:
Ethyl 4-(2-cyclopropylethynyl)-3-(cyclopropylmethoxy)benzoate (0.47 g, 1.65 mmol) and LiOH (120 mg, 4.96 mmol) were placed in a 3:1 mixture of methanol:water (50 mL) and heated at 60° C. for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20 mL, then placed in an ice-water bath and acidified to pH 5 with conc. HCl. A white solid precipitated which was filtered and washed thoroughly with water. The solid was dried in the vacuum oven to give the product (0.44 g, 98%). m/z=257.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[CH3:37][NH:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][C:29]1([CH3:33])[O:28][C:27]2[CH:34]=[CH:35][C:24]([C@H:22]3[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]4[CH:3]=[C:2](/[CH:43]=[CH:42]/[S:39]([NH:38][CH3:37])(=[O:41])=[O:40])[CH:7]=[CH:6][CH:5]=4)[CH2:23]3)=[CH:25][C:26]=2[CH2:31][O:30]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(Br)c4)C(=O)O3)ccc2O1
Reactant: C=CS(=O)(=O)NC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)/C=C/c1cccc(CCCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Yield: 20.5 %

Procedure:
A stirred mixture (5R)-3-{6-[4-(3-bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.0 g), N-methylethenesulphonamide (WO 95/09166), (462 mg), tri-o-tolylphosphine (200 mg), palladium acetate (165 mg) and triethylamine (5 ml) in dry DMF (15 ml) was heated at 90° C. for 18 h. The mixture was cooled and filtered. The filtrate was poured into water (200 ml) and extracted into ethyl acetate (3×50 ml). The combined extracts were washed with water (100 ml) and (Na2SO4) and evaporated in vacuo. The residual oil was purified by chromatography on Biotage (40 g) eluting with diethyl ether-ethyl acetate (9:1) to give the title compound (220 mg). LCMS RT=3.70 min.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3][CH2:2]1.[C:9]([Si:13]([CH3:16])([CH3:15])Cl)([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[C:9]([Si:13]([CH3:16])([CH3:15])[O:7][C@@H:4]1[CH2:5][CH2:6][C@H:1]([OH:8])[CH2:2][CH2:3]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1CC[C@@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)CC1

Procedure:
In a manner similar to the method described in example 94a, cis-1,4-cyclohexanediol (3.8 g, 33 mmol) was reacted with tert-butyldimethylchlorosilane (5 g, 34 mmol) and imidazole in N,N-dimethylformamide to give cis-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol as a colorless oil (2.4 g, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:24]([N:23]([CH3:22])[C:8]([C:5]1[C:4]([C:11]#[N:12])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:27])([CH3:26])[CH3:25]
Reactant: CNC(C)(C)C
Reactant: N#Cc1cc(Br)cnc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ncc(Br)cc1C#N)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
To a solution of 5-bromo-3-cyano-pyridine-2-carboxylic acid (100 mg, 0.44 mmol) in dichloromethane (5 ml) at 0° C. were added DIPEA (0.226 ml, 1.32 mmol, 3 equiv.), methyl tert-butyl amine (0.079 ml, 0.661 mmol, 1.5 equiv.) and HBTU (250 mg, 0.661 mmol, 1.5 equiv.). The reaction mixture was stirred at 25° C. for 14 hours. The solvent was removed in vacuum and the resulting crude material was purified by column chromatography over normal silica gel (10-20% EtOAc in hexane) to afford 5-bromo-3-cyano-pyridine-2-carboxylic acid tert-butyl-methyl-amide (85 mg, 65%) as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C@H:15]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH3:16])=[CH:10][C:9]=1[CH3:33])[CH3:6])[CH3:2].C(OC(=O)C(C)(OC1C=CC(O[C@@H](C2SC(C3C=CC(C(F)(F)[F:64])=CC=3)=NC=2C)C)=CC=1C)C)C>>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:6])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[C:26]([F:64])[CH:27]=3)=[N:19][C:18]=2[CH3:32])[CH3:16])=[CH:10][C:9]=1[CH3:33])[CH3:34])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O[C@@H](C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O[C@H](C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C

Procedure:
(S)-2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]ethoxy}-phenoxy)-propionic acid ethyl ester p1 (R)-2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]ethoxy}-phenoxy)-propionic acid ethyl ester
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Clc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c(Cl)cccc32)nc(N2CCOCC2)cc1=O
Yield: 21.6 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 4-chloroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 84 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a slightly pinkish powder, the characteristics of which are the following:
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:10]=[CH:9][C:8]=1[OH:21])=CC>C(O)(=O)C.C(OCC)(=O)C>[OH:21][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][C:7]=1[CH:4]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC=Cc1cc(Oc2ccccc2Cl)ccc1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1cc(Oc2ccccc2Cl)ccc1O

Procedure:
Ozone gas was introduced into a solution of 2-(1-propenyl)-4-(2-chlorophenoxy)phenol (14.5 g) in a mixture of acetic acid (10 ml) and ethyl acetate (150 ml) with stirring at 2°-7° C. for an hour. After removing of the excess of ozone gas and addition of aqueous solution of sodium dithionite, the organic layer was separated, washed with saturated aqueous sodium bicarbonate and water, dried and evaporated. The residue was purified by column chromatography (silical gel, benzene) to give oily 2-hydroxy-5-(2-chlorophenoxy)benzaldehyde (10.4 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH3:21])[CH:13]=1)[OH:11].[Mn]([O-])(=O)(=O)=O.[Ba+2].[Mn]([O-])(=O)(=O)=O>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH3:21])[CH:13]=1)=[O:11]
Reactant: CCCOc1cccc(C(O)c2nc3ccccc3s2)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Ba+2]
Solvent: CC#N
Product: CCCOc1cccc(C(=O)c2nc3ccccc3s2)c1

Procedure:
A mixture benzothiazol-2-yl(3-propoxyphenyl)methanol (1 g) and barium permanganate (0.95 g) in acetonitrile 15 mL) is refluxed for 30 minutes. The mixture is filtered over a clarcel pad, concentrated under reduced pressure and purified by column chromatography over silica gel (eluant heptane/ethyl acetate: 4/1) to give benzothiazol-2-yl(3-propoxyphenyl)methanone as a white cristalline solid.
Reaction SMILES: CN1CCOCC1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[I:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(#N)C>[CH2:8]([NH:11][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[I:12])[CH:9]=[CH2:10]
Reactant: C=CCN
Reactant: O=C(Cl)c1ccccc1I
Solvent: CC#N
Solvent: CN1CCOCC1
Product: C=CCNC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
470 ml (4.28 mol) of N-methylmorpholine, followed by 224 ml (2.98 mol) of allylamine are added under ice cooling to 750 g (2.81 mol) of 2-iodo-benzoic acid chloride in 7.5 l of acetonitrile, and stirred for 60 min at RT. The precipitate is filtered off and the filtrate concentrated by evaporation on a RE. The residue of evaporation is dissolved in 4 l of EtOAc and 4 l of water, the water phase is separated and extracted twice with EtOAc. The organic phases are washed with water, 0.1 N HCl, water, sat. Na2CO3, water and brine, dried (Na2SO4) and concentrated by evaporation. Stirring of the residue in 2.5 l of hexane and filtering yields 2-iodo-benzoic acid allylamide; m.p. 105-106° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)[OH:5].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>>[Br:13][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1cc(Br)cc(C(O)CCN)c1
Product: Cc1cc(Br)cc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Treatment of 3-amino-1-(3-bromo-5-methylphenyl)propan-1-ol with ethyl trifluoroacetate following the method used in Example 79 gave N-(3-(3-bromo-5-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a light colored oil. Yield (0.38 g, 22%, 3 steps): 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.26 (s, 1H), 7.05-7.07 (m, 1H), 4.80 (dd, J=8.8, 4.0 Hz, 1H), 3.62-3.75 (m, 1H), 3.36-3.44 (m, 1H), 2.33 (s, 3H), 1.90-2.0 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[C:13]([OH:14])[C:11]([OH:12])=[C:9]([OH:10])[CH:8]=1.[CH3:18]O>>[C:6]([O:17][CH3:18])(=[O:16])[C:7]1[CH:15]=[C:13]([OH:14])[C:11]([OH:12])=[C:9]([OH:10])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(O)c(O)c1
Temperature: 10 °C
Reaction time: 7 h
Yield: 82 %

Procedure:
Twenty 20 ml of concentrated sulfuric acid was added dropwise to a solution of 200 g of gallic acid in 600 ml of methanol at room temperature with stirring for 6-8 hours. After approximately 2/3 of the methanol was removed, the residue was cooled to 10° C., poured into 1.2 kg of water and allowed to stand overnight. The white precipitate which formed was filtered and washed with water to give 178 g of product methyl gallate, m.p. 200°-204° C. (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[C:13]=1[Cl:19]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Clc1cccc(I)c1Cl
Product: Clc1ccc2ccn(-c3cccc(Cl)c3Cl)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1,2-dichloro-3-iodobenzene: ESMS m/e: 296.5 (M+H)+.