Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=2[CH:15]([CH3:17])[CH3:16])[S:4]1(=[O:6])=[O:5].[CH3:20][O:21][C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([O:31][CH3:32])=[C:24]([OH:33])[C:23]=1[C:34](=[O:36])[CH3:35].CN1NCCCCCCC(C2CCCCCCCCC=2)=N1.Cl>C(#N)C>[CH3:20][O:21][C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([O:31][CH3:32])=[C:24]([O:33][CH2:2][N:3]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=3[CH:15]([CH3:17])[CH3:16])[S:4]2(=[O:6])=[O:5])[C:23]=1[C:34](=[O:36])[CH3:35]
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: CN1N=C(C2=CCCCCCCCC2)CCCCCCN1
Agent: Cl
Solvent: CC#N
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1c(C(C)=O)c(OC)c3ccoc3c1OC)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
2-Chloromethyl-4-isopropyl-6-methoxysaccharin (0.5 g) was added with stirring at room temperature to a solution of 4,7-dimethoxy-5-acetyl-6-hydroxybenzofuran (0.39 g) and methyltriazabicyclodecene (0.28 g) in acetonitrile (20 mL). The mixture was stirred overnight at room temperature. Since thin layer chromatography showed unreacted 4,7-dimethoxy-5-acetyl-6-hydroxybenzofuran, more 2-chloromethyl-4-isopropyl-6-methoxysaccharin and a drop of base were added, stirring was continued for a total of 24 hours, and the reaction mixture was poured into ice-water containing hydrochloric acid. The resulting golden solid was partially purified using dichloromethane as eluant The reaction was repeated with stirring overnight at 35°-40° C. instead of room temperature. The product and the partially purified product of the first reaction were combined and purified by column chromatography on silica gel affording 2-(4,7-dimethoxy-5-acetylbenzofuran-6-yl)oxymethyl-4-isopropyl-6-methoxysaccharin (0.4 g, 24% yield).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O1CCCC1>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]([C:27](=[O:32])[C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]=2)[C:4]([OH:33])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)c1ccc(OC)c(N(CC(C)C)C(=O)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)O)cc1N(CC(C)C)C(=O)C(C)(C)C

Procedure:
Thus obtained 3-(4-bromophenyl)-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl} propionic acid ethyl ester (104 mg, 0.2 mmol) was dissolved in a mixed solvent of methanol (3 mL) and tetrahydrofuran (3 mL), and the mixture was added with a 2 mol/L aqueous sodium hydroxide solution (3 mL, 6 mmol). The solution was evaporated under reduced pressure so as to remove the solvent, the resultant residue was added with water to be dissolved, and the solution was washed with diethyl ether. The separated aqueous phase was added with a 1 mol/L hydrochloric acid so as to adjust pH of the solution as low as 4 or below. The solution was then extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, to thereby obtain 3-(4-bromophenyl)-2-{3-[(2,2-dimethylpropionyl)isobutyl amino]-4-methoxyphenyl}propionic acid (yield: 89 mg, yield ratio: 90%) as a white solid.
Reaction SMILES: CN.[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][C:14](=O)[CH3:15].[C:17]([BH3-])#[N:18].[Na+].[ClH:21].CN.Cl>CO.CCOCC>[ClH:21].[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][CH:14]([CH3:15])[NH:18][CH3:17]
Reactant: [BH3-]C#N
Reactant: COc1ccc(I)c(CCC(C)=O)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CNC(C)CCc1cc(OC)ccc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A solution of 19.41 g (0.625 mole) of methylamine in 400 ml of anhydrous methanol was treated with 37.92 g (0.125 mole) of 4-(2-iodo-5-methoxyphenyl)-2-butanone, 6.28 g (0.1 mole) of sodium cyanoborohydride and 21.07 g (0.312 mole) of methylamine hydrochloride and allowed to stir at room temperature under an atmosphere of nitrogen for 21/2 hours. The resulting mixture was cooled in an ice bath and treated with concentrated hydrochloric acid to pH 1. The solvent was evaporated in vacuo and the residue partitioned between 1.5 l of water and 600 ml of ether. The water layer was separated and treated with 50% sodium hydroxide solution until basic. The resulting crude product was extracted into 500 ml of ether, washed with brine, and the brine layer extracted with an additional 400 ml portion of ether. The combined ether layers were dried over anhydrous potassium carbonate and evaporated in vacuo to yield 31.09 g (78%) of crude oil. The oil was dissolved in methanol and treated with ethereal hydrogen chloride until neutral. Ether was added to the mixture and the resulting hydrochloride salt separated by filtration to give 19.75 g (44%) of crude product. One recrystallization from 2-propanol yielded pure 2-iodo-5-methy-N-alphadimethylbenzenepropanamine hydrochloride a white solid, mp 189°-190° C.
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)/[CH2:4][N:5](C=O)C=O.C(O)C.O.[ClH:23]>C1(C)C=CC=CC=1>[ClH:23].[NH2:5][CH2:4]/[C:3](=[CH:2]/[F:1])/[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: O=CN(C=O)C/C(=C/F)CCc1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine (E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide (8.0 g, 32.7 mmol), ethanol (19.9 g), water (29.8 g), and aqueous 12M hydrochloric acid solution (13.1 g). Heat to reflux. After 1 hour, add toluene (29.8 g). Cool to 25° C. Separate the layers. Distill the aqueous layer until the volume is reduced by about two thirds. Cool to 50° C. Add concentrated aqueous hydrochloric acid solution (50 g). Cool to -5° C., filter , rinse with toluene, and dry in vacuo at 60° C. to give a solid . Recrystallize the solid from isopropyl acetate, filter, and dry in vacuo at 43° C. to give the title compound: mp 130°-131.5° C. 1H NMR (D2O, 300 MHz) δ 2.50 (m, 2H), 2.79 (m, 2H), 3.47 (d, J=3.0 Hz, 2H), 6.80 (d, J=81.9 Hz, 1H), 7.09 (m, 2H), 7.28 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C(N(CC)CC)C.Cl[CH2:23][C:24](Cl)=[O:25].[H-].[Na+]>C1COCC1>[C:8]1([C:6]2[CH:5]=[CH:4][C:3]3[O:14][CH2:23][C:24](=[O:25])[NH:1][C:2]=3[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(-c2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COc2ccc(-c3ccccc3)cc2N1
Yield: 98.7 %

Procedure:
Using 2-amino-4-phenylphenol (1 g, 5.4 mmol), triethylamine (0.97 mL, 7.0 mmol) and chloroacetyl chloride (0.72 g, 5.9 mmol) in THF (35 mL) followed by sodium hydride (0.27 g of a 60% suspension in oil, 6 mmol) to yield the title compound as a pale yellow solid (1.2 g, 91%). δH (DMSO-d6) 4.62 (2H, s), 7.29-7.56 (8H, m), 10.81 (1H, s).
Reaction SMILES: O=[C:2]([CH3:24])[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:12][CH:11]=1)[C:4](OCC)=[O:5].C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CCO>[NH2:32][C:30]1[N:31]=[C:4]([OH:5])[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:12][CH:11]=2)=[C:2]([CH3:24])[N:29]=1
Reactant: CCOC(=O)C(Cc1ccc(COC2CCCCO2)cc1)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Cc1nc(N)nc(O)c1Cc1ccc(COC2CCCCO2)cc1

Procedure:
A mixture of the product from step (i) (15.66 g) and guanidine carbonate (8.7 g) in EtOH (150 ml) was heated under reflux for 48 h. The mixture was cooled, the solvent removed under reduced pressure and the residue triturated with water. The solid was filtered, washed with water then diethylether and dried to afford the subtitle compound, 11.58 g.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[NH:24][C:23](=[S:25])[NH:22][C:13]2=[N:14][C:15]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.I[CH3:27]>CN(C=O)C>[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[N:24]=[C:23]([S:25][CH3:27])[NH:22][C:13]2=[N:14][C:15]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CI
Reactant: Fc1cnccc1-c1cc2[nH]c(=S)[nH]c2nc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a suspension of sodium hydride 60% (0.098 g, 2.45 mmols) in DMF (5 mL) a suspension of 6-(3-fluoropyridin-4-yl)-5-pyridin-3-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione (0.6 g, 1.86 mmols) in DMF (15 mL) was added dropwise, at 0° C., under argon. The solution was allowed to stir for 30 minutes at 0° C. and then iodomethane (0.116 mL, 1.86 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 2.5 hours. The mixture was concentrated and purified by silica gel flash chromatography (150:40:5 dichloromethane/methanol/ammonia) to give the title compound (0.34 g, 54% of yield).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cnc(N)cn2)cc1C
Temperature: 110 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-bromopyrazin-2-amine (4 g, 22.99 mmol, 1.00 equiv) in 1,4-dioxane (68 mL) and methanol (23 mL) was added 3,4-dimethylphenylboronic acid (3.52 g, 23.47 mmol, 1.02 equiv), sodium carbonate (4.872 g, 45.96 mmol, 2.00 equiv) in water (23 mL), and Pd(PPh3)4 (532 mg, 0.46 mmol, 0.02 equiv) and the resulting solution was stirred for 4.5 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 200 mL of ethyl acetate, washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate=10:1˜1:1, then with dichloromethane/methanol (10:1˜5:1). The collected fractions were combined and concentrated under vacuum. This resulted in 4.82 g (crude) of 5-(3,4-dimethylphenyl)pyrazin-2-amine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]1([C:16]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][CH:2]1[CH2:7][NH:6][C:5]2=[N:8][C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=[C:4]2[CH2:3]1
Reactant: Cc1cnc(N)c(N)c1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Product: CC1CNc2nc(-c3ccccc3)c(-c3ccccc3)nc2C1

Procedure:
The title compound was prepared from 5-methyl-pyridine-2,3-diamine and benzil analogously to Intermediate E;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:19]2[CH:20]([CH3:24])[NH:21][CH2:22][CH2:23][C:18]=2[S:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:18]4[S:17][CH:16]=[C:15]([F:14])[C:19]=4[CH:20]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2scc(F)c21
Product: CC1c2c(F)csc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:9]Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]([O:19]CC)(=[O:18])[CH2:12][C:13](OCC)=O.C[O-].[Na+].C(O)C>CCOCC.CO.S(=O)(=O)(O)O>[CH3:2][CH:3]1[CH2:8][C:7]2[C:13](=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH:12]1[C:11]([OH:19])=[O:18]
Reactant: BrCc1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: CC1Cc2ccccc2C1C(=O)O
Temperature: 200 °C
Yield: 54.2 %

Procedure:
A solution of α,α′-dibromo-o-xylene (203.51 g, 0.77 mol) in 1.5 l of ether is added to a solution of diethyl malonate (127 g, 0.79 mol), sodium methoxide (314 ml, 1.70 mol), ethanol (100 ml) and ether (500 ml). The mixture is refluxed for 5 hours, then filtered, and finally concentrated. The residue is taken up in 500 ml of water. 173 g of potassium hydroxide are added, and the mixture is refluxed for 18 hours. The reaction medium is poured into a hydrochloric acid solution and the precipitate formed is filtered off by suction and then dried. The solid obtained is maintained at 200° C. for 20 minutes and the new solid obtained is recrystallised from 400 ml of heptane. The crystals obtained are taken up in 400 ml of methanol and, after 5 drops of concentrated sulfuric acid have been added, the mixture is refluxed for 4 hours and then concentrated. The residue is dissolved in 600 ml of ether. This ether phase is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over sodium sulfate and concentrated, giving 73.6 g (54%) of a clear oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]([CH2:23][CH2:24][CH3:25])[CH3:22]>>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:21]([CH2:23][CH2:24][CH3:25])[CH3:22])[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC(C)Br
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
95% NaH (2.15 g, 89.0 mmol) and 5-benzyloxyindole (7) (10.0 g, 44.8 mmol) were added to a schlenk vessel, and the system was evacuated and refilled with nitrogen three times before being cooled to −78° C. DMF (100 mL) was added and the vessel was then cooled with an ice/water bath and kept stirring for another 30 min. 2-Bromopentane (2) (10.2 g, 67.2 mmol) was added dropwise and the resulting mixture was warmed to room temperature slowly and kept stirring overnight. The solvent was removed in vacuo. Toluene (200 mL) was added and the mixture was washed with water (150 mL) and dried with Na2SO4. After solvent was removed in vacuo, the resulting oil was purified using silica column chromatography (1:1 chloroform/hexanes) to give 5-(benzyloxy)-1-(pentan-2-yl)-1H-indole (8) (3.90 g, 30%) as an oil. 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J=7.5, 2H), 7.41 (t, J=8.0 Hz, 2H), 7.35-7.20 (m, 2H), 7.18 (dd, J=8.0, 2.0, 2H), 6.97 (dd, J=9.0, 2.5, 1H), 6.41 (d, J=3.0, 1H), 5.13 (s, 2H), 4.46 (m, 1H), 1.87 (m, 2H), 1.55 (d, J=7.5, 3H), 1.26 (m, 2H), 0.90 (t, J=7.5, 3H). See also Luo, J.; Hart, H.; J. Org. Chem., 52(22): 4833 (1987).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]([CH2:13][C:14]([NH:16][C:17]1[C:22]([C:23](=[O:25])[NH2:24])=[C:21]([O:26][CH3:27])[C:20]([NH:28][C:29](=O)[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:19]([C:39](=[O:41])[NH2:40])[C:18]=1[O:42][CH3:43])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[O:31]([CH2:30][C:29]1[NH:40][C:39](=[O:41])[C:19]2[C:20]([N:28]=1)=[C:21]([O:26][CH3:27])[C:22]1[C:23](=[O:25])[NH:24][C:14]([CH2:13][O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:16][C:17]=1[C:18]=2[O:42][CH3:43])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1c(NC(=O)COc2ccccc2)c(C(N)=O)c(OC)c(NC(=O)COc2ccccc2)c1C(N)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1c2nc(COc3ccccc3)[nH]c(=O)c2c(OC)c2nc(COc3ccccc3)[nH]c(=O)c12
Temperature: 25 °C

Procedure:
To a solution consisting of 40 mL of acetic acid and 4 mL of concentrated sulfuric acid, was added 394 mg (0.753 mmol) of 10. The resulting mixture was refluxed for 4 hours. After allowing the mixture to cool to room temperature, the greyish colored precipitate was collected, washed with acetic acid, and then washed with water to afford pure 14 as a yellow solid: 260 mg (71%) yield; dec pt 290° C.; TLC (ethyl acetate/methanol [9:1]), Rf =0.56; IR (KBr pellet) 2967, 1687, 1630, 1599, 1497, 1463, 1427, 1239, 1206, 1066 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ7.32 (4H, t, J=7.4 Hz, aromatic, no assignments made), 7.08 (4H, d, J=7.8 Hz, aromatic, no assignments made), 6.98 (4H, t, J=7.4 Hz, aromatic, no assignments made), 5.02 (4H, s, methylenes), 3.81 (6H, s, methoxys); mass spectrum (EI mode), m/z 486 (P+). Anal. Calcd for C26H22N4O6 : C, 64.19; H, 4.56; N, 11.52. Found; C, 64.09; H, 4.52; N, 11.31.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]=[CH:14][C:13]=2[O:26][C:27]([F:30])([F:29])[F:28])=[CH:8][CH:7]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[C:22]([O:21][C:19]([NH:18][C:16]1[CH:15]=[CH:14][C:13]([O:26][C:27]([F:28])([F:29])[F:30])=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH:17]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)OC(C)(C)C)ccc2OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1

Procedure:
5′-tert-Butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid ethyl ester (200 mg) in ethanol (7 ml) and 2M sodium hydroxide (4 ml) was stirred at 20 C for 18 h. The ethanol was then evaporated and the residue acidified. The solid thus formed was collected by filtration and dried (128 mg)
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:14])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C=C.[CH:15]1[CH:20]=CC=C[CH:16]=1>>[CH3:14][CH:6]([CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:15]([CH3:20])=[CH2:16])[CH:5]=[O:4]
Reactant: C=CCOC/C(C)=C/c1ccccc1
Reactant: c1ccccc1
Product: C=C(C)C(c1ccccc1)C(C)C=O
Temperature: 25 °C
Yield: 80 %

Procedure:
The (1E)-[3-(allyloxy)-2-methyl-1-propenyl]benzene (107.79 g, 0.571 mol), [RuCl2(PPh3)3] (3.13 g), BHT (1 g) and benzene (500 ml) were heated together in an autoclave in an oil bath at 190° C. for 4 hours. After cooling to room temperature, solvents were evaporated and the residue was distilled trough a 20-cm Widmer column to give 85.9 g of the desired compound (0.457 mol, 80%) as a 3:1 mixture of diastereoisomers. B.P.=95° C./0.032 mbar
Reaction SMILES: [CH2:1]([CH:5]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][O:7][C:8]1[C:9]2[S:36][CH:35]=[CH:34][C:10]=2[C:11]2[CH:12]=[C:13]([O:21][CH2:22][CH:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:14]3[S:20][CH:19]=[CH:18][C:15]=3[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH3:4].C1COCC1.[Li+].CCC[CH2-].[CH3:53][Sn:54](Cl)([CH3:56])[CH3:55]>CCCCCC>[CH2:30]([CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][O:21][C:13]1[C:14]2[S:20][C:19]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:18][C:15]=2[C:16]2[CH:17]=[C:8]([O:7][CH2:6][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:9]3[S:36][C:35]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:34][C:10]=3[C:11]=2[CH:12]=1)[CH2:31][CH2:32][CH3:33]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCC(CCCC)COc1cc2c3ccsc3c(OCC(CCCC)CCCCCC)cc2c2ccsc12
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC(CCCC)COc1cc2c3cc([Sn](C)(C)C)sc3c(OCC(CCCC)CCCCCC)cc2c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
5,10-Bis-(2-butyl-octyloxy)-1,6-dithia-dicyclopenta[a,f]naphthalene (1.41 g, 2.3 mmol) was added into a 200 mL flask. The system was vacuumed and backfilled with argon 3 times before 60 mL of anhydrous THF was injected. N-Butyllithium (2.2 mL, 2.5 M in hexane, 5.09 mmol) was added after the mixture was cooled to −78° C. A white precipitate was observed after the mixture was stirred at −78° C. for 30 minutes. Stirring was continued at room temperature for one more hour before the mixture was cooled down to −78° C. again. Trimethyltin chloride (1.20 g, 5.75 mmol) was added in portions and stirring was continued overnight at room temperature. Hexane (100 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 100 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of solvent under vacuum yielded a white solid. The colorless crystalline product, 5,10-bis-(2-butyl-octyloxy)-2,7-bis-trimethylstannanyl-1,6-dithia-dicyclopenta[a,f]naphthalene, (1.70 g, ˜79% yield) was obtained after recrystallization from a hexane/iso-propanol mixture. 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 2H), δ 7.69 (s , 2H), δ 4.25 (d , 4H, J=5.5 Hz), δ 1.99 (m , 2H), δ 1.33 (m , 32H), δ 0.96 (t , 6H, J=7.0 Hz), δ 0.90 (t, 6H, J=7.0 Hz), δ 0.51 (m , 18H).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10]COC)=[N:7][CH:8]=1.Cl>C(O)C>[F:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1
Reactant: COCOCc1ccc(CF)cn1
Agent: Cl
Solvent: CCO
Product: OCc1ccc(CF)cn1
Temperature: 0 °C
Reaction time: 12 h
Yield: 87.5 %

Procedure:
0.45 g of compound (4) dissolved in ethanol is added dropwise to a solution of hydrochloric acid (4.2N) in ethanol (5.5 ml) cooled to 0° C. at the end of the addition, the temperature of the mixture is returned to room temperature and stirring is continued for 12 hours. The reaction mixture is concentrated under vacuum and the residue obtained is washed with isopropyl ether. The ether phase is removed and the residue is taken up in a CH2Cl2/methanol solution (75/25) and then stirred over Na2CO3 (1.2 g). The mixture is filtered and the filtrate evaporated to give a colorless oil (0.3 g), which is used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8](O[C@H](C2C=CC=CC=2)C)=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[CH3:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:42][CH:43]=1>>[CH3:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([NH:47][C:34]([C:31]2([C:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:23]=[CH:24][C:19]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[C:6]=5[NH:7][C:8]([NH:47][S:44]([C:41]5[CH:42]=[CH:43][C:38]([CH3:37])=[CH:39][CH:40]=5)(=[O:45])=[O:46])=[O:9])=[CH:20][CH:21]=4)=[CH:26][CH:27]=3)[CH2:32][CH2:33]2)=[O:35])(=[O:46])=[O:45])=[CH:42][CH:43]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)c5ccc(C)cc5)CC4)cc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 315 using 1-{4′-[3-Methyl-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and p-toluenesulfonamide.