Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[C:6]([NH:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Br)ccc1NCC1CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2cc(Br)ccc2n1CC1CC1
Temperature: 120 °C
Reaction time: 20 h
Yield: 105 %

Procedure:
A mixture of N-{5-bromo-2-[(cyclopropylmethyl)amino]phenyl}-2,2-dimethylpropanamide (step A, 1.41 g, 4.34 mmol) and p-toluenesulfonic acd monohydrate (825 mg, 4.34 mmol) in toluene (50 mL) was stirred at 120° C. for 20 h. After cooling to room temperature, the mixture was quenched with sodium hydrogencarbonate aqueous solution. The organic layer was separated. The aqueous layer was extracted with ethylacetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 as eluent) to afford the title compound (1.40 g, quantum yield) as a light brown oil.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[C:7]=1[CH3:32])=[O:5])C.[CH3:33][S:34]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35].C[Al](C)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][CH2:12][CH2:11][C:9]1[N:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[C:28]([F:29])([F:31])[F:30])[C:7]([CH3:32])=[C:6]([C:4]([NH:41][C:40]2[CH:39]=[CH:38][C:37]([S:34]([CH3:33])(=[O:36])=[O:35])=[CH:43][CH:42]=2)=[O:5])[CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1cc(CCOCc2ccccc2)n(-c2ccc(F)cc2C(F)(F)F)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CCOCc2ccccc2)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a suspension of 5-[2-(benzyloxy)ethyl]-1-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (332 mg, 0.74 mmol) and 4-(methylsulfonyl)aniline (133 mg, 0.78 mmol) in toluene (3 mL), Me3Al (0.41 mL, 0.74 mmol, 1.8 M solution in toluene) was added under N2 atmosphere at room temperature and stirred at 110° C. for 30 min. After the completion of the reaction, it was quenched with 1N HCl, and extracted with AcOEt. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated, and the residue was purified over silica gel (AcOEt/n-hexane, 2:3 v/v) to give the atropisomeric mixture of the title compound (220 mg, 52%) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O.O.O.O.O.O.O.O.O.O.B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>[Pd].C(O)(C)C>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1
Reactant: OCCc1ccc(O)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: OCCC1CCC(O)CC1
Temperature: 80 °C
Reaction time: 22 h
Yield: 99.6 %

Procedure:
In a 1 L reactor are successively introduced: 50 g (362 mmol) of 4-(2-hydroxyethyl)phenol, 5 g (13.6 mmol) of sodium tetraborate decahydrate, 500 mL of isopropanol, 5 g of palladium (10% on charcoal washed with isopropanol). The vessel is closed, purged three times with nitrogen and three times with hydrogen. The mixture is stirred for 22 hours under 10 bar pressure of hydrogen at 80° C., cooled back to room temperature, filtered over a celite pad and rinsed with isopropanol. Filtrate is concentrated under reduced pressure, toluene (100 mL) is added and evaporated under reduced pressure. This last procedure being repetited to remove trace amount of isopropanol and gives 52 g (99% yield) of 4-(2-hydroxyethyl)cyclohexanol as a clear viscous oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([O:28][CH3:29])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:30][C:10]1([CH3:31])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[C:18]([O:28][CH3:29])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(OC)cc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 0.71 mmol), lithium hydroxide hydrate (0.30 g, 7.1 mmol), water (1 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 31%) as a white solid: LC/MS m/e calcd for C23H28N2O4 (M+H)+: 397.5, observed: 397.3.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
Sodium hydride (2.13 g, 53.3 mmol, 60% dispersion in mineral oil) was added to 3-bromo-1H-pyrrolo[2,3-b]pyridine (7.5 g, 38.1 mmol) in DMF (190 mL) at 0° C. This mixture was stirred at 0° C. for 30 minutes, and benzene sulfonyl chloride (7.40 g, 41.87 mmol) was then added by syringe. After 30 minutes at 0° C., TLC indicated most of the starting material had been consumed. Benzene sulfonyl chloride (0.5 mL) was added, and the mixture was stirred for another 15 minutes at 0° C. The mixture was then quenched with saturated ammonium chloride solution (100 mL) followed by water (200 mL). A precipitate had formed. The solids were collected by filtration and dried under high vacuum for 16 hours to give 3-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.2 g, 87%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.46-8.49 (m, 1H), 8.19-8.22 (m, 2H), 7.79-7.83 (m, 2H), 7.57-7.62 (m, 1H), 7.47-7.53 (m, 2H), 7.25-7.29 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.C1COCC1>[Br:1][C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[N:7]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1Br)c1ccsc1c(=O)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a suspension of 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (2.2 g, 6.8 mmol) in a mixture of DMF (15 mL) and THF (15 mL) at 0° C. was added sodium hydride (60%, 0.54 g, 13.6 mmol). The reaction mixture was stirred at 0° C. for 30 min before (2-(chloromethoxy)ethyl)trimethylsilane (3.4 g, 20 mmol) was added. The resulting mixture was stirred at rt overnight and then poured into ice-water (50 mL). The resulting precipitate was filtered and purified by column chromatography (silica, heptane/ethyl acetate) to afford the desired product (2.7 g, 87%) as a light yellow solid: ESI MS m/z 454 [C19H24BrNO3SSi+H]+.
Reaction SMILES: [CH3:1]OC1C=C2C(=CC=1)CC(=O)CC2.C(Br)C=C.[CH2:18]([C@:20]12[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[CH2:27][CH2:26][C:25]1=[CH:24][C:23](=[O:36])[CH2:22][CH2:21]2)[CH3:19]>>[CH2:18]([C@@:20]12[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[CH2:27][CH2:26][C:25]1=[CH:24][C:23](=[O:36])[CH2:22][CH2:21]2)[CH:19]=[CH2:1]
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: CC[C@@]12CCC(=O)C=C1CCc1cc(OC)ccc12
Solvent: C=CCBr
Product: C=CC[C@]12CCC(=O)C=C1CCc1cc(OC)ccc12

Procedure:
(4aR)-4a-allyl-7-methoxy-4,4a,9,10-tetrahydro-3H-phenanthren-2-one was prepared in three steps from 6-methoxy-2-tetralone and allyl bromide in a manner analogous to that described for the synthesis of (4aR)-4a-ethyl-7-methoxy-4,4a,9,10-tetrahydro-3H-phenanthren-2-one in Preparations 1a to 1c.
Reaction SMILES: B(Br)(Br)Br.C([O:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]([CH3:32])[NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=[O:33])C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]([CH3:32])[NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=[O:33]
Reactant: CC1NC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2CCOCc1ccccc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC1NC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2CCO
Yield: 49.6 %

Procedure:
A solution of boron tribromide (4.59 g) in methylenechloride (5 ml) was added dropwise to a stirred suspension of 6-[1-(2-benzyloxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.38 g) in methylene chloride (200 ml) at -40° C. over a period of 10 minutes. After being stirred for 40 minutes at the same temperature, methanol (0.6 ml) was added to the suspension and evaporated in vacuo. The residue was dissolved in n-butanol, washed with brine, and evaporated in vacuo. The residual solid was washed with ethyl acetate and recrystallized from methanol to give 6-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.91 g), mp 237° to 243° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH:24]3[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[CH:19]=2)[CH:14]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(#N)C>[C:30]([C@H:27]1[CH2:26][CH2:25][C@H:24]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH:22]=[CH:21]3)[CH2:29][CH2:28]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOP(=O)(CCNCc1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCP(=O)(O)O)ccc3c2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2-{[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-ethyl)-phosphonic acid diethyl ester (65.00 mg, 0.14 mmol) in acetonitrile (1 mL) was added bromotrimethylsilane (1 mL, 7.58 mmol). The reaction was then stirred at 50° C. overnight. After the solvent was concentrated, the residue was purified with HPLC (acetonitrile-water, 15-85%) to give white precipitate (33 mg, yield: 58). ESI-MS: 420.2 (M+H)+; 1H NMR (400 MHz, DMSO) δ=7.81-7.91 (m, 3H), 7.51 (dd, 1H), 7.41 (d, 1H), 7.19 (dd, 1H), 4.40 (m, 1H), 4.31 (s, 2H), 3.12 (m, 2H), 2.21 (d, 2H), 1.97 (m, 2H), 1.82 (d, 2H), 1.36 (q, 2H), 1.22 (q, 2H), 1.08 (m, 1H), 0.88 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([C:9](=[O:12])[CH2:10][Cl:11])=[CH:6][C:7]=1[Br:8].[BH4-].[Na+]>CO>[Cl:11][CH2:10][CH:9]([C:5]1[N:4]=[C:3]([Cl:13])[C:2]([NH2:1])=[C:7]([Br:8])[CH:6]=1)[OH:12]
Reactant: Nc1c(Br)cc(C(=O)CCl)nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(Br)cc(C(O)CCl)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1 g (3.52 mmol) of 3-amino-4-bromo-2-chloro-6-chloroacetylpyridine are suspended in 15 ml of methanol, the suspension is cooled to 0° C. and 133 mg (3.52 mmol) of NaBH4 are added. After 10 minutes, the mixture is poured onto water, excess NaBH4 is destroyed by acidification with HCl and the mixture is neutralized again with NaHCO3. After extraction with CH2Cl2 and evaporation of the solvent, 1 g (99% of theory) is obtained as the residue.
Reaction SMILES: [F:1]F.[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[N:5]=1.[F-].[Na+]>ClC(Cl)(Cl)F>[F:1][C:7]1[C:6]([Cl:11])=[N:5][C:4]([Cl:3])=[N:9][C:8]=1[Cl:10]
Reactant: FF
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [F-]
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Product: Fc1c(Cl)nc(Cl)nc1Cl
Yield: 47.9 %

Procedure:
0.5 mol of fluorine in the form of a 30% by volume mixture with helium was introduced into a suspension of 36.7 g (0.2 mol) of 2,4,6-trichloropyrimidine, 21 g of sodium fluoride (0.5 mol) and 250 ml of trichlorofluoromethane, at a temperature of -78° C. The rate of introduction was 0.15 mol of fluorine per hour. After the introduction, the reaction mixture was filtered and 19.3 g of pure 5-fluoro-2,4,6-trichloropyrimidine were obtained from the filtrate by distillation over iron filings. This corresponds to a yield of 48% of theory. The boiling point of the isolated product was 80°-87° C. at 10 mbar. The reaction mixture also contained more highly fluorinated pyrimidine derivatives.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH:41]1[CH2:45][C@@H:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43][C@@H:42]1[C:50]([O:52][CH3:53])=[O:51]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([N:41]4[CH2:45][C@@H:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43][C@@H:42]4[C:50]([O:52][CH3:53])=[O:51])=[O:21])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Reactant: COC(=O)[C@@H]1CN[C@@H](C(=O)OC)C1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H]1C[C@H](C(=O)OC)N(C(=O)c2ccc(CCC3CNc4nc(N)nc(O)c4C3)s2)C1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a sample of 225 mg (0.70 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.5 mL anhydrous dimethylformamide and 0.08 mL (0.72 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature and 135 mg (0.77 mmol) 2-chloro-4,6-dimethoxy-1,3,5-triazine were added at once. The reaction was stirred for 0.5 hours at room temperature, and 213 mg (1.14 mmol) of trans-dimethyl pyrrolidine-2,4-dicarboxylate were added in 1.0 mL of dimethylformamide. After stirring at room temperature for another 3.5 hours, the reaction was concentrated in vacuo and chromatographed on silica gel with 2-8% CH3OH/CHCl3 to give 185 mg (54%) of trans-dimethyl 1-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]thien-2-ylcarbonyl}pyrrolidine-2,4-dicarboxylate as a tan solid. Mass Spectrum (FAB+): M+1=490; 1H NMR (300 MHz, DMSO) δ: 1.54-1.64 (m, 3H); 1.76-1.84 (m, 1H); 2.11-2.29 (m, 3H); 2.36-2.43 (m,--1H); 2.72-2.79 (m, 1H); 2.86-2.88 (m, 2H); 3.07-3.23 (m, 2H); 3.61 (s, 6H); 3.95-4.08 (m, 2H); 4.49-4.54 (M, 1H); 5.92 (s, 2H); 6.24 (d, J=1.6 Hz, 1H); 6.91-6.92 (m, 1H); 7.48 (d, J=2.4 Hz, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.[CH3:16][N:17]1[C:21]([CH3:22])=[C:20]([CH:23]=O)[C:19]([CH3:25])=[N:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:23][C:20]3[C:19]([CH3:25])=[N:18][N:17]([CH3:16])[C:21]=3[CH3:22])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: Cc1nn(C)c(C)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1CN1CCN(c2nccnc2Cl)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (2.11 g, 7.77 mmol, 1 eq) in tetrahydrofuran (20 mL) add 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (1.61 g, 11.65 mmol, 1.5 eq). Stir for 10 min and add sodium triacetoxyborohydride (4.20 g, 19.40 mmol, 2.5 eq) in one portion. Stir at room temperature under nitrogen for 1 hr., then add further 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (0.50 g, 3.6 mmol, 0.47 eq). Stir for 30 min., add saturated aqueous sodium hydrogen carbonate (100 mL) slowly, and then extract with DCM (3×50 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 2:98 to 5:95 methanol:DCM), to give the title preparation as a white powder (2.468 g, 98%). MS (ES): m/z=321 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:36])([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][C:4]1[C:5]([CH3:27])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:24](O)=[O:25])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.S(Cl)(Cl)=O.[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].[H-].[Na+]>C(Cl)Cl.C1COCC1.CCOC(C)=O>[F:1][C:2]([F:36])([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:3][C:4]1[C:5]([CH3:27])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:24]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:25])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(F)(F)CCc1ccccc1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1CC(F)(F)CCc1ccccc1

Procedure:
1-{4′-[4-(2,2-Difluoro-4-phenyl-butyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.225 g, 0.441 mmol) was dissolved in CH2Cl2 (2.3 mL) and thionyl chloride (0.07 mL, 0.971 mmol) was added. After 30 minutes the reaction was concentrated. Separately, methanesulfonamide (0.124 g, 1.30 mmol) was dissolved in THF (2 mL) and sodium hydride (60% in mineral oil, 0.044 g, 1.103 mmol) was added. The acid chloride from the first reaction was dissolved in THF and carefully added to the second mixture. The reaction was monitored by analytical LCMS and excess sodium hydride was added until the reaction went to completion. Standard aqueous workup and silica gel chromatography (0-100% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O.CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][NH:21][CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cccc(Br)c1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CNCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) (1.0 g, 3 mmol) in dichloroethane (50 mL) was added methylamine (0.48 g, 6.1 mmol, 2 eq) in water (40%) and 1 mL of AcOH. The solution was allowed to stir at RT for 1 h followed by the addition of sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 2.8 eq). The resulting mixture was stirred at RT for 16 h and quenched with MeOH. After stirring for 30 min the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel by eluting with EtOAc/MeOH to give 0.62 g (60%) of tert-butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.47 (bs, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 7.23 (m, 1H), 5.97 (bs, 1H), 3.18-2.82 (m, 2H), 2.45 (s, 3H), 1.74 (s, 3H), 1.40 (s, 9H). MS (ESI) m/e 342.9 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:33])[C:10]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][Si](C)(C)C)=[CH:23][CH:22]=2)[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=1>CO.O1CCOCC1.O>[CH3:7][O:8][C:9](=[O:33])[C:10]1[CH:19]=[C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[CH:25][CH:26]=2)[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=1
Reactant: COC(=O)c1cc(Oc2ccc(C#C[Si](C)(C)C)cc2)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: C#Cc1ccc(Oc2cc(C(=O)OC)cc(C(=O)OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Powdered potassium carbonate (3.0 g) was added to a solution of dimethyl-5-(4-trimethylsilylethynylphenoxy)-isophthalate (5.0 g) in a mixture of methanol (80 ml) and dioxane (20 ml). A crystalline precipitate gradually formed upon stirring at ambient temperature for two hours. The reaction mixture was diluted with water (100 ml) and filtered to yield dimethyl-5-(4-ethynylphenoxy)isophthalate as a tan crystalline solid (3.0 g), m.p. 124'-125° C. Calculated for C18H14O5 : C, 69.68%; H, 4.55%. Found: C, 69.76%; H, 4.84%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:31])[C:21]=1[CH3:32].CC(C)=[O:35]>S(=O)(=O)(O)O.O>[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:31])[C:21]=1[CH3:32])([OH:35])=[O:1]
Reactant: CC(C)=O
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCC(=O)O)=C(C)C1=O

Procedure:
In 10 ml of acetone is dissolved 172 mg of 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (V:n=17). Separately, 2.672 g of chromic anhydride is dissolved in 2.3 ml of concentrated sulfuric acid and diluted with water to 10 ml. This diluted solution (0.5 ml) is added to the above acetone solution and the mixture is stirred under ice-cooling for 10 minutes. The reaction mixture is diluted with water and extracted with chloroform. The extract is washed with water and dried, and the solvent is distilled off under reduced pressure. The residue is column-chromatographed on silica gel, elution is carried out with chloroform and the eluate is recrystallized from ethanol. The above procedure yields 65 mg of 6-(17-carboxyheptadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I:n=17, R=H) as orange-yellow crystals, m.p. 77°-79° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[NH:16]1[CH:17]=[CH:18][C:14]([NH:13][C:1]2[NH:2][C:6](=[O:7])[C:5]3[C:4]([CH:3]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:15]1
Reactant: N#CCc1ccccc1C(=O)O
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: O=c1[nH]c(Nc2cc[nH]n2)cc2ccccc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
2-Cyanomethyl-benzoic acid (1.61 g, 0.01 mol), 3-amino-pyrazole (1 g, 0.01 mol), acetic acid (15 ml), were sealed in a bottle (20 ml). The mixture was heated at 130° C. for 20 minutes under microwave irradiation. The mixture was concentrated and the residue was dissolved in 5 ml MeOH. The solution was added dropwise to 200 ml water. After stirred for 1 hour, solid was collected and dried to give product (1.8 g, 75% yield). LC-MS: 227 (MH+)