Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH2:4][C@@H:5]([C:14]([OH:16])=O)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[CH2:17]([N:19](CC)CC)[CH3:18].ClC(OCC(C)C)=O.C(N)C>O1CCCC1.C(OCC)(=O)C>[CH2:17]([NH:19][C:14](=[O:16])[C@H:5]([CH2:4][S:3][CH2:1][CH3:2])[NH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH3:18]
Reactant: CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](CSCC)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To 14.92 g (100 mmole) of S-methyl-L-cysteine were added 55 ml of water and 21 ml (110 mmole) of triethylamine and the mixture was dissolved in 55 ml of dimethylformamide at room temperature. Thereafter, 26.4 g (110 mmole) of t-butyl-S-4,6-dimethylpyrimidin-2-ylthiol carbanate was added and the mixture was stirred for about 10 hours at room temperature. After addition of 150 ml of water, the mixture was extracted with 2×200 ml of ethyl acetate. The aqueous layer was ice-cooled, adjusted to pH 2 with addition of 6 N hydrochloric acid and extracted with 1×150 ml and 2×80 ml of ethyl acetate. The organic layers were washed with 3×100 ml of 5% hydrochloric acid and 2×100 ml of aqueous saturated sodium chloride and then dried over magnesium sulfate. The solution was concentrated in vacuo to give 24.5 g (98% yield) of S-ethyl-N-butyloxycarbonyl-L-cysteine as an oil. ##STR10## To a solution of 6.23 g (25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine dissolved in 60 ml of tetrahydrofuran was added 3.48 ml (25 mmole) of triethylamine. To the resulting mixture cooled to -15° C. was added dropwise 3.28 ml (25 mmole) of isobutyl chloroformate and the mixture was stirred at that temperature for 20 minutes. After cooling to -40° C., 3.2 g of aqueous 70% ethylamine solution (50 mmole) was added in a portion and the mixture was stirred for 2.5 hours under ice cooling. After addition of 70 ml of ethyl acetate, the organic layer was washed successively with 30 ml of aqueous 5% sodium bicarbonate, 2×30 ml of aqueous 10% citric acid, 2×30 ml of aqueous 5% sodium bicarbonate and 2×30 ml of saturated saline and dried over anhydrous magnesium sulfate. The solution was then concentrated in vacuo, resulting in precipitation of crystals, which were recrystallized from ethyl acetate-n-hexane to give 4.93 g of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide, 71% yield, m.p. 109°-110° C. ##STR11## To 40 ml of ice-cooled 16% solution of hydrogen chloride in ethyl acetate was added dropwise a solution of 2.00 g (7.25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide in 50 ml of ethyl acetate over 20 minutes. After stirring for 2.5 hours at room temperature, the mixture was concentrated in vacuo and the residual oil was treated with ethyl ether to give 1.31 g (85% yield) of S-ethyl-L-cysteine ethylamide hydrochloride as powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH2:15])[CH3:11].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:15][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(CN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(CNC(=O)c1ccc(Cl)s1)OCC
Temperature: 4 °C
Yield: 64.8 %

Procedure:
Add 5-chlorothiophene-2-carboxylic acid (100 g, 0.60 mol) and dichloromethane (1000 mL) to a 3 L three-necked round bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel, and thermocouple. Stir the resulting solution under nitrogen while cooling to 4° C. Add via addition funnel 2,2-diethyoxyethylamine (88.5 ml, 0.60 mol) in dichloromethane (35 mL) over 12 min. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 g, 0.64 mol) to the chilled mixture. Add additional dichloromethane (165 mL) and stir the reaction mixture for 22 h at RT. Quench the reaction with water (1000 mL) and separate the resulting layers. Back extract the aqueous layer with dichloromethane (500 mL) and combine the organic layers. Dry over sodium sulfate and purify through a silica gel bed eluting with dichloromethane followed by a mixture of 1% MeOH in dichloromethane and then a mixture of 10% MeOH in dichloromethane to afford 108 g (65%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 6H), 3.48-3.57 (m, 4H), 3.68-3.74 (m, 2H), 3.68-3.74 (m, 2H), 6.37 (bs, 1H), 6.85 (d, J=3.5 Hz, 1H), 7.26 (d, J=3.5 Hz, 1H).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].[OH2:7].O.[Na+].[SH:10][C:11]1[CH2:16][O:15][CH2:14][CH2:13][C:12]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)(=O)C>[CH2:20]([O:19][C:17]([C:12]1[CH2:13][CH2:14][O:15][CH2:16][C:11]=1[S:10]([OH:7])(=[O:6])=[O:5])=[O:18])[CH3:21]
Reactant: CCOC(=O)C1=C(S)COCC1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)COCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 219.9 %

Procedure:
Sodium perborate tetrahydrate (24.5 g) was added to acetic acid (130 ml) and the mixture was heated to 50-55° C. Thereto was added dropwise a solution of ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (10.0 g) in acetic acid (30 ml) over 2 h. The mixture was stirred at 50-55° C. for 3 h, and the reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (230 ml) and the mixture was stirred at room temperature for 2 days, and the resultant insoluble material was removed off by filtration and washed with acetonitrile (70 ml). The filtrate and washing were combined and the mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (160 ml) and the mixture was stirred at room temperature for 6 h. The obtained insoluble material was removed off by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added diisopropyl ether (100 ml), and the precipitated insoluble material was filtered off to give 4-(ethoxycarbonyl)-5,6-dihydro-2H-pyran-3-sulfonic acid as a pale-yellow oil (27.6 g) containing an inorganic product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[CH3:33])[CH2:22][CH2:21]3)=[O:19])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].O>CC(C)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:14]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[CH3:33])[CH2:24][CH2:25]3)=[O:19])[CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccc(Cl)cc4)CCN3)CC2)c1
Reactant: CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCN1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [4-(4-chloro-benzenesulfonyl)-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone hydrochloride (100 mg) in acetone (4 mL) was added cesium carbonate (254 mg), followed by 1-bromopentane (27 μL). The reaction mixture was stirred at ambient temperature for 1 h. Additional cesium carbonate (127 mg) and 1-bromopentane (14 μL) were added and stirring was continued at reflux over night. Water was added and the reaction mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded [4-(4-chloro-benzenesulfonyl)-1-pentyl-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone as a white foam, MS: 547.3 ([M+H, 1Cl]+).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([CH2:15]O)[CH2:14][CH2:13]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: OCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ncc1C(=O)OCC1CC1
Reaction time: 72 h
Yield: 58 %

Procedure:
To a solution of 6-fluoro-4-methylpyridine-3-carboxylic acid (4.94 g, 31.8 mmol), cyclopropylmethanol (3.78 mL, 47.8 mmol) and N,N-dimethylpyridin-4-amine (778 mg, 6.37 mmol) in DMF (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (6.71 g, 35.0 mmol), and the mixture was stirred for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:1) to give the title compound (3.86 g, yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:3]=1[CH2:4][N:5]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29][CH2:30][C@H:31]([OH:44])[C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:3]=1[CH2:4][N:5]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][CH:26]([NH:29][CH2:30][C@H:31]([OH:44])[C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH:33]=3)[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)(=[O:15])=[O:16])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)CN(Cc1cc(F)ccc1F)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N(CC(=O)O)Cc4cc(F)ccc4F)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
This compound was prepared from tert-butyl 2-{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate in substantially the same manner, as described in Example 53, with one change; the mixture was stirred at room temperature for 20 hours. The volatiles were removed and the product was purified by reverse phase chromatography to give a white solid (1.44 9, 42% yield): mp 80-82° C.; MS m/e 669 (M+H)+; 1H NMR (DMSO-d6 400 MHz) 81.62 (m, 2H), 2.11 (m, 2H), 2.85 (m, 2H), 2.94 (s, 3H), 2.96 (m, 1H), 3.11 (m, 1H), 3.34 (m, 1H), 3.88 (s, 2H), 3.99 (m, 2H), 4.37 (s, 2H), 4.79 (m, 1H), 6.01 (br, 1H), 6.90 (d, 1H), 7.05 (m, 3H), 7.18 (m, 3H), 7.21 (s, 1H), 7.59 (d, 2H), 8.58 (brs, 1H), 8.66 (brs, 1H), 8.74 (brs, 1H), 10.01 (brs, 1H); Analysis for C29H34F2N4O8S2×2.0 CF3COOH×0.73 H2O Calc'd: C, 43.52; H, 4.11 ; N, 6.15 Found: C, 42.95; H, 3.93; N, 6.08.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:29])=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(Br)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.2 %

Procedure:
A solution of (6-bromo-3-pyridinyl)methanol (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH2Cl2 (100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25% Et2O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91%) as a lachrymatory white solid that was used directly in the next step; 1H NMR (CDCl3) δ 8.38 (d, J=2.5 Hz, 1H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 4.42 (s, 2H).
Reaction SMILES: CS(O[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[C-:25]#[N:26].[Na+].O>CS(C)=O>[C:25]([CH:6]([CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])#[N:26]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(C#N)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (10 g) in dimethyl sulfoxide (100 ml) was added sodium cyanide (2 g) at room temperature and the whole mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residual oil was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to give di-tert-butyl (2-cyano-1,3-propanediyl)biscarbamate (4.04 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(C(F)(F)F)cc4)c3O2)cc1
Yield: 74.3 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-(trifluoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.435 g (74%) of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid. mp 116-118° C.; Anal. calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.37; H, 4.36.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 77.5 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.97 g, 4.92 mmole) were combined in 30 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 85% hexane/methylene chloride to remove impurities and methylene chloride to elute the product, the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 196° C.) after evaporation of the solvent (0.21 g, 40%). MS (ESI) m/z 402(M+H)+.
Reaction SMILES: N1C=CC=[CH:3][CH:2]=1.[CH2:7]([OH:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:7](=[O:21])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:2][CH3:3]
Reactant: c1ccncc1
Reactant: CCCC/C=C\CCCCCCCCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCCCCCC/C=C\CCCC=O
Reaction time: 0.25 h

Procedure:
Chromium trioxide (0.56 g. 5.6 mM) is added to a stirred solution of pyridine (0.90 g. 11.4 mM) in methylene chloride (14 ml). The flask is stoppered with a Drieritefilled tube. The deep red solution is stirred for approximately fifteen minutes at room temperature after which a solution of cis-9-tetradecen-1-ol (0.9 mM) in a small amount of methylene chloride (approximately 0.2 ml) is added rapidly and the mixture stirred for another 15 minutes. The product is recovered by decantation from the tarry precipitate, concentrated in vacuo, and the residue extracted with redistilled petroleum ether (Skelly B). This extract is washed successively with dilute aqueous hydrochloric acid (approximately 1%), brine, dilute aqueous sodium bicarbonate (approximately 5%), and brine (until neutral), then filtered through anhydrous magnesium sulfate and evaporated in vacuo to yield 0.17 g. G.c. analysis showed the product contained cis-9-tetradecen-1-ol in approximately 1:9 ratio to the aldehyde, so the product was chromatographed on Florisil (2.4 cm o.d. × 30 cm; packed up to 25 cm) using redistilled benzene (15 ml fractions). Fractions 4 - 7 are combined. Final yield of alcohol-free cis-9-tetradecenal is 60 mg. In accordance with the foregoing procedure but starting with cis-11-hexadecenal in place of cis-9-tetradecenal, there is obtained crude cis-5-hexadecenal (0.19 g.) and alcohol-free cis-11-hexadecenal (0.10 g.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=O)=O)=[CH:15][CH:14]=1>C(O)(=O)C.CO>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:21]([C:23]3[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=3)=[N:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[N:8]=2)=[CH:17][CH:18]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12
Reaction time: 30 h

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 3.68 g (10 mmol) of 4,4′-dibromobenzil were dissolved in 80 g of a 1:1 mixed solvent of acetic acid/methanol, and reaction was allowed at 70° C. for 30 hr. After the reaction was over, the solvent was removed, and the reaction product was extracted on a silica gel column.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:27])=[CH:9][C:8]=1[CH3:28])C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:28][C:8]1[CH:9]=[C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=4)=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:27])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:3])=[O:29]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(Br)cc3)nc2C)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(SCc2sc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of {4-[2-(4-Bromo-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (53 mg, 0.1076 mmol) in toluene:ethanol (1:1, 2.0 mL) is added palladium tetrakis triphenylphosphine (5.0 mg, 0.0053 mmol), 4-(trifluoromethyl)-phenyl boronic acid (22.5 mg, 0.1184 mmol), and a solution of sodium carbonate (0.216 mL, 1.0M in water, 0.216 mmol). The reaction is purged with nitrogen and heated to reflux. The reaction is monitored by HPLC, and upon completion is allowed to cool to room temperature. The reaction is diluted with EtOAc and then washed with 0.1N sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, then concentrated. The product is purified by flash column chromatography. The pure ester compound is then diluted with THF and 1N sodium hydroxide is added. The reaction is allowed to stir at room temperature, and monitored by TLC. Upon completion, 1N hydrochloric acid is added to neutralize the solution. The reaction is diluted with EtOAc and then washed with water. The organic layer is dried over anhydrous sodium sulfate and concentrated to the pure acid, 50 mg or 94% yield. MS (ES): 530.7 (M++1), the structure is also confirmed by proton NMR.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Fc1cc2nc(-c3cccnc3Cl)[nH]c2cc1F
Product: Fc1cc2nc(-c3cccnc3Cl)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, intermediate a, from 2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-benzene (CAS Reg. No. 100-39-0). Colorless solid (52%). MS (Turbo Spray): m/z=356.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[CH2:19][C:20]1[N:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][CH:21]=1.C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N.O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[CH2:19][C:20]1[N:25]=[C:24]([C:26]([NH2:31])=[O:28])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2[nH]c(-c3ccccc3)c(Cc3cccc(C(=O)O)n3)c2cc1F
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2[nH]c(-c3ccccc3)c(Cc3cccc(C(N)=O)n3)c2cc1F
Temperature: 25 °C
Reaction time: 9 h
Yield: 98.4 %

Procedure:
To a solution of 6-(5-fluoro-6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (105 mg) in tetrahydrofuran (2.8 mL) was added 1,1′-carbonyldiimidazole (90.5 mg), and this mixture was stirred at room temperature for 9 hours. Then, 28% aqueous ammonia (0.56 mL) was added thereto, followed by stirring at room temperature for 14 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (103 mg). 1H-NMR (CDCl3) δ ppm: 3.94 (3H, s), 4.37 (2H, s), 5.30-5.60 (1H, br), 6.97 (1H, d, J=7.0 Hz), 7.16 (1H, d, J=11.5 Hz), 7.23-7.28 (1H, m), 7.34-7.41 (1H, m), 7.41-7.49 (2H, m), 7.49-7.57 (2H, m), 7.66-7.94 (2H, m), 7.98-8.13 (2H, m).