Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>C(#N)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10]
Reactant: COC(=O)CBr
Reactant: Cc1cc(C=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(C=O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-3-methyl-benzaldehyde 52 (0.50 g, 3.67 mmol) is dissolved in 10 mL acetonitrile. Cesium carbonate (2.07 g, 6.35 mmol) and methyl bromoacetate (0.40 mL, 4.35 mmol) are added and the suspension is vigorously stirred at room temperature overnight. The suspension is poured into 1N aqueous HCl and extracted with EtOAc. Drying over MgSO4, filtration and concentration yielded (4-formyl-2-methyl-phenoxy)-acetic acid methyl ester 53: 1H-NMR (400 MHz, CDCl3) δ=9.86 (s, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.68 (dd, J=8.4, 1.6 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 2.34 (s, 3H). MS calculated for C11H13O4 (M+H+) 209.0, found 209.0.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[NH:14]1[CH2:18][CH2:17][C@@H:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:18][CH2:17][C@@H:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:15]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Temperature: 100 °C

Procedure:
A stirred mixture of 2-chloro-6-bromobenzothiazole (2.48 g, 10.0 mmol), (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 2.73 g, 0.0120 mole), and potassium carbonate (6.00 g, 0.04438 mole) in N,N-dimethylformamide (15 mL) was heated to 100° C. with an oil bath for 15 hours. The reaction mixture was cooled to room temperature then poured into water (300 mL). The resulting precipitate was collected by filtration and the filter cake was rinsed with water (600 mL). The solid was dissolved in dichloromethane and the solution was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a solid that was crystallized from hot ethyl acetate to give (R)-6-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.46-1.55 (m, 2H), 1.65 (pentet, J=5 Hz, 4H), 1.92-2.07 (m, 1H), 2.29-2.39 (m, 1H), 2.43-2.64 (m, 4H), 3.00-3.12 (m, 1H), 3.33-3.41 (m, 1H), 3.46-3.57 (m, 1H), 3.66-3.75 (m, 1H), 3.77-3.86 (m, 1H), 4.07-4.35 (m, 4H), 7.35 (d, J=9 Hz, 1H), 7.40 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:11]=1[C:12]([C:14]1[C:15]([Cl:25])=[N:16][C:17](Cl)=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])=[O:13]>CO.[C].[Pd]>[CH3:8][O:9][C:10]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:11]=1[C:12]([C:14]1[C:15]([Cl:25])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:21])[F:22])=[O:13]
Reactant: COc1cc(C)c(C(=O)c2c(C(F)(F)F)cc(Cl)nc2Cl)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)c(OC)c1OC
Reaction time: 6.5 h
Yield: 54.5 %

Procedure:
2.4 ml (17 mmol) of triethylamine and 0.3 g of 5% palladium carbon were added to a solution having 3.4 g (8.0 mmol) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2,6-dichloro-4-trifluoromethylpyridine (compound No. 3) obtained in Synthesis Example 1 dissolved in 50 ml of methanol, followed by stirring under hydrogen atmosphere for 6.5 hours. The mixture was subjected to filtration, 50 ml of water was added thereto, and methanol was distilled off under reduced pressure. Extraction of ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 1.7 g (yield 55%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine (compound No. 11; m.p. 110-112° C.) and 1.1 g (yield 37%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-4-trifluoromethylpyridine (compound No. 7; m.p. 59-62° C.).
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].CO.[H][H]>[C].[Pd].O>[CH3:13][C:2]([N+:14]([O-:16])=[O:15])([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: [H][H]
Reactant: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]
Yield: 34.5 %

Procedure:
To 5-(4-methyl-4-nitropentylidene)hydantoin (3.15 g, 13.9 mmol) were added methanol (60 ml) and water (10 ml), and the mixture was reduced by the addition of palladium-carbon (2.2 g) and hydrogen. After the reaction, palladium-carbon was filtered off and the residue was concentrated to dryness. Decantation with water and dichloromethane gave 5-(4-methyl-4-nitropentyl)hydantoin (1.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][C@@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[OH-:12].[Na+].OO>CO>[CH3:10][C:9]([CH:5]1[CH2:4][C:3](=[O:12])[C:2]2([CH3:1])[O:8][CH:7]2[CH2:6]1)=[CH2:11]
Reactant: [OH-]
Reactant: C=C(C)[C@H]1CC=C(C)C(=O)C1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: C=C(C)C1CC(=O)C2(C)OC2C1

Procedure:
Synthesis of epoxide 10 from S-(+)-carvone as illustrated in FIG. 3. A solution of 4 N NaOH (48 mL, 192.0 mmol, 0.3 equivalents) was slowly added to a solution of S-(+)-carvone (100.0 g, 665 mmol, 1.0 equivalent) in MeOH (1000 mL) at 0° C., followed by the dropwise addition of 35% hydrogen peroxide solution (70.0 mL, 792.6 mmol, 1.2 equivalents) over 3 hours. After the reaction was complete as established by TLC analysis, it was quenched by the slow addition of saturated Na2SO3 solution (200 mL) and extracted with CH2Cl2 (3×300 mL). The organic extracts were dried over Na2SO4 and concentrated to afford the carvone epoxide product which was used without further purification. A solution of this epoxide (101.8 g, 612.4 mmol, 1.0 equivalent) and PtO2 (0.72 g, 3.18 mmol, 0.095 equivalents) in EtOH (500 mL) was stirred under a hydrogen atmosphere (1 atm) at 25° C. for 12 hours. The reaction mixture was then filtered through a celite pad eluting with Et2O and concentrated. The crude product was purified by flash chromatography (silica gel, 5% EtOAc in hexane) to afford epoxide 10 (97.8 g, 87%, two steps) as a colorless oil. Rf=0.40 (silica gel, EtOAc-hexane, 1:10); FT-IR (neat) nmax 2959, 2873, 1708, 1466, 1438, 1369, 1111, 884, 814 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10]C=C)[N:6]1[C:13](=[O:26])[CH:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:16]=[CH2:17])=[O:4].CS(C)=O>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][O:2][C:3]([C@H:5]1[N:6]2[C:13](=[O:26])[C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][CH:16]=[CH:17][CH2:10][C@@H:7]2[CH2:8][CH2:9]1)=[O:4]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N1C(CC=C)CCC1C(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H]2CC=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Reaction time: 2 h
Yield: 60 %

Procedure:
5-Allyl-1-(2-tert-butoxycarbonylamino-pent-4-enoyl)-pyrrolidine-2-carboxylic acid methyl ester, 6, (3.2 g, 8.7 mmol) is dissolved in dichloromethane (40 mL). Grubbs catalyst (0.7 g, 0.85 mmol) is added and the mixture heated to reflux for 4 hours. The reaction is allowed to cool and methylsulfoxide (2 mL) is added. After 2 hours the solution is reduced to a oil, which is purified over silica (50% ethyl acetate hexane) to afford 1.76 g (60% yield) of the desired product as a dark yellow oil. 1H-NMR (300 MHz, CDCl3): δ 5.79 (m, 2H), 5.61 (d, J=6.9, 1H), 4.89 (dd, J=15, 7.2, 5.79 (m, 2H), 5.61 (d, J=6.9, 1H), 4.89 (dd, J=15, 7.2, 5.79 (m, 2H), 5.61 (d, J=6.9, 1H), 4.89 (dd, J=15, 7.2, 1H), 4.54 (m, 1H), 4.15 (m, 1H), 3.75 (s, 3H), 2.81 (m, 2H) 2.49–1.98 (m, 6H), 1.47 (s, 9H). 13C NMR (CDCl3): □ 172.6, 171.3, 155.4, 129.4, 126.0, 79.9, 60.3, 58.9, 52.2, 52.1, 35.5, 33.2, 33.1, 28.6, 27.4. ESI MS: 339.18 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[Br:9]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:9][C:4]1[S:3][C:2]([Cl:1])=[C:6]([CH2:7][OH:8])[CH:5]=1
Reactant: OCc1ccsc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1cc(Br)sc1Cl
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 3.0 g of (2-chlorothiophen-3-yl)methanol in 60 mL of dimethylformamide was added 3.59 g of N-bromosuccinimide at room temperature, and stirred at this temperature for 2 hours. Adding 10 mL of 10% sodium thiosulfate, and the resultant solution was diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 3.7 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:5][C:6]1[O:11][C:10](=[O:12])[C:9]2[C:13]([CH2:17]Br)=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:4]>CCOCC.O1CCCC1>[CH2:3]([O:5][C:6]1[O:11][C:10](=[O:12])[C:9]2[C:13]([CH2:17][CH3:1])=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:4]
Reactant: CCOc1nc2cccc(CBr)c2c(=O)o1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1nc2cccc(CC)c2c(=O)o1
Temperature: -25 °C
Reaction time: 0.42 h

Procedure:
Methyl lithium (4.69 ml, 1.4M, Aldrich) was added to a suspension of cuprous iodide (0.62 gm) in anhydrous ether under argon at -78° C. The solution was stirred at -25° C. for 25 min. This solution was added to a solution of 2-ethoxy-5-bromomethyl-4H-3,1-benzoxazin-4-one (200 mg) in 15 ml anhydrous ether and 3 ml dry tetrahydrofuran at -60° C. Reaction was monitored by TLC until reaction completion. The reaction was quenched with saturated ammonium chloride solution and filtered. The filtrate was extracted in the usual manner. The ethereal layer was washed with water, dried over magnesium sulphate and evaporated to give an oil. The material was purified by thick layer chromatography (Rf =0.75, 3-% ethyl acetate: petroleum ether), to give 2-ethoxy-5-ethyl-4H-3,1-benzoxazin-4-one, m.p. 89°-91° C., H NMR: 1.3, 1.5 (2t, 6H, 2CH3), 3.2 (q, 2H, CH2), 4.5 (q, 2H, OCH2CH3), 7.2 (m, 2H, ArH), 7.6 (t, 1H, ArH).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)([O-:3])=[O:2].[Cl-:9].[Al+3].[Cl-:11].[Cl-]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[S:5][C:6]([Cl:11])=[C:7]([Cl:9])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccs1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)s1

Procedure:
To a solution of 2-nitrothiophene (10.0 g, 77.5 mmol) in 60 ml of chloroform is added aluminum chloride (6.0 g, 45.0 mmol). The mixture is cooled to 10° and chlorine gas is bubbled through for 3 hours at 25°-30°. Nitrogen gas is then bubbled through the mixture for 10 min., after which the mixture is poured into ice water and extracted with chloroform. The combined chloroform layers are washed with water and with brine and dried to give 2-nitro-4,5-dichlorothiophene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[C:19]([Zn]C#N)#[N:20].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O>[C:19]([C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1)#[N:20]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Reactant: N#C[Zn]C#N
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a 10 ml microwave vial was added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (500 mg, 1.612 mmol), dicyanozinc (150 mg, 1.277 mmol) and DMF (5 mL). The mixture was degassed and stirred at rt under N2 for 15 min. To the mixture was added palladium tetrakis (118 mg, 0.102 mmol) and the reaction was stirred at 95° C. for 1 h. The reaction was allowed to cool and poured into saturated aqueous Na2CO3 (50 mL) and EtOAc (50 mL) and stirred for 20 min. The mixture was extracted with ether (100 ml) and EtOAc (100 ml) (1:1), followed by filtration and evaporation to yield a residue. The residue was purified by silica gel chromatography (Analogix IF280, 0-8% EtOAc/hexanes, SF25-40 g, 30 minutes) to give methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (130 mg, 0.497 mmol, 38.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J=1.52 Hz, 1H) 7.82 (s, 1H) 7.71 (d, J=1.52 Hz, 1H) 4.85-4.97 (m, 1H) 3.90 (s, 3H) 2.29 (s, 3H) 1.45 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 257.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].I[CH3:33]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:33])[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.0 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 15 min and thereto iodomethane(35 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(C)CC2C=NC=CC=2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16].CC1C=CC([O:54][S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[S:64]([N:67]([CH3:75])[CH2:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)(=[O:66])=[O:65])(=[O:57])=[O:56])=C(C=1)OCCCON.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:54][S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[S:64]([N:67]([CH3:75])[CH2:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)(=[O:65])=[O:66])(=[O:57])=[O:56])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)Cc2cccnc2)c(OCCCON)c1
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)Cc2cccnc2)c(OCCCONC(=N)N)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)Cc2cccnc2)c1
Yield: 76 %

Procedure:
3-[5-Methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyguanidine dihydrochloride: The title compound was prepared in 76% yield from 3-[5-methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl) phenylsulfonyloxy]phenoxy]propoxyamine, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.2 Hz, 2H), 8.23 (m, 3H), 8.06 (t, J=7.7 Hz, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.88 (t, J=7.9 Hz, 1H), 7.71 (br s, 4H), 6.75 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 4.72 (s, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 2.88 (s, 3H), 2.22 (s, 3H), 2.01 (pentet, J=6.4 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H29N5O7S2: 564.2 (M+H), 586.1 (M+Na). Found: 564.1, 586.2.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>CN(C=O)C>[CH2:9]([C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7])[CH3:10].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: O=C1C=CC(=O)N1
Solvent: CN(C)C=O
Solvent: c1cc[nH]c1
Product: CCC1=CC(=O)NC1=O
Reaction time: 0.5 h

Procedure:
SA-SH is mixed with a 25 nmol/μl solution of maleimide-pyrrole (3.4 μl; 85 nmol) prepared by taking up 2 mg of maleimide-pyrrole in 200 μl of DMF. The reaction lasts 30 minutes.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[C:10]2[C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]=1[O:39][CH2:40][CH2:41][CH3:42])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[C:35]([C:27]1[C:26]([O:39][CH2:40][CH2:41][CH3:42])=[C:25]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:43])=[O:2])[CH:8]=3)[NH:12][CH:11]=2)[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: CCCOc1c(-c2cn(S(=O)(=O)c3ccccc3)c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 127.7 %

Procedure:
3-[1-Benzenesulfonyl-3-(3,5-di-tert-butyl-2-propoxy-phenyl)-1H-indol-5-yl]-but-2-enoic acid methyl ester (171 mg, 0.28 mmol) was dissolved in methanol (1.5 mL)/dioxane (3 mL) and treated with 1N NaOH (2 mL) at 60° C. for 4 h. The reaction was diluted with 1N HCl (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic portions were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to provide 160 mg of a brown solid. The material was purified using radial chromatography (eluent:hexane/ethyl acetate gradient) to provide 73 mg (58%) of a yellow foam. Mp. 105-115° C. 1H NMR (250 MHz, CDCl3): δ 8.31 (bs, 1H), 7.98 (bs, 1H, 8.7), 7.92 (m, 2H) 7.70 (m, 21), 7.47-7.35 (m, 5H), 6.27 (bs, 1H), 3.42 (t, 2H, J=6.4) 2.68 (d, 3H, J=1.0), 1.49 (s, 9H), 1.37 (s, 9H), 1.32 (m, 2H) 0.68 (t, 3H, J=7.4). MS [EI+] 448 (M+E)+, [EI−] 446 (M−H)+. Analytical (C29H37NO3): Calculated C, 77.81; H, 8.33; N, 3.13. Found: C, 77.89; H, 8.68; N, 2.94.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[CH:25]1[O:27][CH2:26]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[CH:17]=2)[CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C1CO1
Reactant: Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Product: OC(COc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1)C(F)(F)F
Temperature: 95 °C
Yield: 74.4 %

Procedure:
The N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine (400 mg, 1.35 mmol) product from EX-655A and 1,1,1-trifluoro-2,3-epoxypropane (348 mg, 3 mmol) were placed in a sealed vial, then stirred and heated to 95° C. for 15 h under an atmosphere of nitrogen. The vial was cooled, and more 1,1,1-trifluoro-2,3-epoxypropane (112 mg, 1 mmol) was added. The vial was sealed, then stirred and heated to 95° C. for a further 20 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:6) to give 518 mg (77%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ 7.20-7.32 (m, 3H), 7.14 (t, 1H), 7.07 (t, 1H), 6.95 (d, 2H), 6.80 (m, 2H), 6.74 (s, 1H), 6.48 (dd, 1H), 6.38 (m, 2H), 4.59 (ABq, 2H), 4.31 (m, 1H), 4.18 (dd, 1H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.54 (dd, 1H), 2.92 (d, 1H), 2.61 (d, 1H). 19F NMR (CDCl3) δ −78.0 (d, 3F), −79.2 (d, 3F). HRMS calcd. for C25H23F6 NO4:516.1611 [M+H]+, found: 516.1618.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][N:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].O>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COCCOCCOCc1cc(C(=O)OC(C)(C)C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCc1cc(C(=O)OC(C)(C)C)nn1CC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 350 mg 5-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-2H-pyrazole-3-carboxylic acid tert-butyl ester in 5 ml of DMF and 46 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature 290 mg of 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added. The reaction was stirred at room temperature for 3 h. Then 10 ml of water were added and the mixture was filtered through a chem elut® cartridge by elution with DCM. After concentration under reduced pressure the crude was subjected to the next reaction without further purification. Yield: 400 mg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:18]
Reactant: Cc1cccc(-c2ccccc2C=CC(=O)O)c1C
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ccccc2C=CC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 18.2 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-acrylic acid (120 mg, 0.40 mmoles) and benzoic acid N′-isopropyl-hydrazide (71 mg, 0.40 mmoles) in DMF (4 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmol) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (30 mg, 18%). LC-MS m/e 403.49(M+H+)