Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.[CH:24]1[C:29]([CH2:30]Cl)=[CH:28][CH:27]=[C:26]([Cl:32])[CH:25]=1.O>COCCOC>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:30][C:29]2[CH:28]=[CH:27][C:26]([Cl:32])=[CH:25][CH:24]=2)[CH:16]=1
Reactant: c1ccc2c(CCN=c3sc4ccccc4s3)c[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(Cn2cc(CCN=c3sc4ccccc4s3)c3ccccc32)cc1
Reaction time: 4 h

Procedure:
Sodium hydride (50% dispersion in mineral oil; 155 mg) is slurried in 5 ml of anhydrous 1,2-dimethoxyethane and treated dropwise with N-(1,3-benzodithiol-2-ylidene)-1H-indol-3-ethanamine (1g, prepared as described in Example 30) in 5 ml of anhydrous 1,2-dimethoxyethane. The mixture is heated at reflux for 3 hours. A solution of α,p-dichlorotoluene (520 mg) in 5 ml of anhydrous 1,2-dimethoxyethane is added dropwise to the refluxing reaction mixture. Refluxing is continued for four hours after addition is complete. The reaction mixture is then poured into water (50 ml) and extracted with two 50 ml portions of dichloromethane. The combined dichloromethane extracts are washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant solid is chromatographed on silica gel (200 ml) eluting with dichloromethanepentane (1:1). The fractions containing product with Rf =0.8 (silica gel, dichloromethane) are concentrated. The solid thus obtained is recrystallized from hexane to yield 600 mg of the title compound, melting point 120°-121° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[CH3:11][N:12]([CH3:32])[CH2:13][CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:18][C:17]1=[O:31]>>[CH3:11][N:12]([CH3:32])[CH2:13][CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH3:3])=[CH:18][C:17]1=[O:31]
Reactant: CCC(=O)c1ccccc1
Reactant: CN(C)CCCn1ccc(C(=O)c2ccc(O)cc2)cc1=O
Product: CCC(=C(c1ccc(O)cc1)c1ccn(CCCN(C)C)c(=O)c1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, propiophenone (0.838 g, 3.0 eq) was reacted with 1-(3-(dimethylamino) propyl)-4-(4-hydroxybenzoyl)pyridin-2(1H)-one (0.8 g, 1.0 eq) to give the desired product (Z was prepared by preparative HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.54 (brs, 1H), 7.34 (d, J=6.8 Hz, 1H), 7.17-7.29 (m, 5H), 7.04 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 5.83 (d, J=1.6 Hz, 1H), 5.75 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.75 (t, J=6.8 Hz, 2H), 2.93 (t, J=6.8 Hz, 2H), 2.73 (s, 6H), 2.37 (q, J=7.2 Hz, 2H), 1.86-1.90 (m, 2H), 0.83 (t, J=7.2 Hz, 3H); m/z=403[M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].C(N1C=C(C2SC3C(=NC=CC=3OC3C=CC(NC(NC(=O)CC4C=CC=CC=4F)=S)=CC=3F)C=2)N=C1)C.[CH3:64][O:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([N:75]=[C:76]=[S:77])=[O:74]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:76]([NH:75][C:73](=[O:74])[CH2:72][C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=4[O:65][CH3:64])=[S:77])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Yield: 82 %

Procedure:
Starting from the compound 308, following the procedure described above for the synthesis of 310a but replacing 2-(2-fluorophenyl)acetyl isothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate, title compound 310b was obtained in 82% yield. 1H NMR (DMSO-d6) δ (ppm): 12,57 (s, 1H), 11.76 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.07 (m, 1H), 7.96 (d, J=1 Hz, 1H), 7.79 (d, J=1 Hz, 1H), 7.69 (s, 1H), 7.6 (m, 2H), 7.26 (m, 2H), 7.0 (d, J=7.4 Hz, 1H), 6.92 (m, 1H), 6.59 (d, J=5.5 Hz, 1H), 4.06 (q, J=7.5 Hz, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 1.4 (t, J=7.4 Hz, 3H). MS (m/z): 562.0 (M+1).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[Cl:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:26])=O>>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:26])=[O:19])=[CH:16][C:15]=1[Cl:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Product: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1Cl

Procedure:
To 1.0 g of this 4-n-dodecyloxy-3-chlorobenzoic acid was added 10 g of thionyl chloride, and the mixture was refluxed for 3 hours and unreacted thionyl chloride was removed under a reduced pressure. Thus, 4-n-dodecyloxy-3-chlorobenzoic acid chloride was quantitatively obtained. A solution of the so-obtained compound in toluene was added dropwise to a solution of 0.59 g of p-benzyloxyphenol and 0.3 g of triethylamine in toluene, and the mixture was stirred overnight. The thus-obtained solution was diluted with ethyl acetate, and the dilution was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous sodium sulfate and concentrated under a reduced pressure to obtain p-benzyloxyphenyl 4-dodecyloxy-3-chlorobenzoate. The so-obtained ester was dissolved in ethyl acetate and 1 g of 5%-Pd/C was added to the solution, and the mixture was stirred at room temperature under a pressure of 3 atmospheres in a hydrogen atmosphere for three days and three nights. The Pd/C was removed by filtration and the filtrate was recrystallized from n-hexane to obtain 500 mg of 4-hydroxyphenyl 4-dodecyloxy-3-chlorobenzoate.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:12](#[N:14])[CH3:13]>C1COCC1.Cl>[CH:3]1([C:8](=[O:10])[CH2:13][C:12]#[N:14])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCC1
Temperature: 70 °C
Yield: 76.7 %

Procedure:
To a suspension of sodium hydride (1.87 g, 55% in mineral oil, 42.9 mmol) in THF (10 ml) was added a solution of methyl cyclopentanecarboxylate (5 g, 39.0 mmol) and acetonitrile (1.92 g, 2.45 ml, 46.8 mmol) in THF (3 ml) dropwise at 70° C. The mixture was heated to 70° C. overnight, then cooled to room temperature, diluted with 1N HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 95:5-85:15) to afford the title compound (4105 mg, 77%) as light yellow liquid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[S:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)s2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)s4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc/hexanes) gave the product as a pale yellow solid (0.044 g, 15% yield). MS: m/z 529.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N-:13]=[N+]=[N-].[Na+].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[NH:13][CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCNC(=O)CC1
Temperature: 10 °C
Yield: 70 %

Procedure:
In a 250 ml three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 5.6 ml (5.98 g, 34 mmoles, 1 eq) of ethyl 4-oxocyclohexanecarboxylate 27 were dissolved in 50 ml of CHCl3. 6.65 g (102 mmole, 3 eq) of sodium azide were added, followed by 22.1 ml (32.8 g, 341 mmoles, 10 eq) of methanesulfonic acid dissolved in 20 ml of over 30 min. The mixture was heated to reflux for 1 hour and cooled down to 10° C. 200 ml of saturated sodium bicarbonate solution were added, the mixture decanted and the aqueous phase extracted with 3×150 ml of CHCl3, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (800 g SiO2, CH2Cl2/MeOH, 97/3) to give 5.1 g of crude compound. It was crystallised from 40 ml of diethylether to give 4.41 g of pure ester 28, 70% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22].C1(C)C=CC=CC=1>C(OCC)C>[O:19]1[CH2:18][CH2:24][O:23][CH:20]1[CH2:21][NH:22][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(CN)OC
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc([N+](=O)[O-])c(NCC2OCCO2)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 285.4 %

Procedure:
4-t-Butyl-2,6-dinitrochlorobenzene (1.8 grams; 0.007 mole), aminoacetaldehyde dimethyl acetal (1.5 grams; 0.0014 mole) and toluene (50 ml) were placed in a glass reaction vessel equipped with a stirrer, heating mantle, reflux condenser and thermometer and stirred overnight. Diethyl ether (50 ml) was added to the reaction mixture which was filtered and the filtrate then was evaporated. Toluene (50 ml), ethylene glycol (0.49 grams) and P-toluenesulfonic acid were added and the solution was refluxed for 2 hours. Then one-half the toluene was removed by distillation. The residue was chromatographed on silica to remove unreacted starting materials. The product (1.3 grams) was obtained as a yellow solid (melting point 81°-82° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:12]([CH3:13])[C:10](=[O:11])[NH:9][C:7]1=[S:8].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:12]([CH3:13])[C:10](=[O:11])[N:9]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]1=[S:8]
Reactant: Cc1c(-c2ccccc2)n(COCCO)c(=S)[nH]c1=O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)n(COCCO)c(=S)n(Cc2ccccc2)c1=O
Yield: 31.4 %

Procedure:
To 2 ml of dimethylformamide, 0.62 g (2.0 mmol) of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine, 0.26 ml (2.2 mmol) of benzyl bromide and 0.38 ml (2.2 mmol) of ethyldiisopropylamine were added and allowed to react for 5 days at room temperature under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was adsorbed on a silica gel column and eluted with 1% methanol/chloroform to obtain 0.24 g of the target compound (Yield: 30%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Yield: 96.4 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and ethanolamine (1.32 g, 22 mmol) to give the title compound (5.4 g, 98%) as an off-white solid. MS (ISP) 280.0 [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:46])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39]C4CCCCO4)[CH:34]=3)[S:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1.O1CCOCC1>[OH:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:19]([S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21])[C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[CH:11][C:10]([NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:46])=[CH:18][CH:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)NCCc3ccncc3)cc2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(C=CC(=O)NCCc3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of N-(2-pyridin-4-yl-ethyl)-3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylamide (0.059 g, 0.09 mmol) in 0.4 mL methanol and 0.1 mL tetrahydrofuran was added HCl (0.5 mL of a 4.0 M solution in 1,4-dioxane, 2 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. The residue was purified by preparative TLC (eluting with 10% methanol/methylene chloride) to afford 0.018 g of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-N-(2-pyridin-4-yl-ethyl)-acrylamide. 1H NMR (CDCl3) δ 8.32 (d, 2H, J=4.8 Hz), 7.27 (d, 1H, J=16.4 Hz), 7.18 (d, 2H, J=5.2 Hz), 7.03–6.98 (m, 4H), 6.90–6.86 (m, 4H), 6.69 (s, 2H), 6.60 (d, 1H, J=7.2 Hz), 6.24 (d, 1H, J=15.6 Hz), 4.67 (s, 2H), 3.62–3.57 (m, 2H), 2.88 (t, 2H, J=6.4 Hz), 2.41 (s, 6H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[O:42]=[C:43]([C@H:49]([CH3:65])[C@@H:50]([O:56][C:57]([O:59][CH2:60][C:61]([Cl:64])([Cl:63])[Cl:62])=[O:58])[C@@H:51]([CH3:55])[CH2:52][CH:53]=[CH2:54])[C:44]([CH3:48])([CH3:47])[CH:45]=[O:46]>C(Cl)Cl>[O:42]=[C:43]([C@H:49]([CH3:65])[C@@H:50]([O:56][C:57]([O:59][CH2:60][C:61]([Cl:62])([Cl:63])[Cl:64])=[O:58])[C@@H:51]([CH3:55])[CH2:52][CH:53]=[CH2:54])[C:44]([CH3:48])([CH3:47])[C@@H:45]([OH:46])[C@H:2]([CH3:3])[C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S)-3-propionyl-4-benzyloxazolidinone (91 mmol) in 200 mL of CH2Cl2 at 0° C. is treated sequentially with dibutylboron triflate (27 mL) and triethylamine (16.7 mL) at such a rate so as to keep the reaction temperature below 3° C. After stirring for 30 minutes, the mixture is cooled to −78° C. and treated with a solution of (4R,5S, 6S)-3-oxo-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonenal (90 mmol) in 10 mL of CH2Cl2. After 1 hour, the mixture is allowed to warm slowly to 0° C. and stirred an additional 1 hour. The reaction is quenched by addition of 100 mL of pH 7 phosphate buffer and 300 mL of methanol. A mixture of 2:1 methanol/30% aq. H2O2 (300 mL) is then added while maintaining the temperature below 10° C. After stirring for 1 hour, the mixture is concentrated under vacuum to a slurry, which is extracted with ether. The extract is washed sequentially with 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated. The product is isolated by silica gel chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:7]O)([O-:3])=[O:2].S(Cl)([Cl:21])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:7][Cl:21])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CCl)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
170.5 g of 3-nitro-6-(phenylthio)-benzyl alcohol are suspended in 54.5 ml of pyridine and 170 ml of chloroform and treated dropwise at a temperature below 20° C over a period of 30 minutes with a solution of 78 g of thionyl chloride in 55 ml of chloroform. The mixture is stirred for 30 minutes at 30° C and subsequently diluted with water. The organic phase is washed successively with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated. There is obtained crude 3-nitro-6-(phenylthio)-benzyl chloride of melting point 58°-60° C.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].O1CCOCC1.[Br:15]Br.C(=O)(O)[O-].[Na+]>C(OCC)C.ClCCl>[Br:15][CH:3]([CH:2]=[O:1])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)CCC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CC(Br)C=O
Reaction time: 2 h
Yield: 107 %

Procedure:
A 500-mL round bottom flask was charged with methyl 4-oxobutanoate (8.52 g, 73.3 mmol), dioxane (0.7 mL) in diethyl ether (70 mL). Bromine (3.94 mL, 77.0 mmol) was added at room temperature over 1.5 h. After this time, the mixture was diluted with dichloromethane (250 mL) and solid sodium bicarbonate (13.6 g, 161 mmol) was added. After stirring for 2 h the mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound (15.3 g, 100%) as a colorless oil. MW=195.01. 1H NMR (CDCl3, 300 MHz) δ 9.54 (s, 1H), 4.68 (dd, J=6.9, 6.6 Hz, 1H), 3.74 (s, 3H), 3.25 (dd, J=17.4, 7.2 Hz, 1H), 2.94 (dd, J=17.1, 6.6 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCc3ccccc3)cc2)cc1
Yield: 45.9 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzamide from Example 247, step 2 (0.1 g, 0.41 mmol), benzylamine (0.040 g, 0.38 mmol), 4 Å molecular sieves (1 g) in methanol (5 mL), and stir for 18 h at ambient temperature. Add sodium borohydride (0.058 g, 1.52 mmol), agitate 66 h at ambient temperature. Filter through a 5 g SCX column, eluting first with 1:1 dichloromethane/methanol. Discard the first washings, then elute with 1:1 dichloromethane/2 M ammonia in methanol. Collect the eluants and concentrate in vacuo. Purify by Chromatotron, on a 2 mm silica plate, eluting with 90:10:1 dichloromethane/ethanol/ammonium hydroxide to afford the title compound (0.058 g, 46%): mass spectrum (ion spray): m/z=333.06 (M+1); 1H NMR (DMSO-d6): 7.82 (m, 3H), 7.39-7.18 (m, 5H), 7.02-6.97 (m, 4H), 3.67-3.66 (2s, 4H).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:24][C:25]([CH3:27])=[CH2:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[FH:28]>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]([CH2:24][C:25]([F:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:12][CH:13]=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]2[CH2:24][C:25]([CH3:27])([CH3:26])[O:20][C:19]2=[O:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: F
Reactant: C=C(C)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)CC(NS(=O)(=O)c2ccc(Cl)cc2)C(=O)O1
Product: CCOC(=O)C(CC(C)(C)F)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %
Yield: 46 %

Procedure:
pyridine (10 mL) was added to a 0° C. solution of ethyl 2-(4-chloro-benzenesulfonylamino)-4-methyl-4-pentenoate (1.0 g, 3.0 mmol) in THF (15 mL). The reaction mixture was allowed to warm to rt. After 5 h, an additional portion (10 mL) of hydrogen fluoride.pyridine was added. The mixture was stirred for 24 h, then a third portion of hydrogen fluoride.pyridine (10 mL) was added. After a total of 53 h, the reaction was quenched with ice chips (20 mL). The crude mixture was poured into ice water (500 mL) and extracted with CH2Cl2 (2×200 mL). The combined organic layers were washed with sat. aq. NaHCO3 (100 mL) and concentrated in vacuo. The crude concentrate was purified using silica gel column chromatography (10:1 to 5:1 gradient, hexanes/EtOAc) to afford 0.395 g (37% yield) of ethyl 2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoate and 0.425 g (46% yield) of 4-chloro-N-(5,5-dimethyl-2-oxo-tetrahydro-furan-3-yl)-benzenesulfonamide. Data for ethyl 2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoate: LCMS (M+Na)+374.1; 1H NMR (500 MHz, CDCl3) 7.78 (d, 2H, J=8.9), 7.47 (d, 2H, J=8.5), 5.19 (d, 1H, J=7.9), 4.08 (m, 1H), 3.93 (m, 2H), 2.09-1.94 (m, 2H), 1.42 (d, 3H, J=21.6), 1.37 (d, 3H, J=21.6), 1.12 (t, 3H, J=7.0). Data for 4-chloro-N-(5,5-dimethyl-2-oxo-tetrahydro-furan-3-yl)-benzenesulfonamide: LCMS (M+Na)+326.0; 1H NMR (400 MHz, DMSO-d6) 8.41 (d, 1H, J=9.1), 7.86 (d, 2H, J=8.6), 7.67 (d, 2H, J=8.8), 4.57 (m, 1H), 2.22 (dd, 1H, J=12.4, 9.0), 1.72 (t, 1H, J=12.0), 1.33 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[I:9]C.[CH:11](OC(C)C)(C)C>ClCCl>[I-:9].[CH3:1][N+:2]1([CH3:11])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC(C)OC(C)C
Reactant: CI
Reactant: CN1CCC(=O)CC1
Solvent: ClCCl
Product: C[N+]1(C)CCC(=O)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-4-piperidone (1.0 g) in dichloromethane (5 ml) was slowly added iodomethane (1 ml) at 0° C. and stirred for 30 minutes at ambient temperature. To the reaction mixture was added isopropyl ether (10 ml), and the resulting precipitate was collected by filtration to give 1,1-dimethyl-4-oxopiperidinium iodide (1.416 g).