Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([O:28][CH2:29][CH3:30])[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:8]1=[O:27])C.[OH-].[Na+].Cl.O>CO>[CH2:29]([O:28][CH:6]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:8]1=[O:27])[CH2:5][C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)CC(OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid ethyl ester (50 mg, 0.11 mmol) in MeOH (3.0 mL) is added 2.0 N NaOH solution (1.0 mL). The reaction mixture is stirred at room temperature for 2 h. Then 1.0 M HCl solution (3.0 mL) and water (10 mL) are added and the reaction mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, dried and concentrated to give 45 mg (96%) of the crude 3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=O)[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>CCOCC>[CH2:23]([NH:27][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[N:5][CH2:4][CH2:3][CH2:2][CH3:7])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12)[CH2:24][CH2:25][CH3:26]
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Reactant: CCCCN
Solvent: CCOCC
Product: CCCCN=C1c2ccccc2CCc2c1nc1c(cnn1CC)c2NCCCC

Procedure:
10.8 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.035 mol.) and 100 ml. of butylamine are reacted in an autoclave by the procedure of Example 5, yield: 9.8 g. (70%); m.p. 124°-125° (ether; refrigerator).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18]3[N:22]([CH2:23][CH:24]=[CH2:25])[CH:21]=[CH:20][N:19]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[SH:27][C:28]1[S:29][CH:30]=[N:31][N:32]=1.B(F)(F)F.CCOCC>C(#N)C>[CH2:23]([N:22]1[CH:21]=[CH:20][N:19]=[C:18]1[NH:17][CH:16]1[C:15](=[O:26])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:7][S:8][C@H:9]12)[CH:24]=[CH2:25]
Reactant: Sc1nncs1
Reactant: C=CCn1ccnc1NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: C=CCn1ccnc1NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Yield: 11.4 %

Procedure:
To a suspension of 3-acetoxymethyl-7-(3-allylimidazol-2-yl)aminoceph-3-em-4-carboxylic acid (0.038 g.) and 2-mercapto-1,3,4-thiadiazole (0.012 g.) in acetonitrile (0.2 ml.) was added boron trifluoride etherate (48% w/w, 32 μl) and the mixture heated at 60° for 2.5 hours. The solvent was evaporated and the residue dissolved in water/MeOH/HOAc 70:30:1 v/v/v (2 ml.). The solution was decanted from the residual tar and then purified by HPLC using water/MeOH/HOAc 70:30:1 then 60:40:1 v/v/v as eluants to give 7-(3-allylimidazol-2-yl)amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (5 mg.) having the following n.m.r. in d6DMSO+CD3CO2D: 3.20 (d, 2H); 3.50 (d, 1H); 3.75 (d, 1H); 4.31 (d, 1H); 4.60 (d, 1H); 5.0-5.38 (m, 3H); 5.52 (d, 1H); 5.8 (m, 1H); 6.5 (s, 1H); 9.49 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13](C(OCC2C=CC=CC=2)=O)[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:13][C@@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=[CH:31][CH:30]=1)[C@@H:11]([OH:15])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)nc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2ccc(C[C@H](N)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 74B (0.312 g, 0.48 mmol) in methanol (5 mL) was treated with Pd(OH)2 on carbon (0.10 g, 20% Pd by wt.) and HCl solution (0.240 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite®, rinsed with methanol and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound as the hydrochloride salt (0.178 g, 53% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:11]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:10]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccc([N+](=O)[O-])cc1)CN2c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccc(N)cc1)CN2c1ccccc1
Yield: 99.9 %

Procedure:
tert-Butyl 3-(4-nitrobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.59 g, 5.55 mmol) and palladium on carbon (10 wt. %, wet, Degussa type E101 NE/W) (0.52 g) in ethyl acetate (30 mL) was stirred at room temperature under hydrogen (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate evaporated and dried under vacuum to give product as an oil (2.42 g, quant.); 1H NMR (DMSO-d6); δ1.45 (s, 9H); 1.57 (d, J=14 Hz, 2H); 2.39 (m, 2H); 3.45 (m, 2H); 3.88 (m, 2H); 4.36 (s, 2H); 4.52 (s, 2H); 5.09 (s, 2H); 6.53 (m, 2H); 6.64 (d, J=8 Hz, 2H); 6.75 (t, J=7.6 Hz, 1H); 6.96 (d, J=8.4 Hz, 2H); 7.16 (dd, J=7.2 Hz and 8.8 Hz, 2H); MS for C25H32N4O3 m/z 437 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:21]1([S:34][CH2:35][CH2:36]O)[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:1]([O:3][C:4]([CH:5]1[C:21]2([CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[S:34][CH2:35][CH2:36][N:6]1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:38])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OCC)C2(SCCO)CCN(Cc3ccccc3)CC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCSC3(CCN(Cc4ccccc4)CC3)C2C(=O)OCC)cc1

Procedure:
A mixture of ethyl(1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)acetate (5.0 g, 8.9 mmol), tributylphosphine (4.04 g, 20 mmol) and 1,1-(azodicarbonyl)-dipiperidine (5.04 g, 20 mmol) was stirred in dry THF at room temperature for 6 h. The reaction mixture was quenched with water, extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel column chromatography eluting with 60% ethyl acetate/hexane to give ethyl-9-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl)-1-thia-4,9-diazaspiro[5.5]undecane-5-carboxylate as a pale yellow oil; Yield: 4.2 g (87.5%); Electrospray Mass Spec: 543 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:25]([O:22][C:15]1[C:14]2[C:12](=[O:13])[CH:11]=[C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:4][CH:3]=[CH2:8])[CH:7]=3)[O:20][C:19]=2[CH:18]=[C:17]([O:21][CH2:7][CH:6]=[CH2:5])[CH:16]=1)[CH:26]=[CH2:27]
Reactant: C=CCBr
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCC=C)c2c(=O)cc(-c3ccc(OC)c(OCC=C)c3)oc2c1
Temperature: 40 °C
Reaction time: 22 h

Procedure:
30 g of diosmetin in 300 ml of dimethylformamide are added to a suspension of 11.7 g of sodium hydride in 150 ml of dimethylformamide. The mixture is maintained at 40° C. with stirring until the evolution of gas has ceased. 48 g of allyl bromide are then added and stirring at 40° C. is continued for 22 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][C:6]=1[CH3:15].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:44]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:42][C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:44]=3)[CH:12]=2)[CH2:7][C:6]=1[CH3:15]
Reactant: COC(=O)CC1=C(C)Cc2ccc(O)cc21
Reactant: ClCc1ccc2ccccc2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC1=C(C)Cc2ccc(OCc3ccc4ccccc4n3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
A mixture of 2-methyl-5-hydroxy-1H-indene-3-acetic acid methyl ester (1.8 g, 8.25 mmol), powdered anhydrous potassium carbonate (1.13 g, 8.25 mmol) and 18-crown-6 (0.219 g) in acetonitrile (21 mL) is stirred at room temperature for 15 minutes. 2-(Chloromethyl)quinoline (1.6 g, 9.08 mmol) is then added and the mixture is stirred for 15 hours at 65° C. After the solvent is removed, the residue is partitioned between water and ethyl acetate. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by flash chromatography (eluant: methylene chloride-ethyl acetate) to afford 2.35 g (79%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])#[N:2].ClCCCl.S(=O)(=O)(O)O.[N+:32]([O-])([O-:34])=[O:33].[K+]>O>[C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:8]([CH:7]=1)[C:9]([OH:11])=[O:10])#[N:2]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 0 °C

Procedure:
The product from (a) (9.22 g) was added in portions to a mixture of 1,2-dichloroethane (25 ml) and concentrated sulphuric acid (40 ml) stirred at 0° C. Potassium nitrate (3.13 g) was then added in portions with stirring at 0° C., over a period of 15 minutes. The mixture was then stirred at 0° C. for 30 minutes, allowed to warm to room temperature, and poured into 200 ml of ice and water. The mixture was stirred until the ice had melted, and filtered with suction. The solid which separated on evaporation of the dichloroethane was washed with water and taken up in ether. The ether solution was treated with charcoal, dried and petroleum (b.p. 40°-60° C.) added. The solid which separated was identified as the required benzoic acid derivative (7.8 g) having a melting point of 190°-192° C.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][CH:7]([C:13](OCC)=[O:14])[C:8](OCC)=[O:9].C[O-].[Na+]>C(O)C>[NH2:4][C:3]1[N:5]=[C:8]([OH:9])[C:7]([CH3:6])=[C:13]([OH:14])[N:2]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(N)nc1O
Temperature: 65 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred mixture of guanidine hydrochloride (1.91 g, 20.0 mmol) and diethyl methylmalonate (3.48 g, 20.0 mmol) in ethanol (30 ml) was added sodium methoxide (2.7 g, 50.0 mmol, 25% in methanol) dropwise. The cloudy mixture was stirred at 60-70° C. for 16 hours. After evaporation of volatiles under reduced pressure, the residue was treated with 1.0 M hydrochloric acid until pH=2. Filtration and drying provided 2-amino-4,6-dihydroxy-5-methyl-pyrimidine (2.5 g, 90% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([Br:15])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([Br:15])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1csc(Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
4.78 g (purity 77%, 10.882 mmol) of 2-amino-4-(2-bromo-1,3-thiazol-4-yl)-6-sulfanylpyridine-3,5-dicarbonitrile were initially charged in 30 ml of DMF, 2.923 g (11.971 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 2.742 g (32.647 mmol) of sodium bicarbonate were added and the mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the precipitated solid was filtered off with suction, washed with water and dried under high vacuum. The contaminated product was applied to silica gel and purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). The product-containing fractions were concentrated, the residue was triturated with dichloromethane and the solid was filtered off, washed with dichloromethane and dried under high vacuum. This gave 1.1 g of the target compound in a purity of 91% (yield: 17% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[NH3:15]>>[N+:1]([C:4]1[C:5]([C:10]([NH2:15])=[O:11])=[C:6]([C:7]([OH:9])=[O:8])[CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
52.5 g (0.27 mol) of 3-nitrophthalic anhydride were stirred in portions over the course of 30 minutes into 75 ml of concentrated aqueous ammonia at room temperature. The mixture was then cooled to 0° C., after which a precipitate crystallized out and was filtered off with suction. This precipitate was dissolved in 125 ml of water by gently heating, and 25.6 ml of 32% strength hydrochloric acid were rapidly added. The mixture was cooled to 0° C., and the crystals which separated out were filtered off with suction. 45 g of the product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[C:30]([OH:40])=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:28][C:29]1[C:30]([OH:40])=[C:31]([S:36]([N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=2)(=[O:38])=[O:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: Fc1ccc(CCNCc2cccc(CSCCc3ccccc3)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(CCc1ccc(F)cc1)Cc1cccc(CSCCc2ccccc2)c1
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-N-(3-(phenethylthiomethyl)benzyl)ethanamine (70 mg, 0.184 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (63 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol). The resulting reaction mixture was stirred at it for 1.5 h. The reaction mixture was concentrated and the residue was dissolved in MeOH. The mixture was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated in vacuo and lyophilized to give the title compound (50 mg, 44%) as a white solid. 1H NMR (CDCl3) δ 9.15 (s, 1H), 7.55 (d, J=4.0 Hz, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.34-7.15 (m, 9H), 6.98-6.89 (m, 4H), 4.40 (s, 2H), 3.70 (s, 2H), 3.35 (t, J=8.0 Hz, 2H), 2.86 (t, J=4.0 Hz, 2H), 2.69-2.63 (m, 4H). MS (ESI): 602.0 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7](/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2/[CH:21]=[CH:20]/[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)CCCCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1
Yield: 92 %

Procedure:
A solution of 1.70 g (3.38 mmol, 75% pure) of methyl 4-{7-cyano-3-[2-(2-hydroxyphenyl)vinyl]heptyl}benzoate from Example 95A in 20 ml of dry acetonitrile is mixed with 1.53 g (7.76 mmol) of 4-(tert-butyl)benzyl bromide and 1.4 g (10.13 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The resulting crude product is taken up on silica gel and purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 1700 mg (3.12 mmol, 96% purity, 92% yield) of an oil are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>CC(C)=O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=Cc1ccco1
Solvent: CC(C)=O
Product: Oc1cccc2ccc(C=Cc3ccco3)nc12
Temperature: 25 °C

Procedure:
A mixture of 8-hydroxyquinaldine (5.09 g) and 2-furaldehyde (8.0 mL) are heated at reflux overnight. The reaction is cooled to room temperature. The residue is taken up in acetone and adsorbed onto silica. A silica gel column eluting with 100% CH2Cl2 is run and the product-containing fractions evaporated under reduced pressure to give an orange/yellow oil. The product is crystallized with EtOH/H2O, filtered, washed thoroughly with water, and dried (1.18 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:10][CH2:9]2>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:10][CH2:9]2
Reactant: COC(=O)C=Cc1ccc2c(c1)CCN2C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc2c(c1)CCN2C1CCCCC1

Procedure:
A solution of 3-(1-cyclohexyl-2,3-dihydro-1H-indol-5-yl)-acrylic acid methyl ester (1.60 g, 5.61 mmol) in methanol (30 mL) with 10% palladium on carbon (0.16 g) was hydrogenated at 55 psi and room temperature for 20 hours. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography, using 7.5% ethyl acetate in hexane as the eluant, to give the product, 1.36 g (84%), an oil. MS: m/z 288 (MH+). 1H NMR (CDCl3): 1.04-1.21 (m, 1 H), 1.26-1.43 (m, 4 H), 1.64-1.73 (m, 1 H), 1.78-1.86 (m, 4 H), 2.82 (t, 2 H), 2.84-2.92 (m, 4 H), 3.29 (m, 1 H) super imposed on 3.34 (t, 2 H), 3.66 (s, 3 H), 6.31 (d, 1 H), 6.85 (d, 1 H) and 6.87 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:18]O>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:18])=[O:7]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of 3-(trifluoromethyl)benzoic acid (5 g, 26.30 mmol, 1.00 equiv) in methanol (25 mL) was added dropwise thionyl chloride (9.39 g, 78.93 mmol, 3.00 equiv) and the resulting solution was stirred for 2 h at 75° C. in an oil bath. The mixture was concentrated under vacuum, diluted with 100 mL of ethyl acetate and then washed with 2×30 mL of sodium carbonate and 2×30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 4.6 g (86%) of methyl 3-(trifluoromethyl)benzoate as yellow oil
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][OH:34])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.CCOCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH2:33][O:34][C:43](=[O:44])[NH:42][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 100 mL round bottomed flask under N2 were charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxymethylphenyl]propionic acid tert-butyl ester (3.0 g, 6.11 mmol), cyclohexylisocyanate (4.7 mL, 36.7 mmol), and anhydrous CH2Cl2 (25 mL). A 1.0 M HCl solution in ether (3.06 mL, 3.06 mmol) was added, and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The mixture was diluted with CH2Cl2 (100 mL), washed with brine, dried (Na2SO4), and concentrated to a brown oil. This crude oil was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 5:95) to a colorless oil (3.1 g, 82%). 1H NMR (400 MHz, CDCl3) 1.08-1.24 (m, 1H), 1.26-1.40 (m, 11H), 1.56-1.62 (m, 2H), 1.68-1.72 (m, 2H), 2.41 (t, J=8.3 Hz, 2H), 2.80 (t, J=7.8 Hz, 2H), 3.47 (br s, 1H), 4.56 (br s, 1H), 4.95 (s, 2H), 6.57 (dd, J=8.3, 2.7 Hz, 1H), 6.80 (s, 1H), 6.87 (d, J=8.6 Hz, 1H), 7.33-7.44 (m, 6H), 7.69-7.72 (m, 4H). MS (ES) m/e 616 (M+1).