Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])(=O)C.[NH4+].[N+:27]([CH3:30])([O-:29])=[O:28]>>[N+:27]([CH:30]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1)([O-:29])=[O:28]
Reactant: C[N+](=O)[O-]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCCCCCCCCCCCOc1ccc(C=C[N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
4-Dodecyloxybenzaldehyde (7.91 g; 27.25 mmol), ammonium acetate (1.57 g; 20.4 mmol) and nitromethane (2.57 ml; 48 mmol) are mixed together and the mixture is heated for 1.5 hours at 105° C. Cooling to 25° C. and extraction with tert-butyl methyl ether (50 ml) are then carried out, and the organic phase is dried over Na2SO4. After filtration, concentration to dryness by evaporation is carried out and the residue is suspended in methanol (80 ml). Filtration is then carried out, and the pale yellow crystals are washed with methanol and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:6]([N+:13]([O-])=O)=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c2cc(C)oc12
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c2cc(C)oc12
Yield: 58.3 %

Procedure:
7-Methoxy-2-methyl-4-nitro-benzofuran (1.24 g, 6.0 mmol) was hydrogenated using Pd/C (10%, dry, 700 mg) and H2 balloon in EtOH (30 mL) at r.t. for 2 h. The reaction mixture was filtered. Purification of the concentrated filtrate by column chromatography (EtOAc:Hexane=2.5:7.5) afforded 7-methoxy-2-methyl-benzofuran-4-ylamine as a brown oil (620 mg, 58%). 7-Methoxy-2-methyl-benzofuran-4-ylamine (620 mg, 3.5 mmol) was dissolved in CH2Cl2 (10 mL). TCDI (thiocarbodiimidazole, 686 mg, 3.9 mmol) was added to the solution and the reaction mixture was stirred at r.t. for 30 min. Silica gel was added to the reaction mixture and the solvent was removed under vacuum. Purification of the silica gel coated crude product by flash column chromatography (EtOAc:Hexane=2:8) afforded the title product as a pale yellow oil (630 mg, 82%).
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[OH:8][C:9]1([CH2:15][CH2:16][N:17]2[C:21](=[O:22])[CH2:20][S:19][CH:18]2[CH2:23][CH2:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C(#N)C>[CH3:1][S:2]([NH:5][C:6](=[O:7])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][CH2:23][CH:18]2[N:17]([CH2:16][CH2:15][C:9]3([OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:21](=[O:22])[CH2:20][S:19]2)=[CH:34][CH:33]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: CS(=O)(=O)N=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 4 h

Procedure:
A solution of methanesulfonylisocyanate (1.33 g., 0.011 mole) in acetonitrile (10 ml.) is added dropwise during 10 minutes to a solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (3.9 g., 0.01 mole) and triethylamine (1.0 g., 0.01 mole) in acetonitrile (30 ml.). The resulting solution is stored at 25° C. for 4 hours and then evaporated at reduced pressure. The residue is treated with water. The crude product is extracted into chloroform and purified by chromatography on a silica gel column with elution by 4% methanol in chloroform.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.C[CH:22]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:25][N:24]([CH2:37][CH:38]([NH:42]C(=O)C2C=CC(C)=CC=2)[CH:39]([CH3:41])[CH3:40])[CH2:23]1>C(Cl)Cl>[Cl:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[Cl:35])[CH2:28][N:27]1[CH2:26][CH2:25][N:24]([CH2:37][C@H:38]([NH:42][S:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]1
Reactant: Cc1ccc(C(=O)NC(CN2CCN(Cc3ccc(Cl)c(Cl)c3)C(C)C2)C(C)C)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)NS(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Triethylamine (21 ml, 0.15 mmol) and 4-fluorobenzenesulfonyl chloride (29 mg, 0.15 mmol) were added to a solution of 1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (50 mg, 0.15 mmol) [prepared as described in Example 1 above] in methylene chloride (1.5 ml). The reaction mixture was stirred for 2 h, then concentrated. Purification by flash chromatography with 20:1 methylene: methanol as the eluant gave N-{1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamide (49 mg) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]>C(O)C.C(O)(=O)C.O.[Pd]>[NH2:2][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(CN)cc1F
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Combine a solution of methyl 4-cyano-2-fluoro-benzoate (1 g, 5.58 mmol) in absolute ethanol (42 mL) and acetic acid (1.9 mL) with a mixture of 10% Pd/C (Degussa type E101, 0.17 g, 0.078 mmol) in water (15.6 mL) at room temperature wider nitrogen. Purge with nitrogen and then with hydrogen at 55 psi and stir for 1 h. Purge the reaction with nitrogen, filter through Celite® and wash the filter cake with ethanol (100 mL), THF (100 mL) and isopropanol (100 mL). Concentrate in vacuo and purify by SCX chromatography and then chromatography on silica gel (40g RediSep® column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 9:1 gradient over 30 min; 35 mL/min) to afford the desired intermediate as a white solid (0.602 g, 59%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30](/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:18][C:19]1[CH:31]=[C:30](/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cccc(C)c3C)c2)c1
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL of N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 52 mg of tert-butyl 2-amino-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2,3-dimethylbenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate.
Reaction SMILES: [C:1]([N:5]1[C:9]([OH:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][CH:35]([F:38])[CH2:36]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[C:1]([N:5]1[C:9]([O:10][CH2:36][CH:35]([F:38])[F:34])=[CH:8][C:7]([C:11]([F:13])([F:14])[F:12])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)cc1O
Reactant: OCC(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)cc1OCC(F)F
Reaction time: 5 h
Yield: 58.4 %

Procedure:
To a solution of 50.0 g (240.2 mmol) of 1-tert-butyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 1000 ml of tetrahydrofuran were added 75.6 g (288.2 mmol) of triphenylphosphine and 23.7 g (288.8 mmol) of 2,2-difluoroethanol at room temperature, followed by stirring. Under ice-cooling, 58.3 g (288.3 mmol) of diisopropyl azodicarboxylate was added into the reaction solution, followed by 5 hours of stirring. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with diethyl ether. The resulting organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled under reduced pressure to obtain 38.2 g (yield: 58.4%) of 1-tert-butyl-5-(2,2-difluoroethoxy)-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:16]O.O.O.Cl[Sn]Cl>CCOC(C)=O.CCOCC.CC(O)=O>[CH3:16][O:5][C:3](=[O:4])/[C:2](/[CH3:1])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: CC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)/C(C)=C/c1ccc(N)cc1
Temperature: 25 °C

Procedure:
α-Methyl-4-nitrocinnamic acid (53 mg, 0.25 mmol) was dissolved in EtOAc and MeOH and a solution of CH2N2 in Et2O was added until a persistent yellow color was observed. A couple of drops of AcOH were added to destroy the excess CH2N2. The mixture was diluted with EtOAc and the organic layer was washed with H2O, aqueous NaOH (1N) and brine, dried over anhydrous MgSO4 and concentrated to dryness. The residue was re-dissolved in EtOH (2 mL), SnCl2.2H2O (289 mg, 1.28 mmol) was added and the reaction mixture was heated to reflux for 1 h. The mixture was cooled to RT, diluted with EtOAc and quenched by the addition of aqueous, saturated NaHCO3. The organic layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated to dryness to give the title compound (40 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:21][CH2:20][C:19]([C:23]([O:25]C)=[O:24])(F)[CH2:18]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(Cl)Cl.C[OH:31].[NH4+].[OH-]>>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:21][CH2:20][C:19]([C:23]([OH:25])=[O:24])([OH:31])[CH2:18]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CO
Reactant: CCCCCCCCCc1ccc(CN2CCC(F)(C(=O)OC)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(CN2CCC(O)(C(=O)O)C2)cc1

Procedure:
The title compound was prepared using an analogous procedure described in EXAMPLE 34, Step E substituting (R/S)-1-(4-nonylphenyl)methyl-3-hydroxypyrrolidin-3-yl carboxylic acid, methyl ester (from Step A) for (R/S)-1-(4-nonylphenyl)methyl-3-fluoropyrrolidin-3-yl carboxylic acid, methyl ester: RF: 0.15 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H-NMR (500 MHz, CD3OD) δ 0.89 (t, J=6.9, 3H), 1.28-1.33 (m, 12H), 1.60-1.63 (m, 2H), 2.10 (m, 1H), 2.49 (m, 1H), 2.64 (t, J=7.7, 2H), 3.25 (m, 1H), 3.49-3.62 (m, 3H), 4.38 (ABq, J=13.0, 2H), 7.28 (d, J=7.8, 2H), 7.42 (d, J=7.8, 2H); ESI-MS 348 (M+H); LC-1: 3.0 min.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:18].[K+].[K+].OO>CS(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH2:16])=[O:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-Phenoxyphenylacetonitrile (1.0 g; 4.8 mmol) was dissolved in DMSO (3 mL) and cooled in an ice-water bath. Potassium carbonate (0.2 g; 1.5 mmol) was added, followed by dropwise addition of 1.0 mL of 30% hydrogen peroxide. The bath was removed, and the mixture allowed to warm to room temperature while stirring for 40 min. Water was added, and the product isolated as a white crystalline solid by filtration, and washed with fresh water. mp 115-117° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])=[CH:6][C:5]=1[CH3:20].C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[CH3:24])=[CH:6][C:5]=1[CH3:20]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1ccc(CNc2ccc(O)cc2F)cc1C
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2ccc(O)cc2F)cc1C
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
A mixture of 4-[(2-fluoro-4-hydroxy-phenylamino)-methyl]-2-methyl-benzoic acid methyl ester (1.89 g, 6.53 mmol) and 37% formaldehyde (2.0 mL) in acetic acid (20 mL) is stirred for 40 minutes. Sodium triacetoxyborohydride (2.80 g, 13.2 mmol) is added and stirred at room temperature. Upon completion of the reaction, the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is separated and extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4) and concentrated under reduced pressure. The residue is purified on 120 g silica eluting with a gradient of ethyl acetate in heptane (10% to 60%) to provide the titled compound (1.0 g, 51%) as a white solid. LC-ES/MS m/e 304.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:52]([O:55][CH2:56][C:57]1[C:58]([N:72]2[CH2:83][CH2:82][N:81]3[C:74](=[CH:75][C:76]4[CH2:77][C:78]([CH3:85])([CH3:84])[CH2:79][C:80]=43)[C:73]2=[O:86])=[N:59][CH:60]=[CH:61][C:62]=1[C:63]1[CH:68]=[C:67](Br)[C:66](=[O:70])[N:65]([CH3:71])[CH:64]=1)(=[O:54])[CH3:53].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:52]([O:55][CH2:56][C:57]1[C:58]([N:72]2[CH2:83][CH2:82][N:81]3[C:74](=[CH:75][C:76]4[CH2:77][C:78]([CH3:85])([CH3:84])[CH2:79][C:80]=43)[C:73]2=[O:86])=[N:59][CH:60]=[CH:61][C:62]=1[C:63]1[CH:68]=[C:67]([NH:9][C:6]2[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:66](=[O:70])[N:65]([CH3:71])[CH:64]=1)(=[O:54])[CH3:53]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COc1ccc(N)nn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)nn1
Yield: 59.3 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 6-methoxypyridazin-3-amine (65 mg, 0.52 mmol), XantPhos (29 mg, 0.050 mmol), Pd2 dba3 (45 mg, 0.050 mmol), [4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-{4,4-dimethyl-9-oxo-1,10-diazatricy-clo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 273a (281 mg, 0.52 mmol), Cs2CO3 (326 mg, 1.0 mmol), and 1,4-dioxane (10 mL). After bubbling nitrogen through the resulting mixture for 20 minutes, it was heated at reflux for 2 h. After the completion of the reaction, the mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (20 mL) and water (10 mL). The ethyl acetate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 306a (180 mg, 60%). MS-ESI: [M+H]+ 584.3.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[C:22]([F:21])([F:31])[F:32])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide to react with 2-trifluoromethylbenzyl chloride, the title compound was obtained as a white solid (32% yield). m.p. 106-108° C. 1H NMR (500 MHz, CDCl3) δ 7.97-8.04, 7.83, 7.65, 7.55, 7.37, 6.96, 3.77, 3.73, 3.56, 2.63, 1.52, 0.71-0.80, 0.45-0.49, 0.08-0.13. MS (ES+) m/z 434 (M+1).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Cl:16])=[C:11]([OH:17])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:5]3[S:1][C:2]4[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=4[CH:4]=3)[CH:7]=2)[C:12]=1[Cl:16])[CH3:34]
Reactant: Oc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
A mixture of 6-benzo[b]thiophen-2-yl-1-chloro-naphthalen-2-ol (3.19 g, 10.2 mmol) and cesium carbonate (6.8 g, 21 mmol) in acetone (100 mL) was stirred at ambient temperature for one hour and 15 minutes. Ethyl bromoacetate (1.4 mL, 12 mmol) was added, and the reaction mixture was stirred for 3.5 hours at ambient temperature. The insoluble solids were then filtered, and the filtrate was solvent evaporated. The residue was dissolved in hot chloroform and washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was then stirred in hexane for about ten minutes and filtered and rinsed with hexane. Drying at 65° C. in vacuo for two hours yielded (6-benzo[b]thiophen-2-yl-1-chloro-naphthalen-2-yloxy)-acetic acid ethyl ester as a light yellow solid (2.7 g, 67%): MP: 187–8° C.; Mass spectrum (+ES, [M+H]+) m/z 397/399. 1HNMR (500 MHz, DMSO-d6): δ8.34 (d, 1H, J=1.68 Hz), 8.21 (d, 1H, J=8.85 Hz), 8.13 (dd, 1H, J=8.93 and 1.76 Hz), 8.01–8.07 (m, 3H), 7.89–7.90 (m, 1H), 7.52 (d, 1H, J=9.15 Hz), 7.37–7.44 (m, 2H), 5.11 (s, 2H), 4.20 (q, 2H, J=7.12 Hz), 1.23 ppm (t, 3H, J=7.10 Hz). Elemental Analysis for C22H17ClO3S: Calcd: C, 66.58; H, 4.32; N, 0.00; Found: C, 66.43; H, 4.27; N, 0.00.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:25])([CH2:13]OC(OC2C=CC(F)=CC=2)=S)[CH2:10][C@H:9]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:25])([CH3:13])[CH2:10][C@H:9]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(COC(=S)Oc2ccc(F)cc2)C[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4R)-4-fluoro-4-(4-fluoro-phenoxythiocarbonyloxymethyl)-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (290 mg, 0.57 mmol) in dioxane (5 mL) were added VAZO (69 mg, 0.28 mmol) and tris(trimethylsilyl)silane (0.24 mL, 0.77 mmol). The reaction mixture was refluxed for 30 min then was stirred for 16 h at RT and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 4:1). MS (UPLC/MS): 338 [M+H]+; tR (HPLC conditions f): 2.38 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C2CCCN2)c(C)c1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(C)cc2C)cc1

Procedure:
The title compound, white solid, m.p. 130° C. and MS: m/e=329 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(2,4-dimethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1.Cl[CH2:12]I.C([Zn]CC)C>ClC(Cl)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=COc1ccc(Br)cc1
Reactant: ClCI
Agent: CC[Zn]CC
Solvent: CC(Cl)Cl
Product: Brc1ccc(OC2CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
39.0 g (176 mmol) 1-Bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled to 0° C. During 1 h 200 mL (200 mmol) diethylzinc solution (c=1 mol/l in hexane) are added and stirring is continued for 2 h at 0° C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH4Cl solution and extracted with TBME (2×). The organic phases are combined, washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CNCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 39.3 %

Procedure:
To a solution of ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}glycinate (D73) (130 mg) in tetrahydrofuran (10 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (28 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. for 4 hours. The reaction mixture was concentrated to about 5 mL and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}glycine (E47) (48 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 3.84 (2H, s), 4.43 (2H, s), 4.90-4.93 (1H, m), 7.34 (1H, t), 7.48 (1H, d), 7.72-7.73 (1H, m), 8.02 (1H, d), 8.05 (1H, d), 8.23 (1H, dd), 8.41 (1H, d), 9.34 (1H, br s), 11.38 (1H, s). MS (ES): C22H21ClN4O4 requires 440; found 366.1 (M—NHCH2COOH+).