Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](OCC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:19][CH2:18][CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:33])([F:34])[F:35])(=[O:24])=[O:25])=[N:16][CH2:15]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4C(F)(F)F)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a mixture of ethyl {2-[7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (1.4 g), lithium borohydride (0.30 g) and tetrahydrofuran (20 mL) was added methanol (3 mL), and the mixture was stirred at room temperature for 3 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:5-7:3), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (0.79 g, yield: 61%) as colorless needle crystals. MS: 484 (MH+). melting point 153-154° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=O.Cl>C1COCC1.CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: O=C(CCCBr)Nc1ccc(O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(NCCCCBr)cc1
Reaction time: 0.25 h

Procedure:
A solution of 18.06 g (0.07 mol) of 4-bromo-N-(4-hydroxyphenyl)butanamide in about 120 mL of THF was filtered to remove 0.6 g of a solid and placed in a 2 L flask under nitrogen. It was stirred magnetically in an ice bath while 280 mL (0.28 mol) of 1M borane-THF complex was dripped in over 20 minutes. The reaction was stirred cold for 1/2 hour, then at room temperature for 15 minutes, then at reflux for two hours on a steam bath. The reaction was cooled with an ice bath and diluted with 275 mL of methanol followed by 20 mL of 8N ethanolic HCl. This solution was heated at reflux for six hours on a steam bath and then allowed to stand at room temperature overnight. The next morning the solution was evaporated and the residue was dissolved in acetonitrile and evaporated again. The oily residue was slurried three times with ether and the ether decanted after each addition. After the last decanting the solution was evaporated on a rotary evaporator to yield an oil which was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[O:18][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A solution of 3-benzyloxy-4-nitrophenol (EP application 095121) (6.3 g, 25.7 mmol), t-butyldimethychlorosilane (5.81 g, 38.6 mmol), imidazole (3.5 g, 51.4 mmol), and dimethylaminopyridine (2-3 mg) in DMF (20 mL) is stirred 18 h. The solution is poured into EtOAc and extracted once with water and five times with brine. The organic phase is dried, filtered, and concentrated to afford the title compound: 1H NMR (CDCl3δ 7.73 (d, J=9.1 Hz, 1H), 7.21 (m, 5H), 6.31 (d, J=2.5 Hz, 1H), 6.26 (dd, J=8.8, 2.5 Hz, 1H), 5.02 (s, 2H), 0.78 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: CS(C)=O.[CH2:5]([OH:7])[CH3:6].[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:49])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:48])=[C:34]([O:36][CH:37]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[C:41](F)[C:40]=4[Cl:47])[CH3:38])[CH:35]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:49])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:48])=[C:34]([O:36][CH:37]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[C:41]([O:7][CH2:5][CH3:6])[C:40]=4[Cl:47])[CH3:38])[CH:35]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(Oc1cc(-c2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccc(Cl)c(C(C)Oc2cc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cnc2N)c1Cl
Temperature: 40 °C

Procedure:
To 4 mL of DMSO was added 0.124 ml ethanol followed by 32 mg NaH. After stirring for 30 minutes 250 mg of 250 mg 4-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester was added and the reaction was heated to 40° C. After three hours the reaction was cooled and poured into water to precipitate. After neutralization to pH 6, 200 mg of a tan solid was isolated, 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][NH2:13].[C:14]([N:19]=[C:20](OCC)[CH2:21][CH2:22][CH2:23][CH3:24])(OCC)=[O:15].C(Cl)Cl>CO>[CH2:21]([C:20]1[NH:19][C:14](=[O:15])[N:12]([C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[Cl:1])[N:13]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=NC(=O)OCC)OCC
Reactant: COC(=O)c1ccc(Cl)c(NN)c1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)[nH]1
Yield: 37 %

Procedure:
By the procedure of Example 4, Step C, the title compound was prepared from methyl 4-chloro-3-hydrazinobenzoate (from Step B) and ethyl N-carbethoxyvalerimidate (from Example 4, Step B) in 37% yield as an orange gum (TLC in 95:5 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 310 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([OH:14])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1.[OH-].[Na+]>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([O:14][C:16](=[O:18])[CH3:17])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CC(O)c1ccc(C)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCOC(=O)CC(OC(C)=O)c1ccc(C)nc1
Yield: 90.4 %

Procedure:
4.3 g (0.021 mol) of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester, 3.0 g (0.03 mol) of acetic anhydride, 2.7 g (0.034 mol) of pyridine and 0.17 g (0.0017 mol) of 4-dimethylaminopyridine were stirred at 0° C. for 24 hours. The solution was mixed with 25 ml of 5 percent sodium hydroxide solution and extracted twice, each time with 25 ml of methylene chloride. The organic extracts were evaporated; the residue (4.7 g) contained 3-acetoxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester (yield 90.4 percent).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12](Cl)(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC(C)=O.[NH3:23]>O>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([NH2:23])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)Cl
Reactant: N
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(N)(=O)=O

Procedure:
4-Chloro-3,5-dinitro-o-toluenesulfonyl chloride (10 grams, 0.0318 mole) is dissolved in 150 ml. of acetone and chilled to -15° C. Ammonia (1.08 grams, 0.064 mole) is condensed and then vaporized into the acetone solution. When the addition is complete, the reaction mixture is poured into an equal volume of water and the precipitated solid collected. The crude yield of white solid is 6.8 grams with melting point 205° C. to 215° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.3 g (1.6 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (route 15, step a) in 3 mL DCM at 0° C. were added 0.33 mL (2.4 mmol) triethylamine and 0.19 mL (2.4 mmol) methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 3 hours. 10 mL DCM was added and the mixture was washed with H2O (3×15 mL). The organic phase was dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3 to 6:4).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH3:32][C:33]1([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=2)[NH:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>CN(C)C=O.O>[F:30][C:2]([F:1])([F:31])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:37]3[C:33]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=4)([CH3:32])[C:34](=[O:39])[NH:35][C:36]3=[O:38])[CH2:20][CH2:19]2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCN2C(=O)NC(=O)C2(C)c2ccc(OC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
2-(4-{4-[1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}piperazin-1-yl)ethanol (7.8 mg, 0.0170 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (A11)(15.6 mg, 0.0631 mmol) and triphenylphosphine (15.8 mg, 0.0601 mmol) were dried with a vacuum pump, dissolved in N,N-dimethylformamide (284 μL), added DEAD (23 μL, 0.0167 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water (1.0 mL) and 2N aqueous solution of hydrochloric acid (1.0 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (3.1 mg (yield 26%)) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH:6]([CH2:12][CH2:13][CH3:14])[C:7]([O:9]CC)=O)[CH3:2].Cl.[C:18]([NH2:21])(=[NH:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH2:12][CH2:13][CH3:14])=[C:7]([OH:9])[N:21]=[C:18]([CH3:19])[N:20]=1)=[O:16])[CH3:2]
Reactant: CC(=N)N
Reactant: CCCC(C(=O)OCC)C(=O)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCc1c(O)nc(C)nc1C(=O)OCC
Temperature: 70 °C

Procedure:
A mixture of 120 (20 mmol), acetamidine hydrochloride (40 mmol) and K2CO3 (6.9 g, 50 mmol) in EtOH (50 ml) is heated at 70° C. overnight. The solid is filtered and the residue is dissolved in water (30 ml). Acetic acid is added to adjust the pH to 4. The mixture is then extracted with CH2Cl2 (4×50 ml) and the combined extracts are washed with brine (100 ml). The solution is dried (Na2SO4) and evaporated in vacuo to give a light yellow solid (121), which is used directly in the next step.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)(=O)=O.[C-:18]#[N:19].[Na+]>CS(C)=O>[C:8]12([CH2:7][CH2:6][C:18]#[N:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCC12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCC12CC3CC(CC(C3)C1)C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate 44 (4.1 g, 16.01 mmol) in dimethyl sulfoxide (18 mL) was slowly added sodium cyanide (0.98 g, 20 mmol). The reaction mixture was stirred at 100° C. for 1.5 hours and at room temperature overnight. The crude was partitioned between ether and water and the organic layer was washed with water. The solvent was removed under reduced pressure and the title compound was obtained as a colourless solid (2.9 g, 98%) and used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH:17]([C:19]2[S:23][N:22]=[CH:21][CH:20]=2)[OH:18])=[C:5]([C:24]([F:27])([F:26])[F:25])[N:4]=1.[CH3:29]I>>[F:28][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]([CH:17]([O:18][CH3:29])[C:19]2[S:23][N:22]=[CH:21][CH:20]=2)=[C:5]([C:24]([F:27])([F:26])[F:25])[N:4]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2ccns2)c1CC(C)C
Reactant: CI
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(OC)c2ccns2)c1CC(C)C

Procedure:
Methyl 2-(difluoromethyl)-5-[(isothiazol-5-yl) hydroxymethyl]-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (prepared by the procedure similar to example H of U.S. Pat. No. 5,260,262) was alkylated with methyl iodide by the procedure in example 61 of U.S. Pat. No. 5,169,432.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:9][NH2:10]>O>[CH3:9][NH:10][C:3]([CH3:5])=[CH:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: CN
Reactant: COC(=O)CC(C)=O
Solvent: O
Product: CNC(C)=CC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of methyl acetoacetate (23.2 g, 0.2 mol) in water (15 mL) at 10° C. was added dropwise methylamine (40% aqueous solution, 18.6 g, 0.24 mol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting solid precipitate was collected by filtration and washed with ice water (2×), and then dried in a vacuum oven at 55° C. overnight to provide the title compound as a white solid (20.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].II.[I:14]([O-])(=O)(=O)=O.[Na+].S(=O)(=O)(O)O>O.C(O)(=O)C>[I:14][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)cc1I
Temperature: 105 °C
Reaction time: 6 h
Yield: 149.2 %

Procedure:
Commercially available 2,4-dimethylbenzoic acid (6.6 g, 44.0 mmol), iodine (12.1 g, 47.8 mmol), and sodium periodate (4.38 g, 22.1 mmol) were placed in a reaction vessel, and acetic acid (60 ml), anhydrous acetic acid (3 ml), and sulfuric acid (0.75 g) were added thereto. The resulting mixture was stirred at 105° C. for 6 hours. The reaction solution was poured into water (300 ml). The resulting insoluble material was isolated by filtration, washed with water (500 ml), and then dissolved in ethyl acetate (400 ml). The obtained solution was washed sequentially with 5% aqueous sodium thiosulfate solution (100 ml) and saturated sodium chloride solution (200 ml). Then, the solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid material was recrystallized with a 2:1 mixture of ethanol and water (450 ml) to yield 5-iodo-2,4-dimethylbenzoic acid (9.1 g, 75%) as needle crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36]>C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([S:37]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:38])=[O:39])[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccc(F)c(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) was suspended in DCM (4 ml), and triethylamine (121 μl, 1.65 mmol) was added obtaining a solution. 3,4-difluorobenzene-1-sulfonyl chloride (53.1 μl, 0.40 mmol) was added, and the reaction was stirred at RT for 3 hours. The reaction was diluted with DCM and washed with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The residue was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(3,4-difluorophenylsulfonamido)-2-phenylacetate (40 mg; 28% yield), which was used as such in the next step.
Reaction SMILES: [CH3:1]C(C)(C)C#C/C=C/C/C(=C\CCCCOC1C=CC=C(C2C=CSC=2)C=1)/CO.C(I)C.[CH3:33][C:34]([CH3:61])([CH3:60])[C:35]#[C:36]/[CH:37]=[CH:38]/[CH2:39]/[C:40](=[CH:43]\[CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]/[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[CH:59]=[CH:58][S:57][CH:56]=2)[CH:50]=1)/[CH2:41][OH:42].CI>>[CH3:1][O:42][CH2:41]/[C:40](/[CH2:39]/[CH:38]=[CH:37]/[C:36]#[C:35][C:34]([CH3:61])([CH3:60])[CH3:33])=[CH:43]/[CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]/[C:49]1[CH:50]=[C:51]([C:55]2[CH:59]=[CH:58][S:57][CH:56]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)C#C/C=C/C/C(=C\CCC/C=C/c1cccc(-c2ccsc2)c1)CO
Reactant: CC(C)(C)C#C/C=C/C/C(=C\CCCCOc1cccc(-c2ccsc2)c1)CO
Solvent: CI
Solvent: CCI
Product: COC/C(=C/CCC/C=C/c1cccc(-c2ccsc2)c1)C/C=C/C#CC(C)(C)C

Procedure:
The compounds of Examples 30 and 31 are obtained by carrying out the same reaction as in Example 29 except that (E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-7-[3-(3-thienyl)phenoxy]-2-hepten-1-ol and/or ethyl iodide are used in place of (E,E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-8-[3-(3-thienyl)phenyl]-2,7-octadien-1-ol and/or methyl iodide which is the raw material compound used in the above reaction.
Reaction SMILES: [CH3:1][CH:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[C:10](=[O:11])[NH:9][C:7]1=[O:8].O[N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][CH:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[C:12]([CH2:14][CH2:15][O:16][N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])[C:10](=[O:11])[NH:9][C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(CCCn1cc(CCO)c(=O)[nH]c1=O)C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCCn1cc(CCON2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)C(=O)O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
1-(4-Methylcarboxybutyl)-5-(2-hydroxyethyl)uracil (13.2) no (6.213 g. 23 mmol) was dissolved in anhydrous tetrahydrofuran. N-Hydroxyphthalimide (7.505 g, 46 mmol) and triphenylphosphine (12.046 g, 46 mmol) were added and the solution stirred at ambient temperature. Diethylazodicarboxylate (9.95 g, 57 mmol) was added in 0.5 ml aliquots over 10 minutes, the reaction was then stirred for a further hour. The product was recrystallized twice from chloroform : diethyl ether mixtures to yield 1-(4-methylcarboxybutyl)-5-(2-phthalimidooxyethyl)uracil (13.3) (8.77 g, 91.8%). The structure was confirmed by mass spectroscopy and proton NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=O)[CH:8]=O.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:8][NH:14][CH2:11][CH2:12][NH:13]1
Reactant: NCCN
Reactant: Cc1ccsc1C(=O)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccsc1C1CNCCN1
Reaction time: 3 h

Procedure:
A 5 g portion of the above aldehyde was dissolved in 100 ml of ethanol, cooled to 0°-5° C. and a solution of 2.14 g of ethylenediamine in 10 ml of ethanol was added dropwise with stirring. The mixture was allowed to come to room temperature over 3 hours, then 2.4 g of sodium borohydride was added and the mixture was stirred for 18 hours. Water was added, then the mixture was concentrated. The residue was dissolved in dichloromethane, cooled, extracted with water, dried, filtered and evaporated to an oil which crystallized, giving 4.6 g of 2-(3-methyl-2-thienyl)piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C>[N:18]1([CH2:17][CH2:16][CH2:15][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1ccccc1O
Reactant: ClCCCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 2-hydroxybenzoate (2.4 ml, 16.38 mmol), K2 CO3 (4.98 g), and DMF (30 ml) was added N-(3-chloropropyl)morpholine hydrochloride (3.93 g). The mixture was stirred at room temperature for 30 minutes, then was warmed on a steam bath overnight. The reaction mixture was cooled, filtered and stripped to afford a liquid which was partitioned between EtOAc (350 ml) and water. The organic layer was separated, washed with water (2×200 ml), dried over MgSO4 and stripped to afford ethyl 2-[3-(4-morpholinyl)propoxy]benzoate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:27]([Cl:28])=[C:26]([O:29][CH:30]([F:32])[F:31])[N:25]([CH3:33])[N:24]=3)=[C:19]([F:34])[CH:18]=2)=[C:7]([CH:14]=1)[O:8][CH:9]([CH3:13])[C:10](Cl)=[O:11])[CH3:2].[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([NH:39][C:10](=[O:11])[CH:9]([O:8][C:7]1[CH:14]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:27]([Cl:28])=[C:26]([O:29][CH:30]([F:31])[F:32])[N:25]([CH3:33])[N:24]=2)=[C:19]([F:34])[CH:18]=1)[CH3:13])(=[O:38])=[O:37]
Reactant: CCc1ccc(COc2ccc(-c3nn(C)c(OC(F)F)c3Cl)c(F)c2)c(OC(C)C(=O)Cl)c1
Reactant: CS(N)(=O)=O
Solvent: ClCCl
Product: CCc1ccc(COc2ccc(-c3nn(C)c(OC(F)F)c3Cl)c(F)c2)c(OC(C)C(=O)NS(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
A stirring mixture of 2.6 0 grams (0.0050 mole) of 2-[5-ethyl-2-[3-fluoro-4-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)phenoxymethyl]phenoxy]propanoic acid chloride and 0.52 gram (0.0055 mole) of methylsulfonylamine is heated at about 120° C. for two hours. The reaction mixture is then cooled and dissolved in about 35 mL of methylene chloride. The solution is washed with water, dried with magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, yielding the title compound.