Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C@@H:24]1[CH2:29][N:28]([C:30]2[O:31][C:32]3[C:37]([C:38](=[O:40])[CH:39]=2)=[CH:36][C:35]([C:41]([OH:43])=O)=[CH:34][C:33]=3[CH:44]2[CH2:48][CH2:47][CH2:46][N:45]2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:27][CH2:26][O:25]1.CCN(C(C)C)C(C)C.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CC(N(C)C)=O>[CH3:23][C@@H:24]1[CH2:29][N:28]([C:30]2[O:31][C:32]3[C:37]([C:38](=[O:40])[CH:39]=2)=[CH:36][C:35]([C:41]([N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)=[O:43])=[CH:34][C:33]=3[CH:44]2[CH2:48][CH2:47][CH2:46][N:45]2[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:27][CH2:26][O:25]1
Reactant: C1COCCN1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4ccccc4)c3o2)CCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N4CCOCC4)cc(C4CCCN4c4ccccc4)c3o2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
TBTU (148 mg, 0.46 mmol) was added to a stirred solution of 2-((R)-2-methylmorpholino)-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxylic acid (80 mg, 0.18 mmol), DIPEA (0.080 mL, 0.46 mmol) dissolved in DMA (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 30 min. Morpholine (0.048 mL, 0.55 mmol) was added to the mixture and stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fractions containing the desired compound were evaporated to dryness to afford 2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-8-(1-phenylpyrrolidin-2-yl)-4H-chromen-4-one (60 mg, 65%) as a gummy solid.
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[CH2:6][O:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[C:10]([Cl:16])[N:9]=1)[CH2:2][CH3:3].CO.Cl.[OH-].[Na+]>O1CCCC1.C(Cl)Cl.O>[Cl:14][C:13]1[C:8]([O:7][CH2:6][CH2:5][NH:4][CH2:1][CH2:2][CH3:3])=[N:9][C:10]([Cl:16])=[C:11]([Cl:15])[CH:12]=1
Reactant: CCCNC(=O)COc1nc(Cl)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCCNCCOc1nc(Cl)c(Cl)cc1Cl
Yield: 86.2 %

Procedure:
To a stirred solution of 36.8 g (0.124 mole) N-(n-propyl)-3,5,6-trichloropyridyloxyacetamide (Example 2) in 300 ml tetrahydrofuran at room temperature, 27.2 ml 10.272 mole)boranemethyl sulfide were added in three portions (9 ml, 9 ml and 9.2 ml) rapidly through a syringe. The reaction mixture was stirred at its own exotherm, and then at ambient temperature under nitrogen gas overnight. The gel-like mixture was then refluxed under nitrogen gas for two hours. The stirred reaction mixture was then placed in an ice water bath while 60 ml methanol was added dropwise over 1/2 hour resulting in gas (H2) evolution to give a clear solution. The solution was stirred until bubbling (gas evolution) ceased. The reaction mixture was stripped in vacuo to give an oil. The oil was dissolved in 325 ml methylene chloride. To that stirred mixture in an ice bath, 36 ml concentrated hydrochloric acid were added dropwise over 1/2 hour. The resulting mixture was stirred at ambient temperature until gas evolution ceased (about 5 hours). Water (250 ml) was added to the reaction mixture; then concentrated sodium hydroxide (50%) was added until the pH of the mixture reached 10 (about 25 ml). Additional water (200 ml) and methylene chloride (200 ml) were added to the reaction mixture. The resulting mixture was stirred until there were 2 clear layers. The organic layer was separated, washed with water (about 250 ml), dried over magnesium sulfate and filtered. The filtrate was stripped in vacuo to give an oily residue. The residue was slurried in petroleum ether. The petroleum ether mixture was filtered (to remove solids). The filtrate was stripped in vacuo to give 30.3 g of the above-identified product as an oil.
Reaction SMILES: OCCC(NO)=N.ONC(=N)CC.FC(F)(F)CC(NO)=N.[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1([C:33](=N)[NH:34]O)[CH2:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(OC(NC1(C(O)=O)CC1)=O)(C)(C)C>>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1([C:33]#[N:34])[CH2:32][CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1(C(=N)NO)CC1
Agent: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCC(=N)NO
Agent: N=C(CC(F)(F)F)NO
Product: CC(C)(C)OC(=O)NC1(C#N)CC1

Procedure:
The following compounds were prepared using similar procedures as described above: 3,N-Dihydroxy-propionamidine, N-Hydroxy-propionamidine, 3,3,3-Trifluoro-N-hydroxy-propionamidine, N-Hydroxy-dimethylamine-1-carboxamidine, [1-(N-Hydroxy-carbamimidoyl)-cyclopropyl]-carbamic acid tert-butyl ester; (1-Cyano-cyclopropyl)-carbamic acid tert-butyl ester was prepared from 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid according to literature procedures (Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C(OCC)C>[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a stirred suspension of 7.9 g (0.21 mole) of lithium aluminum hydride (Aldrich) in 350 ml of dry ethyl ether was added dropwise a solution of 32.8 g (0.2 mole) of 4-phenylbutyric acid (Aldrich) in 250 ml of dry ethyl ether. The reaction mixture was stirred at ambient temperature for 2 hr, treated successively with 8 ml of water, 25 ml of a 15% sodium hydroxide solution and 8 ml of water, and filtered through Celite®. The filtrate was washed successively with water (200 ml), twice with 300 ml portions of sodium bicarbonate solution, 300 ml of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 25.0 g (83%) of colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH2:12][OH:13])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CO)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-benzyloxy-2-methyl-benzoic acid (621, 3.0 g, 0.012 mol) in tetrahydrofuran (100 mL), lithium aluminum hydride (25 mL, 1M solution in tetrahydrofuran, 0.025 mol) was added dropwise at 0° C. for 5 minutes. The reaction mixture was then stirred at room temperature overnight under an atmosphere of nitrogen. After sodium sulfate decahydrate (20.0 g, 0.062 mol) was added, the reaction mixture was stirred at room temperature for 10 minutes. A white solid was collected by filtration. The solid compound was further washed with a mixture of hexane and dichloromethane (9:1) and dried under high-vacuum (622, 2.8 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.7 %

Procedure:
6-Chloronicotinaldehyde (10 g, 70.6 mmol, Eq: 1.00) was suspended in 700 ml DCM. 1-Methylpiperazine (8.84 g, 88.3 mmol, Eq: 1.25) and acetic acid (8.48 g, 8.09 ml, 141 mmol, Eq: 2.0) were added. Sodium triacetoxyborohydride (22.5 g, 106 mmol, Eq: 1.5) was added in portions over several minutes. The reaction mixture stirred at room temperature. After 3.5 hrs, there was no sign of starting material. LCMS showed product plus a little reduced starting material. Water was added, followed by DCM and the layers were separated. The DCM layer was washed with saturated ammonium chloride and the aqueous layer was combined with the initial aqueous layer. The aqueous extractions were bacidified with 1M NaOH. The resulting aqueous layer was extracted 3 times with DCM, and then dried, and concentrated to give 13.5 grams of a light yellow oil (84.7%) which was used without further purification.
Reaction SMILES: [N+:1]([CH2:4][C:5]([S-:7])=S)([O-:3])=[O:2].[K+].[K+].[N+]([CH2:13]C([S-])=S)([O-])=O.[CH3:17][NH:18][CH3:19].S(OC)(OC)(=O)=O>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH3:17][N:18]([CH3:19])[C:5]([S:7][CH3:13])=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC(=S)[S-]
Reactant: CNC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSC(=C[N+](=O)[O-])N(C)C
Reaction time: 6 h

Procedure:
To a solution of dipotassium nitrodithioacetate (118 g) dissolved in water (630 ml), dimethylamine (1.1 equivalents) was added as a 40% w/w solution in water. After stirring for 6 hours at 20°-25° C., benzyltrimethylammonium chloride (7 g ) was charged followed by dimethyl sulphate (175 g ) over one hour. After stirring overnight, the reaction mixture was extracted three times with 100 ml aliquots of dichloromethane. After drying over MgSO4, the combined organic phases were concentrated to a red oil which was chromatographed on a silica gel column, using ethyl acetate as eluant to give, after recrystallisation from isopropanol, 36 g (40%) of the title compound, m.p. 60° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:8][CH:9]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH3:7])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:8][CH2:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)CC=C(c1ccccc1)c1cccs1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN(C)CCC(c1ccccc1)c1cccs1
Reaction time: 16 h
Yield: 21.7 %

Procedure:
0.055 g (0.174 mmol) N-[3-Phenyl-3-(thien-2-yl)-2-propenyl]sarcosine ethyl ester (Compound 41 from Example 6) was hydrogenated over 0.055 g 10% Pd/C in 2 ml of EtOH. The hydrogenation was conducted at 40 psi for 16 hours at room temperature (see Reaction 20, FIG. 2). After filtering off the catalyst the solution was concentrated and the residue was purified by preparative TLC with 1:2 ethyl acetate:hexanes to give 0.012 g (22%) N-[3-phenyl-3-(thien-2-yl)propyl]sarcosine ethyl ester (Compound A42) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[CH3:18]N(C)CCN(C)C.C([Li])CCC.IC.Cl>CCCCCC.O1CCCC1>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1
Reactant: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(C(F)(F)C(F)(F)F)c1F
Temperature: -40 °C
Reaction time: 4 h
Yield: 11.4 %

Procedure:
5.00 g (98% by weight; 19.0 mmol) of 3-fluoro-4-(pentafluoroethyl)benzoic acid were introduced into 40 ml of dry tetrahydrofuran. 4.73 g (40.7 mmol) of 1,2-bis(dimethyl-amino)ethane were added, and the mixture was then cooled to −40° C. Then 16.3 ml of a 2.5 M solution (40.7 mmol) of n-butyllithium in hexane were added dropwise at a rate such that the temperature was in a range from −33° C. to −35° C. The contents were stirred at a temperature of −35° C. for 4 hours. Then a solution of 8.25 g (58.1 mmol) of iodomethane in 10 ml of dry tetrahydrofuran was added dropwise, and the mixture was stirred at a temperature of −35° C. for 1 hour. Thereafter the contents were warmed to room temperature (RT) and stirred at this temperature for 16 hours. For working up, 50 ml of 2M hydrochloric acid were cautiously added, and then the aqueous phase was extracted with diethyl ether. The combined organic phases were dried and freed from the solvents on a rotary evaporator. The residue was stirred in n-heptane and subsequently filtered. This gave 2.33 g of residue as a clean product. The filtrate was freed from the solvent, and the residue was again stirred in n-heptane. Filtration produced 590 mg of residue, which was identified as a product with a purity of 70% by weight.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[F:12][C:13]([F:17])([F:16])[CH2:14]I>O>[F:12][C:13]([F:17])([F:16])[CH2:14][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: FC(F)(F)CI
Solvent: O
Product: O=C1C(=O)N(CC(F)(F)F)c2ccccc21
Temperature: 55 °C

Procedure:
Sodium hydride (8.65 g of a 60% oil dispersion, 0.22 mol) was washed with hexane and suspended in hexamethylphosphoramide (200 mL). Isatin (29.4 g, 0.20 mol)) was added carefully. After the gas evolution subsided, 2,2,2-trifluoroethyl iodide (46.2 g, 0.22 mol) was added and the mixture was heated to 55° C. for 4 hours. The solution was cooled, diluted with water (1 L), and the precipitate was collected. The filtrate was acidified with 6 N HCl and a new precipitate formed and was collected. The combined solids were recrystallized from 95% ethanol. Yield 22.5 g (49%). mp 161-163° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9](O)=[O:10])[C:6](=[O:12])[C:5]([NH:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1.Cl.Cl.[N:30]1[NH:31][CH:32]=[C:33]2[C:38]=1[CH2:37][CH2:36][CH:35]([CH2:39][NH2:40])[CH2:34]2>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([NH:40][CH2:39][CH:35]2[CH2:36][CH2:37][C:38]3[C:33](=[CH:32][NH:31][N:30]=3)[CH2:34]2)=[O:10])[C:6](=[O:12])[C:5]([NH:13][S:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=2)(=[O:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NCC1CCc2n[nH]cc2C1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)n1CC(=O)O
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)n1CC(=O)NCC1CCc2n[nH]cc2C1

Procedure:
The title compound was prepared from 2-[6-methyl-2-oxo-3-({[4 (trifluoromethyl)benzyl]sulfonyl}amino)-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-2H-indazol-5-y-lmethanamine dihydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1)=[CH2:22]>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:27][C:26]2[CH:34]=[CH:35][C:23](/[CH:21]=[CH:22]/[C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=3)=[CH:24][CH:25]=2)[CH2:29][CH2:30]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccc(CN2CCOCC2)cc1
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccc(CN3CCOCC3)cc2)c2ccc(C=O)cc21

Procedure:
According to the method of example A57A, 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (402 mg, 1 mmol) was reacted with 4-(4-vinylbenzyl)morpholine (304 mg, 1.5 mmol) to give the title compound upon silica gel purification (1:1 hexane/ethyl acetate) as a yellow solid (120 mg, 25%). MS ESI 478.3 [M+H]+, calcd for [C27H35N3O3Si+H]+ 478.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: COc1ccc(Cl)c(CBr)c1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)c(CSc2nc(C)cc(O)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To the 2-(bromomethyl)-1-chloro-4-methoxybenzene (3.79 g, 16.09 mmol) in anhydrous ethanol (30 mL) at room temperature, 6-methyl-2-sulfanylpyrimidin-4-ol (2.28 g, 16.09 mmol) was added. Triethylamine (1.79 g, 17.7 mmol) was then added. The reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solvent was evaporated, and the crude residue was suspended in water and sonicated. The white precipitated product was filtered off and washed with water, ether, and ethyl acetate to provide the 2-{[(2-chloro-5-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (4.05 g, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.71 (s, 3H), 4.39 (s, 2H), 5.99 (bs, 1H), 6.88 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccc(I)cn2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Oc2ccc(I)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-iodo-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [C:1]([Si:5]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:6][CH2:7][CH:8]([CH3:35])[O:9][C:10]1[CH:11]=[C:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15]2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[OH-].[Na+]>[C:42]([Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[O:6][CH2:7][CH:8]([CH3:35])[O:9][C:10]1[CH:11]=[C:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)CO[Si](c3ccccc3)(C(C)(C)C)C(C)(C)C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Ethyl 7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.4 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at 50° C. for 1 hr. 1M Aqueous sodium hydroxide solution (1 mL) was added to the reaction solution, and the mixture was stirred at 50° C. for 40 min. 1M Aqueous sodium hydroxide solution (1 mL) was added again, and the mixture was further stirred at 50° C. for 30 min. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid, and subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (1.9 g, yield 83%) as a pale-red amorphous solid. MS 644 (MH+).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([O:39][CH3:40])[O:37][CH3:38])[CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([O:37][CH3:38])[O:39][CH3:40])[CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(C(OC)OC)c3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(C(OC)OC)c3)cc2)cc1)C(=O)O
Yield: 100.3 %

Procedure:
In a similar manner to that described in Example 27, ethyl 2-butyl-3-[4-[2-(3′-dimethoxymethylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (1.46 g), which is the product of Reference example 14, was reacted with aqueous sodium hydroxide solution (1N, 5.40 ml) and the reaction mixture was treated to give 2-butyl-3-[4-[2-(3′-dimethoxymethylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid (1.39 g) as a syrup. This compound (365 mg) was reacted and the reaction mixture was treated in a similar manner to that described in Example 27 to give the title compound (335 mg) as a yellowish brown solid.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1)=O>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(OC)cc(OC)c3)cs2)c(C)s1
Yield: 27.8 %

Procedure:
100 mg (0.404 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-3′,5′-dimethoxy acetophenone (0.444 mmol) in a manner similar to Example 22, step (a) to afford 44 mg (27% yield) of methyl 4-[4-(3,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: CN(C)CCN.[CH3:7][O:8][CH2:9][CH2:10][O:11][N:12]1C(=O)C2=CC=CC=C2C1=O.C(O)(=O)C.[C:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])(=O)[CH3:28]>CCO>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:30]([C:27](=[N:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[CH3:28])[CH:35]=1
Reactant: COCCON1C(=O)c2ccccc2C1=O
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: COCCON=C(C)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
N,N-Dimethylethylenediamine (2.54 mL, 22.0 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (3.32 g, 15.0 mmol) in EtOH (50 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (20 mL) was then added to adjust the mixture to Ca. pH 4, followed by the addition of a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (3.02 g, 10.0 mmol) in EtOH (2 mL), and the mixture stirred for 65 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 1:1) afforded N-{4-chloro-2-[1-(2-methoxyethoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 185 (3.0 g, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.40, br s, 1H; 7.65, d, J=8.8 Hz, 1H; 7.47, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 4.37, m, 2H; 3.71, m, 2H; 3.41, s, 3H; 2.32, s, 3H. HRMS (M+) 374.0308.