Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[CH2:9][S:8]1)=[O:6].Cl>CO.O>[CH3:18][O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH:7]([C:5]([OH:6])=[O:4])[S:8][CH2:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)C1Cc2ccc(OC)cc2CS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CSC(C(=O)O)C2
Temperature: 60 °C
Yield: 87.3 %

Procedure:
Potassium hydroxide (0.80 g, 14.3 mmol) was added to a solution of 7-methoxy-isothiochroman-3-carboxylic acid methyl ester (0.34 g, 1.43 mmol) in MeOH (50 mL). The solution was heated at 60° C. for 2 h, cooled to room temperature, and diluted with H2O (100 mL). The solution was made acidic with 6 M HCl and extracted with EtOAc (3×100 mL). The organic extracts were combined, dried (MgSO4) and concentrated to give 7-methoxy-isothiochroman-3-carboxylic acid (0.28 g, 88%) as a pale yellow solid. The solid was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(-c3ccccc3)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 87.2 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), phenylboronic acid (100 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), toluene (6 ml), ethanol (0.8 ml) and 2M aqueous sodium carbonate solution (0.8 ml) was heated under reflux under a nitrogen atmosphere for 6 hrs. To the reaction mixture were further added dihydroxyphenylborane (100 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), ethanol (0.8 ml) and 2M aqueous sodium carbonate solution (0.8 ml), and the mixture was heated under reflux for 6 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (260 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[F:21][C:2]([F:20])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OCC(=O)c1ccccc1
Yield: 65.4 %

Procedure:
Reaction of product of Example 35 with bromoacetophenone and potassium carbonate similar to the above Example 63 gave a crude product which was recrystallized successively from methanol and cyclohexane to give 4.45 g (65.4%) of product as a solid; mp 95°-97° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH:23]=[C:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1>CO.[Pd]>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCC1=CCC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)NCC1
Agent: [Pd]
Solvent: CO
Product: CCCC1CCNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)CC1
Reaction time: 48 h
Yield: 26.5 %

Procedure:
To a solution of 5-Propyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (112.4 mg, 0.212 mmol) in methanol (8.0 mL) was added 10% Pd/C degusa wet form (100 mg). The resulting suspension was hydrogenated at 50 psi for two days. The reaction mixture was filtered through celite, then a 0.45 μm PTFE membrane and evaporation to dryness to furnish the crude product (96 mg, 88%). The crude product was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm, 5–60% acetonitrile in H2O w/0.1% AcOH over 30 min, 20 mL/min flow rate) to provide the title compound (23.5 mg, 21.5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[ClH:15].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][Cl:23])=[CH:18][CH:17]=1.[OH-]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[ClH:23].[ClH:15].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:5]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:4]3[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the procedure of Example 5 from 1.0 g (4.08 mmole) of 2-bromofluorene, 1.5 g of 4-picolylchloride hydrochloride, 100 mg of cetyl tri-n-butyl phosphonium bromide, 20 ml of 50Sodium hydroxide solution, and 20 ml toluene by reaction at 50° for 1 hr. The product was chromatographed (silica, CH2Cl2 /CH3OH, 100:1), m.p. (dihydrochloride) >300° NMR (200 MHz,CDCL3) δ: 3.39 (dd,4H), 6.48(d,4H), 7.10-7.67 (m,7H-arom.), 8.12(d,J=5.7Hz, 4H). HRMS calculated for C25H19BrN2 : 426.0758 Found: 426.0758
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH:9]=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:8][CH2:9][C@@H:10]([OH:12])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)C1

Procedure:
A solution of (+)-(1S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enol (1.43 g, 6.67 mmol) (from Example 29a supra) and Wilkinson's catalyst (1.23 g, 1.33 mmol) (Aldrich) in toluene (55 mL) was subjected to atmospheric pressure hydrogenation for 16.5 hours. The reaction mixture was then filtered, concentrated to a small volume, and purified by silica gel column chromatography with a 0–25% ethyl acetate in hexanes gradient to give (+)-(1R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol as a colorless oil. (Yield 745 mg, 61%).
Reaction SMILES: [NH2-].[Na+].O1CCCC1.[C:8]([CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:9].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>O>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][C:10]1([C:8]#[N:9])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: N#CC1c2ccccc2-c2ccccc21
Reactant: CN(C)CCCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCC1(C#N)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a stirred solution of 2.6 g. of sodium amide in 200 ml. of tetrahydrofuran was added dropwise over thirty minutes a solution of 12.7 g. of 9-cyanofluorene in 300 ml. of tetrahydrofuran. The reaction mixture was next heated to reflux for three hours, and then cooled to room temperature. While the reaction mixture was being stirred at room temperature, a solution of 14.2 g. of 3-dimethylaminopropyl chloride in 500 ml. of tetrahydrofuran was added dropwise over one hour. Following complete addition, the reaction mixture was again heated to reflux and stirred for sixteen hours. After cooling the mixture to room temperature, it was added to 500 ml. of water. The product was extracted into diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded, after distillation, 2.3 g. of 9-(3-dimethylaminopropyl)-9-cyanofluorene. B.P. 195°-201° C.at 0.1 torr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.[Pt]>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)cc1F
Agent: [Pt]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCCN2C(=O)OC(C)(C)C)cc1F

Procedure:
A mixture of EXAMPLE 50B (5.5 g) and 5% Pt/C (20 mg) in acetic acid (200 mL) was hydrogenated at 60 psi for 12 hours and filtered. The filtrate was concentrated and the concentrate partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase was isolated and concentrated. The concentrate was flash chromatographed on silica gel with 10-30% ethyl acetate/hexanes.
Reaction SMILES: C(O)C(N)(CO)CO.[CH3:9][O:10][C:11]([C:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[NH:17][C:16](=[O:27])[NH:15][C:14]=1[CH2:28][O:29][CH3:30])=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([C:13]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[NH:17][C:16](=[O:27])[NH:15][C:14]=1[CH2:28][O:29][CH3:30])=[O:12]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: NC(CO)(CO)CO
Solvent: CC#N
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)NC(=O)N1
Reaction time: 216 h

Procedure:
A 100-L reaction vessel was charged with 50 mM Tris buffer (Tris HCl (77.4 g) and Tris Base (196.7 g) in deionized water (42.3 L)), subtilisin (12.0 L, Genencor Purafect 4000L), acetonitrile (5.7 L), and (±)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine, (2), (120 g, 0.38 mol) and the mixture was allowed to react at 37° C., pH 8.3 for 9 days. The reaction mixture was extracted with toluene (10 L). The aqueous layer was separated and washed with toluene (5 L). The combined organic extracts were washed with brine (10 L). The organic layer was concentrated by rotary evaporation, filtered, then adjusted to 400 mL volume with toluene. The (+)-2 was crystallized by adding heptane (80 mL), followed by seeding. The mixture was stirred for 1 hr, then heptane (520 mL) was added over 8 hrs. The crystals were filtered, washed with 3:2 heptane-toluene (150 mL), then dried under high vacuum to yield (+)-(6S)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine, ((+)-2) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1(Br)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([NH:4][CH2:3][CH2:2][OH:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrC1CCCCCCC1
Reactant: NCCO
Product: OCCNC1CCCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cyclooctyl-1,3-thiazolidine.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([CH:21]=[CH2:22])=[C:16]2[CH2:23]O)=[O:9].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:3][CH2:23][C:16]1[C:15]2[C:20](=[C:11]([NH:10][C:8](=[O:9])[C:7]3[C:6]([Cl:5])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])[CH:12]=[CH:13][CH:14]=2)[N:19]=[CH:18][C:17]=1[CH:21]=[CH2:22]
Reactant: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To N,N-dimethylformamide (1 ml) was added thionyl chloride (73.2 mg), and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added 8-(2,6-dichlorobenzoylamino)-4-hydroxymethyl-3-vinylquinoline (176.7 mg), and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added saturated sodium bicarbonate solution (10 ml) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. The resulting precipitate was collected by filtration and washed with water to give 4-chloromethyl-8-(2,6-dichlorobenzoylamino)-3-vinylquinoline (182.8 mg).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH2:18][Br:23])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(CO)ccc1CCc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-hydroxymethylbenzoate (13.10 g., 45.43 mmol), carbon tetrabromide (18.08 g, 54.52 mmol) and triphenylphosphine (14.30 g, 54.52 mmol) in dichloromethane (400 ml) was stirred at ambient temperature for 4 hours. More carbon tetrabromide (7.54 g, 23.00 mmol) and triphenylphosphine (5.96 g, 23.00 mmol) in dichloromethane (50 ml) were added and then stirred for a further 2 hours. The reaction was applied directly to a silica flash column and eluted with iso-hexane/ethyl acetate (92.5:7.5) to give as a clear gum methyl 2-(4-fluorophenethyl)-5-bromomethylbenzoate (9.30 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].I[CH2:26][O:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:26][O:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)OC(=O)OCI
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)OCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 35.8 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.3 g, 0.79 mmol) dissolved in 5 mL of anhydrous toluene was reacted with 0.58 g (2.4 mmol) of methylethyl (iodomethoxy)formate in the presence of 0.27 g (1.0 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.14 g (36% yield) of the title compound (27a) as a colorless oil. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.07 (s, 3H), 1.08 (s, 3H), 1.31-1.34 (m, 6H), 2.25-2.32 (m, 2H), 3.32-3.36 (m, 2H), 3.63-3.65 (m, 2H), 3.90 (s, 1H), 3.96 (d, J=9.2 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.37 (d, J=11.2 Hz, 1H), 4.64 (d, J=11.2 Hz, 1H), 4.89-4.95 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.87 (d, J=5.6 Hz, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 495.02 (M+H)+, 516.98 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 121.4 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamate (95 g, 0.3 mol) and MeI (46.7 mL, 0.75 mol) in DMF (500 mL) was added sodium hydride (60%, 18 g, 0.45 mol) at 0° C. The reaction was stirred at 0° C. for 3 h and LC-MS showed the reaction was complete. The reaction was quenched with saturated NH4Cl solution and filtered. The filtrate was concentrated to remove most of DMF and the residue was dissolved in EtOAc (1.5 L). The organic layer was washed with water and brine, dried over Na2SO4. The above steps were repeated with another 127 g of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamate. The organic layers were combined and concentrated. The resulting residue was purified on silica gel column using a mixture of hexanes and EtOAc to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (120 g, 40% for 4 steps). LRMS (M+H+) m/z 230.2.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)=[O:11])=[CH:8][N:9]=1)[C:2]([NH2:4])=[NH:3].[ClH:26]>>[ClH:26].[NH:1]([C:5]1[S:6][C:7]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])=[CH:8][N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2cnc(NC(=N)N)s2)cc1
Agent: Cl
Product: N=C(N)Nc1ncc(C(=O)Nc2ccc(OCC(=O)O)cc2)s1

Procedure:
239 mg of ethyl {4-[(2-guanidino-thiazole-5-carbonyl)-amino]-phenoxy}-acetate are stirred for 27 hrs. in 4.8 ml of 25% hydrochloric acid. The precipitate is filtered off under suction, washed with water and dried. There are obtained 222 mg of [4-[(2-guanidino-thiazole-5-carbonyl)-amino]-phenoxy]-acetic acid hydrochloride (1:1), m.p. 336° C., MS: 364 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16].Cl.[NH2:19][CH2:20][C:21]1[C:22](=[O:35])[NH:23][C:24]([CH3:34])=[CH:25][C:26]=1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>O.CS(C)=O>[CH2:27]([C:26]1[CH:25]=[C:24]([CH3:34])[NH:23][C:22](=[O:35])[C:21]=1[CH2:20][NH:19][C:11]([C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16])=[O:13])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Reactant: CC(C)c1cn(C)c2c(C(=O)O)cc(Br)cc12
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCCl
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2cc(Br)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
A 20 mL, oven dried vial was charged with 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (0.075 g, 0.253 mmol), 3-(aminomethyl)-4-benzyl-6-methylpyridin-2(1H)-one hydrochloride (0.080 g, 0.304 mmol), 1-hydroxy-7-azabenzotriazole (0.041 g, 0.304 mmol) and EDC (0.058 g, 0.304 mmol). Dimethyl sulfoxide (DMSO) (2 mL) was added via syringe, followed by N-methylmorpholine (0.111 mL, 1.013 mmol). The mixture was capped and stirred at RT over weekend. The reaction was poured into 60 mL water and the resultant mixture stirred for 10 min, then placed in a freezer for 10 min. The solids were filtered, washed with water (10 mL), air dried for 5 min, and placed in a vacuum oven (40° C.) for 2 h. Collected the solids and further dried in a vacuum oven (45° C.) for 18 h to give N-((4-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-bromo-3-isopropyl-1-methyl-1H-indole-7-carboxamide (120 mg, 0.225 mmol, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1H), 8.63 (t, J=4.9 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.30 (m, 2H), 7.22 (m, 3H), 7.13 (s, 1H), 7.05 (d, J=1.8 Hz, 1H), 5.78 (s, 1H), 4.39 (d, J=4.8 Hz, 2H), 3.96 (s, 2H), 3.64 (s, 3H), 3.11 (dt, J=13.6, 6.8 Hz, 1H), 2.09 (s, 3H), 1.26 (m, 6H). MS (ES) [M+H]+ 506.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14][OH:15])=[CH:9][C:8]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:34][C:33]([C:31]3[CH:30]=[C:29]([Cl:39])[CH:28]=[C:27]([Cl:26])[CH:32]=3)([C:35]([F:36])([F:38])[F:37])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C=NO)ccc1C(=O)OC(C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.2 %

Procedure:
To a solution of 4-(hydroxyimino-methyl)-2-methyl-benzoic acid tert-butyl ester (Example I18) (32.5 g) in N,N-dimethylformamide (280 ml) was added N-chlorosuccinimide (“NCS”) (18.44 g). The reaction mixture was stirred at ambient temperature for 3.5 hour. A solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (33.3 g) (prepared according to WO 2005/085216) and triethylamine (19.25 ml) in N,N-dimethylformamide (220 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. Water and ethyl acetate were added and the phases were separated. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate and heptane to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (40.12 g). 1H-NMR (CDCl3, 400 MHz): 7.88 (d, 1H), 7.55-7.45 (m, 5H), 4.10 (d, 1H), 3.75 (d, 1H), 2.60 (s, 3H), 1.65 (s, 9H).