Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:4][CH:3]=1.[C:22]1([CH2:28][O:29][C:30]([NH:32][CH2:33][CH:34]=C)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B1C2CCCC1CCC2.[OH-].[Na+]>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].OO>[C:16]1([CH2:15][O:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH2:34][CH2:33][NH:32][C:30]([O:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:31])=[CH:3][CH:4]=2)=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NCCCc1ccc(Br)cc1)OCc1ccccc1
Reactant: C=CCNC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Product: O=C(NCCCc1ccc(CCNC(=O)OCc2ccccc2)cc1)OCc1ccccc1
Yield: 35.4 %

Procedure:
N-[3-(4-Bromophenyl)propyl](phenylmethoxy)carboxamide (1.5 g, 4.3 mmol), (phenylmethoxy)-N-eth-2-enylcarboxamide (0.92 g, 5.17 mmol, prepared in example 8), 9-BBN-dimer (0.84 g, 3.45 mmol), [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (11), PdCl2(dppf), (0.175 9, 0.22 mmol), 3N sodium hydroxide (3 mL), and pH=7 buffer hydrogen peroxide (2:1, 10 mL) were combined in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, (phenylmethoxy)-N-[3-(4-{2-[(phenylmethoxy)carbonylamino]ethyl}phenyl)propyl]carboxamide, (0.68 g, 35%). Electron spray M.S. 447 (M*+H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[CH:15]=2)[CH2:10]1
Reactant: Cc1ccc(/C=C/c2ccc3c(c2)CC(NC(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ccc(/C=C/c2ccc3c(c2)CC(N)C3)cc1

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-((E)-2-(4-methylphenyl)ethenyl]indan (20 mg, 0.060 mmol) synthesized in Reference Production Example 2, 4N hydrochloric acid-dioxane (2.0 ml) and acetic acid (6.0 ml), a similar procedure to Production Example 213 was carried out to obtain 2-amino-5-((E)-2-(4-methylphenyl)ethenyl]indan hydrochloride (16 mg, 0.06 mmol) having the following physical properties:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[C:32]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:32]1([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH3:25])[CH:18]=3)[N:9]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: O=C1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4C3CCCC3)n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 120 mg (0.28 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 3 mL chloroform was treated with 0.25 mL (2.8 mmol) cyclopentanone and 180 mg (0.84 mmol) NaBH3(CN), followed by addition of 5 mL methanol. The mixture was stirred at ambient temperature for 3 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 480 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[N:7]1[C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])=[O:5])C.CO.[OH-].[Na+].Cl>[Cl-].[Na+].O.O>[CH3:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:6]([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: C=C(C)C(=O)N1c2ccc(OC)cc2CC1C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)N1c2ccc(OC)cc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 2,3-dihydro-5-methoxy-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid ethyl ester from Example 23 (8.5 g.) in 45 ml. of reagent-grade methanol was added a solution of 1.32 g. of sodium hydroxide (98% purity) in 16 ml. distilled water with hand swirling. This reaction mixture was stirred at room temperature for 2 hours. With vigorous mechanical stirring, the reaction solution was poured into brine and the slightly turbid mass was acidified with concentrated hydrochloric acid. The resulting mixture was stirred, chilled in an ice-water-salt-bath for one hour and the solids were collected on a sintered-glass funnel and washed twice with cold water, to give 2,3-dihydro-5-methoxy-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid (7.32 g., m.p. 108°-111°). Recrystallization from ethyl acetate improved the m.p. to 115°-118°.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[CH2:9][Br:10])[C:5](Cl)=[O:6].[NH2:17][CH:18]1[C:29](=[O:30])[N:20]2[CH:21]([C:26]([OH:28])=[O:27])[CH:22]([OH:25])[CH2:23][S:24][C@H:19]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[CH2:9][Br:10])[C:5]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[CH:21]([C:26]([OH:28])=[O:27])[CH:22]([OH:25])[CH2:23][S:24][C@H:19]12)=[O:6]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 118.2 %

Procedure:
2-Methoxyimino-3,3-diethoxy-4-bromobutyryl chloride (syn isomer, 400.5 g) and 7-amino-3-hydroxycepham-4-carboxylic acid (230 g) were treated in a similar manner to that of Example 41 to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 621 g).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][N:21]([CH3:29])[C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:20][N:21]([CH3:29])[C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: CN(C)c1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(N(C)C)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-dimethylamino-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a yellow oil.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:19][CH2:20][OH:21])[C:12]([CH2:23][CH3:24])([CH3:22])[CH:11]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:19][CH2:20][O:21][C:33](=[O:35])[CH3:34])[C:12]([CH2:23][CH3:24])([CH3:22])[CH:11]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1CCO
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1CCOC(C)=O
Yield: 42.8 %

Procedure:
To a solution of 2.5 g of 2,6-diethyl-1-(2-hydroxyethyl)-2,3,6-trimethyl-4-piperidyl benzoate (Compound 45 - prepared following the procedure described in Preparation 9) in 50 ml of dimethylformamide were added 2.0 g of triethylamine and 1 g of acetic anhydride; the mixture was then heated at 80°-90° C. for 5 hours. When the reaction was complete, the reaction mixture was concentrated and 50 ml of benzene were added. The mixture was then washed with, in turn, an aqueous solution of sodium carbonate and water, and was dried over anhydrous sodium sulphate. After removing the solvent, the residue was subjected to distillation under reduced pressure, giving 1.2 g of Compound 50 as a colourless oil (bp 195° C./0.0008 mmHg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[K+].[K+].COC(OC)COCC(OC)OC.O>O>[C:18]([C:17]1[N:13]([CH3:12])[C:14]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]#[N:11])=[CH:4][CH:3]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: N#CNCc1ccc(Br)cc1
Agent: COC(COCC(OC)OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(C#N)ccc1-c1ccc(CNC#N)cc1
Temperature: 100 °C
Yield: 27 %

Procedure:
(4-bromophenyl)methyl cyanamide (0.100 g, 0.47 mmol) tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), potassium carbonate (0.345 g, 2.5 mmol) and dimethoxyethylether/water 3:1 were placed in a microwave reaction vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen. Using microwave assisted conditions, the mixture was heated to 100° C. for 15 minutes. The mixture was poured into water, extracted with ethyl acetate, the ethylacetate dried over magnesium sulfate, and evaporated in vacuo. The residue was flash chromatographed using 9/1 Hexane/ethylacetate to give [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]methylcyanamide (0.030 g, 27%). HPLC purity 100% at 210-370 nm, 10 min.; the Xterra™ RP18 instrument, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C14H12N4+H+, 237.11347; found (ESI, [M+H]+), 237.1127.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:20][CH2:21][CH3:22])=[C:8]2[C:3]=1[C:4](=[O:23])[CH2:5][CH2:6][CH2:7]2.C(=O)(O)[O-].[Na+].[BH4-].[Na+].Cl>CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:20][CH2:21][CH3:22])=[C:8]2[C:3]=1[CH:4]([OH:23])[CH2:5][CH2:6][CH2:7]2
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)C(=O)CCC2
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)C(O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
6,7,8,9-Tetrahydro-5-hydroxy-4,6-dioxo-10-propyl-4H-naphtho-[2,3-b]pyran-2-carboxylic acid (158 mg; 0.5 mmole) was dissolved in 10 ml of a pH10 buffer made from sodium bicarbonate (0.65 g) sodium carbonate (1.32 g) in water (100 ml). Sodium borohydride (20 mg; 0.53 mmole=2.12 equivalents) was added and the solution was stirred for 1 hour at room temperature and then poured into dilute hydrochloric acid and the yellow solid was filtered off, washed with water and dried in a vacuum oven over phosphoric oxide to yield a pure sample of the title compound (120 mg; 75.5%) mp 245°-9°.
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[OH:27][CH2:26][CH2:28][N:29]1[C:23](=[O:25])[CH2:24][CH:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:22]
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: NCCO
Product: CCCCCCCCC=CCCCCCCCCC1CC(=O)N(CCO)C1=O
Yield: 75.3 %

Procedure:
A 50 mL reaction flask was charged with 35.1 g of octadecenyl succinic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 6.1 g of ethanolamine (manufactured by Tokyo Chemical Industry Co., Ltd.), and the resulting mixture was reacted at 110° C. for 6 hours under continuous nitrogen purging and with vigorous stirring. The reaction product was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane), yielding 29.6 g of N-(2-hydroxyethyl)-9-octadecenyl succinimide (yield: 75.3%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10]2)(=[O:4])[CH2:2]C.C(C1C=CC=C2C=1NC(=O)C2)(=O)C1C=CC=CC=1.C1(C(C2C=CC=C3C=2NC(=O)C3)=O)SC=CC=1.C1SC=CC=1C(C1C=CC=C2C=1NC(=O)C2)=O.CC1C=C2C(=C(C(=O)C)C=1)NC(=O)C2.CSC1C=C2C(=C(C(=O)C)C=1)NC(=O)C2.FC1C=C2C(=C(C(=O)C3C=CC=CC=3)C=1)NC(=O)C2.BrC1C=C2C(=C(C(=O)C3SC=CC=3)C=1)NC(=O)C2>>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10]2)(=[O:4])[CH3:2]
Reactant: CCC(=O)c1cccc2c1NC(=O)C2
Agent: CC(=O)c1cc(C)cc2c1NC(=O)C2
Agent: CSc1cc2c(c(C(C)=O)c1)NC(=O)C2
Agent: O=C1Cc2cc(Br)cc(C(=O)c3cccs3)c2N1
Product: CC(=O)c1cccc2c1NC(=O)C2

Procedure:
Starting with the appropriate reagents and following the procedure of Preparation K, 7-propionyloxindole, 7-benzoyloxindole, 7-(2-thenoyl)oxindole, 7-(3-thenoyl)oxindole, 5-methyl-7-acetyloxindole, 5-methylthio-7-acetyloxindole, 5-fluoro-7-benzoyloxindole and 5-bromo-7-(2-thenoyl)oxindole are prepared.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[S:41][CH:42]=[CH:43][N:44]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCOCC1.CC(C)=O.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[S:41][CH:42]=[CH:43][N:44]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nccs1)c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
Benzimidazole (0.313 mmol) and MgO (0.376 mmol) was stirred in 1,4-dioxane (2 mL) for 10 min. at room temp. To the solution, copper iodide (0.627 mmol), palladium acetate (0.016 mmol), triphenylphosphine (0.062 mmol), and 4-bromo-N-thiazol-2-yl-benzenesulfonamide (0.313 mmol) were added. The reaction was sealed and heated to 150° C. After 7 h the reaction was cooled to 120° C. and stirred overnight. The reaction was cooled to room temperature and diluted with acetone. The solution was filtered through Celite and concentrated in vacuo. The crude was purified by reverse phase chromatography to yield 4-(1H-benzoimidazol-2-yl)-N-thiazol-2-yl-benzenesulfonamide (0.007 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:35]1([CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:42]([O:44][CH3:45])=[O:43])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: COC(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)CCCCNC(=O)OC(C)(C)C)c1ccccc1
Yield: 95.7 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 7.7 g at a yield of 95.7% in the same manner as in Example 1 except that 5.0 g (23 mmol) of 5-(N-t-butoxycarbonylamino)pentanoic acid instead of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 25 ml of THF and 4.1 g (25.3 mmol) of CDI was added; 9.05 ml (69 mmol) of diisopropylamine and 25 ml of THF were added and 42 ml (69 mmol) of 1.63N BA solution was added dropwise; 10.4 g (69 mmol) of methyl phenylacetate was dissolved in 25 ml of THF; and 30 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 50 g of 4N hydrochloric acid was added, and 100 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[C:16]([Si:19]([CH3:21])([CH3:20])[O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH2:1])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(N)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 2-amino-5-methyl-phenol (500 mg, 4.0 mmol) and imidazole (298 mg, 4.4 mmol) in DMF (5 ml) was added TBDMSCl (660 mg, 4.4 mmol). The reaction mixture was stirred at RT for 3 h then diluted into water and extracted with AcOEt. The organic fraction was dried over Na2SO4, filtered and evaporated to dryness. The resulting residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME containing 5% of 7M NH3 in MeOH 95:5→8:2) to yield the title compound (724 mg, 3.1 mmol, 77%) as a reddish oil. TLC: RF=0.94 (heptane/DCM/TBME 1:1:2 containing 5% of 7M NH3 in MeOH); HPLC: AtRet=1.80 min; API-MS: m/z 238.1 [M+H]+; 1H NMR (400 MHz, CDCl3): 0.26 (s, 6H), 1.04 (s, 9H), 2.23 (s, 3H), 3.56 (br. s., 1H), 6.56-6.67 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][S:9][C:10]1[C:11](=[O:16])[NH:12][CH:13]=[CH:14][N:15]=1.Br[C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[C:20]([CH3:30])[CH:19]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[OH:26][C:24]([CH3:27])([CH3:25])[CH2:23][O:22][C:21]1[CH:28]=[CH:29][C:18]([N:12]2[CH:13]=[CH:14][N:15]=[C:10]([S:9][CH2:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:11]2=[O:16])=[CH:19][C:20]=1[CH3:30]
Reactant: Cc1cc(Br)ccc1OCC(C)(C)O
Reactant: O=c1[nH]ccnc1SCCc1ccccn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(-n2ccnc(SCCc3ccccn3)c2=O)ccc1OCC(C)(C)O
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
A mixture of 3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one (100 mg, 0.429 mmol), which was prepared by the procedure described in Method 7 except for substitution of 2-(2-pyridylethylthiol) for 2-(4-chlorophenethanol), 1-(4-bromo-2-methylphenoxy)-2-methylpropan-2-ol (133 mg, 0.514 mmol), N1,N2-dimethylethane-1,2-diamine (113 mg, 1.286 mmol), K3PO4 (0.106 mL, 1.286 mmol) and copper(1) iodide (82 mg, 0.429 mmol) in dioxane (1.0 mL) was stirred at 115° C. for 90 min. The reaction mixture, after cooling to RT, was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 100% ethyl acetate) to yield 1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one (140 mg, 0.340 mmol, 79% yield) as white solid. MS (M+H 412). 1H NMR (400 MHz, MeOD) δ ppm 8.67 (1H, d), 8.48 (1H, td, J=7.91, 1.51 Hz), 8.02 (1H, d, J=8.28 Hz), 7.81-7.95 (1H, m), 7.07-7.29 (4H, m), 6.93 (1H, d, J=8.78 Hz), 3.76 (2H, s), 3.35-3.57 (4H, m), 2.22 (3H, s), 1.27 (6H, s).
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=[O:17])=[CH:12][CH:11]=1.O1CCOCC1>C(OCC)(=O)C>[CH3:19][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:17])=[CH:12][CH:11]=1
Reactant: CCOC(O)C(F)(F)F
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A 500 mL round-bottom flask was charged with trifluoroacetaldehyde ethyl hemiacetal (12.3 g, 85.0 mmol), p-toluamide (10.0 g, 74.0 mmol), and dioxane (150 mL). The thick white slurry was stirred at ambient temperature for 3 hours, then heated at reflux for 44 hours. The homogeneous solution was cooled and concentrated in vacuo to provide a white solid. The crude material was dissolved in ethyl acetate (50 mL), adsorbed onto silica gel (50 g), and eluted through a medium porosity fritted filter funnel (elution with 25% ethyl acetate/hexanes, then ethyl acetate) to provide 14.1 g of the desired product as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](=O)[CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCC(=O)Cc1ccc2c(c1)OCO2
Reactant: CCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCCCNC(CCC)Cc1ccc2c(c1)OCO2

Procedure:
A mixture of 2.0 g (9.7 mmol) of 1-(1,3-benzdioxol-5-yl)pentan-2-one, 0.71 g (9.7 mmol) of n-butylamine, 2.88 g (13.6 mmol) of sodium triacetoxyborohydride and 0.58 g (9.7 mmol) of acetic acid were stirred in 1,2-dichloroethane (34 ml) under argon gas for four days at room temperature. Thereafter, the mixture was alkalized with 1 N sodium hydroxide. Water (50 ml) was added to the mixture and was extracted three times with ether (70 ml). The obtained organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography. Chloroform was used for eluting solvent. 1-(1,3-Benzodioxol-5-yl)-2-butylaminopentane was obtained as light yellow oil.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].O(Cl)[Cl:47].O>C(OCCOCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:47])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClOCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A 2 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 12 ml of ethoxyethyl acetate. To the solution was added 6 g of NaHCO3 and the mixture was stirred at room temperature. Thereto was added dropwise over 1 hour 12.1 ml of a 0.285M solution of Cl2O in carbon tetrachloride. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 2.0 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 94% yield.