Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Hydroxymethylquinoline (0.4325 g, 2.72 mmoles) (prepared by the method of: C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953, 18, 55-58.) and triethylamine (1.5147 mL, 10.87 mmoles) were dissolved in anhydrous dichloromethane (16 mL) and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.421 mL, 5.43 mmoles) was added and the mixture was stirred under argon at 0° C. for 1 h. Additional triethylamine (0.758 mL, 5.435 mmoles) and methanesulfonyl chloride (0.211 mL, 2.72 mmoles) were added and the reaction was allowed to proceed for a further 1 h at 0° C. The mixture was evaporated to dryness to give the title compound which was used without further purification in the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C[N:16](C)C=O.N>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([NH2:16])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc2c(c1)OCO2
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a suspension of 50.0 g (260 mmol) 3-Benzo[1,3]dioxol-5-yl-acrylic acid in 300 ml tetrahydrofuran and 3.0 ml N,N-dimethyl formamide 44.5 ml (350 mmol) oxalyl chloride was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 750 ml of an 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 49.5 g (99%) 3-Benzo[1,3]dioxol-5-yl-acrylamide were obtained.
Reaction SMILES: [Br-:1].[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]1[C:52]([CH2:53]O)=[CH:51][C:50]([C:55]([F:58])([F:57])[F:56])=[N:49]1>>[Br:1][CH2:53][C:52]1[N:48]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[Cl:41])[N:49]=[C:50]([C:55]([F:58])([F:57])[F:56])[CH:51]=1
Reactant: [Br-]
Reactant: OCc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry 250 mL flask was charged with triphenylphosphonium dibromide (6.3 g, 14.9 mmol) and a solution of [2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-methanol (3.54 g in 100 mL of CH2Cl2) was added portionwise. The reaction was stirred at room temperature for 2 h then was washed into a separatory funnel with water and CH2Cl2. The CH2Cl2 was separated, dried (MgSO4), and concentrated in vacuo. The crude bromide was purified by silica gel flash chromatography (Jones Flashmaster, 70 g Silica gel, gradient elution from 100% hexanes to 10% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford 5-bromomethyl-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole as a colorless oil, yield: 2.74 g (64% for both steps); 1H NMR (400 MHz, CDCl3): δ 7.35-7.55 (m, 4H), 6.70 (s, 1H), 4.21 (br s, 2H).
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1.C1C=CC=CC=1>O>[F:15][CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5]
Reactant: [F-]
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C(F)CCCl
Yield: 52.8 %

Procedure:
A mixture of 68 g of 4-chlorophenyl 1-bromo-3chloropropyl ketone, 27.5 g of dry potassium fluoride, 11 g of 18-crown-6 and 200 ml of dry benzene is heated under reflux for 8 hours. Thereafter, 200 ml of water are added, and the organic phase is separated off, washed several times with water, dried over sodium sulphate and evaporated down in vacuo. The residue is stirred with light benzine, with the addition of a small amount of toluene. After the resulting solid has been filtered off under suction and drying has been carried out, 28.5 g (53% of theory) of 4-chlorophenyl 1-fluoro-3-chloropropyl ketone of melting point 53° C. are obtained. ##STR217##
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[S:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10][CH2:11][CH:12]([CH3:13])[CH3:14])[N:8]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)CSc1nc(C(=O)O)ccc1C1CC1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)CSc1nc(C(=O)N[C@@H](CC(C)C)C(N)=O)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylthio)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=364.5 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([NH2:14])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:15][O:16][CH2:17][C:18]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([NH:14][C:18](=[O:19])[CH2:17][O:16][CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:19]
Reactant: COCC(=O)Cl
Reactant: COC(=O)c1cc(N)cc(N)c1
Agent: Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(NC(=O)COC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3,5-diaminobenzoate dihydrochloride (7.2 g) in pyridine (100 ml) is added dropwise methoxyacetyl chloride (6.0 ml) at room temperature. The mixture is stirred at room temperature for 2 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water and chloroform. The organic layer is separated and washed with water and then with aqueous saturated sodium chloride solution, dired over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The resulting solid substance is recrystallized from ethanol to give the title compound (5.2 g) having the following physical properties.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:33]=2)=[CH:20][C:19]=1[CH3:44]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (159 mg, 0.94 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (160 mg, 0.31 mmol, example 6), Pd(PPh3)2Cl2 (36 mg, 0.031 mmol), CuI (16 mg, 0.087 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 1 hour at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester in 18 mg (10%) yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[Br:11])=[O:5])C.[Li+].[OH-]>CO.O>[Br:11][C:10]1[N:9]([CH3:12])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C)c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1Br

Procedure:
To a solution of 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (6.9 g, 29.6 mmol) in CH3OH (25 mL) and water (25 mL) was added LiOH (0.78 g, 32.6 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl (˜3 mL). The resulting mixture was then extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[C:13]([CH:18]=O)[N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12.[CH3:20][NH:21][CH3:22].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[C:13]([CH2:18][N:21]([CH3:22])[CH3:20])[N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12
Reactant: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1C=O
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A mixture of the aldehyde 111 (344 mg, 1.18 mmol) and dimethylamine (0.7 mL, 1.41 mmol) in methanol (24 mL) and acetic acid (few drops) were stirred at RT overnight. Sodium cyanoborohydride (237 mg, 3.77 mmol) was added and the reaction mixture was allowed to stir at room temperature until completion of the reaction. The solvents were evaporated and water was added to the residue and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 2.5% MeOH/97.5% DCM to 10% MeOH/90% DCM) to afford title compound 112 as a yellow solid (129 mg, 34% yield). MS (m/z): 321.1 (M+H).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([CH:7]1[CH2:11][CH:10]([OH:12])[CH2:9][N:8]1[C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([N:8]1[CH2:9][CH:10]([OH:12])[CH2:11][CH:7]1[CH2:5][OH:4])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CC(O)CN1C(=O)CCCCCNC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCCCCCC(=O)N1CC(O)CC1CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the solution of lithium borohydride (1.34 g) in anhydrous tetrahydrofuran (50 mL) was added a solution of methyl ester 2a in THF (50 mL) over a period of 30 mins at 0° C. After the addition the reaction mixture was brought to room temperature and stirred further under argon. The completion of the reaction was ascertained by TLC after 4 h. (Rf=0.4 in 10% MeOH/CHCl3). The reaction mixture was evaporated to dryness and cooled to 0° C. To the residue 3N HCl (100 mL) was added slowly. After stirring for 30 mins the product was extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Organic layer was filtered and evaporated to dryness. Compound 3a was purified by column chromatography first by eluting with ethyl acetate to remove impurities followed by dichloromethane/methanol (5%) gave 14.3 g (70%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]=1[CH:16]=[CH2:17])=[O:4].BrBr.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[O:15][CH:17]=[CH:16][C:6]=12)=[O:4]
Reactant: C=Cc1c(C(=O)OC)c2ccccc2[nH]c1=O
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1c2ccccc2nc2occc12
Yield: 43.2 %

Procedure:
To a solution of 2.6 g (11.2 mmol) Methyl-2-oxo-3-vinyl-1,2-dihydroquinoline-4-carboxylate 5 in 200 mL chloroform was added slowly over a dropping funnel a solution of 2.16 g (13.5 mmol) bromine in 15 mL chloroform and subsequently 6.8 mL of triethylamine. The reaction mixture was heated at reflux for 4.5 hour. After evaporation of the solvent the residue was purified by column chromatography on silica gel, eluting with toluene/ethyl acetate/methanol 4:1:1, to give 1.1 g of the desired product 6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (246 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (226 mg, 71%).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Br:22][C:23]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=2)=[C:29]2[C:24]=1[N:25]=[CH:26][CH:27]=[N:28]2>CC#N>[Br:22][C:23]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[C:34]=2[F:21])=[C:29]2[C:24]=1[N:25]=[CH:26][CH:27]=[N:28]2
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3nccnc23)c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc(OC)c(F)c(-c2ccc(Br)c3nccnc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
SelectFluor (20.5 g, 58 mmol, 2 equiv) was added portionwise to a solution of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 1.4) (10 g, 29 mmol) in CH3CN (300 mL) at rt. The reaction mixture was stirred at rt for 0.5 h, quenched by addition of H2O and concentrated to remove CH3CN. The resulting mixture was diluted with EtOAc/H2O and filtered to provide a white solid (batch 1). The filtrate was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford batch 2. The two batches were combined and purified by silica gel MPLC (Hex/EtOAc, 7:3) to afford a sample of 5-bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step 94.3) and a sample of the title compound which was further purified by trituration in EtOAc to provide 2.28 g of a white solid. Title compound: ESI-MS: 381.0/382.9 [M+H]+; tR=4.92 min (System 1); TLC: Rf=0.26 (Hex/EtOAc, 7:3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].C([Mg]Cl)(C)C.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>C1COCC1.N1C=CN=C1>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([C:18]([CH:15]1[CH2:17][CH2:16]1)=[O:19])[C:6](=[O:7])[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(Cl)C1CC1
Agent: CC(C)[Mg]Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)C(=O)C1CC1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of ethylacetoacetate (11.0 g, 85 mmol) in THF (20 ml) at 0° C. under argon atmosphere was added isopropylmagnesium chloride (42 ml, 2 M in THF, 85 mmol) dropwise. The reaction was stirred for 0.5 h. This solution was then transferred by cannula to a solution of cyclopropylcarbonylchloride (8.8 g, 85 mmol) and imidazole (0.3 g, 4 mmol) in THP (30 ml), also under argon at 0° C. The reaction was stirred for 2 h at 0° C. and 1 h at room temperature before the reaction was quenched by addition of 10% citric acid solution. The reaction was then extracted with EtOAc, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 5:95) afforded the title compound (11.9 g, 71%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.99-1.02 (2H, m), 1.22-1.24 (2H, m), 1.35 (3H, t, J=6 Hz), 2.32 (3H, s), 2.41-2.51 (1H, m), 4.30 (2H, q, J=6 Hz), 17.95 (1H, s).
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].N1CCOCC1.[CH2:13]([NH:16][C:17](=[O:24])[C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH2:15]>C(OCOCC)C>[CH2:13]([NH:16][C:17]([CH:18]1[C:3]([OH:5])([CH3:4])[CH:2]([CH3:6])[S:1][CH:19]1[Si:20]([CH3:21])([CH3:22])[CH3:23])=[O:24])[CH:14]=[CH2:15]
Reactant: CC(=O)C(C)S
Reactant: C=CCNC(=O)C#C[Si](C)(C)C
Solvent: C1COCCN1
Solvent: CCOCOCC
Product: C=CCNC(=O)C1C([Si](C)(C)C)SC(C)C1(C)O
Reaction time: 4 h
Yield: 81.8 %

Procedure:
A solution of 3-mercapto-2-butanone (2.1 g, 0.020 mol) and morpholine (1.5 g, 0.017 mol) in diethoxymethane (20 mL) was heated to reflux and treated with N-allyl-3-trimethylsilylpropiolic amide (3.04 g, 0.017 mol). The mixture is heated at reflux under a nitrogen atmosphere overnight. An additional portion of the 3-mercapto-2-butanone (0.7 g, 0.0067 mol) was added, and heating was continued for 4 hours more. A final portion of the 3-mercapto-2-butanone (0.7 g, 0.0067 mol) was added, heating was continued for 4 hours at reflux, then the mixture was cooled and evaporated under reduced pressure. The residue was extracted with two 40 mL portions of hot heptane, filtered, and allowed to cool (ice/salt bath). The resulting solid precipitate was collected by filtration and dried to give 4.0 g of 4-hydroxy-4,5-dimethyl-2-trimethylsilanyl-dihydrothiophene-3-carboxylic acid allylamide (84% yield).
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C@H:13]([CH3:30])[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31]N(C=O)C>>[C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:31])[CH:21]=2)=[O:19])[C@H:13]([CH3:30])[CH2:12]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1cn(C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
NaH (2 mg, 60% pure, 0.05 mmol) was added to a solution of compound 5a (10 mg, 0.027 mmol) in DMF. After 30 minutes, Mel (5 mg, 0.035 mmol) was injected into the mixture via syringe. The reaction mixture was stirred for 8 hours at room temperature and quenched with methanol. The mixture was partitioned between ethyl acetate (2 ml) and H2O (2 ml). The aqueous phase was extracted with EtOAc (3×2 ml). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo to give a crude product which was purified using a Shimadzu automated preparative HPLC System to give compound 21a (2.5 mg, 24%).
Reaction SMILES: [OH:1][CH:2]([C@H:4]1[CH:7]([S:8][C:9]([S:11][CH2:12][S:13][CH3:14])=[S:10])[NH:6][C:5]1=[O:15])[CH3:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:1][CH:2]([C@H:4]1[CH:7]([S:8][C:9]([S:11][CH2:12][S:13][CH3:14])=[S:10])[NH:6][C:5]1=[O:15])[CH3:3]
Reactant: CSCSC(=S)SC1NC(=O)[C@H]1C(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CSCSC(=S)SC1NC(=O)[C@H]1C(C)OC1CCCCO1
Temperature: 30 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2.67 g (10 mmole) 3-(R)-(1-hydroxyethyl)-4-(methylthiomethylthio[thiocarbonyl]thio)-2-azetidinone in 30 ml methylene chloride at room temperature is added 0.8 g pyridinium p-toluenesulfonate and 1.26 g (15 mmole) dihydropyran and the mixture is stirred at 30° C. for five hours. The solvent is evaporated in vacuo, the residual oil is dissolved in ethyl ether, washed with brine, water, dried (Na2SO4) and concentrated in vacuo to afford the title compound. B. A solution of 3.51 g (10 mmole) of the product of Part A, above, and 4.0 g (20 mmole) t-butoxycarbonyloxymethyl glyoxylate in 150 ml benzene is heated at reflux overnight while removing water in a Dean-Stark trap. The resulting product is isolated and purified as described in Example 4 to obtain the desired 2-hydroxyacetate.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: c1ccccc1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: C=C(C)C(=O)c1ccccc1

Procedure:
Benzene (1 mL), methacryloyl chloride (0.156 mg), and aluminium chloride (199 mg) were reacted in carbon disulfide (2 mL) at from 0° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (106 mg).
Reaction SMILES: [P:1]([O:6]C)([O:4][CH3:5])[O:2][CH3:3].[CH2:8]1[O:12][C@@H:11]2[C@H:13]([O:16][N+:17]([O-:19])=[O:18])[CH2:14][O:15][C@@H:10]2[C@H:9]1[OH:20].C(Br)(Br)(Br)Br>N1C=CC=CC=1>[P:1]([O:20][C@H:9]1[CH2:8][O:12][C@@H:11]2[C@H:13]([O:16][N+:17]([O-:19])=[O:18])[CH2:14][O:15][C@H:10]12)([O:4][CH3:5])([O:2][CH3:3])=[O:6]
Reactant: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: COP(OC)OC
Agent: BrC(Br)(Br)Br
Solvent: c1ccncc1
Product: COP(=O)(OC)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trimethyl phosphite (2.95 mL, 25.0 mmol) was added dropwise over ca. 1 hour to a stirred 0° C. mixture of isosorbide-5-mononitrate (3.82 g, 20.0 mmol) and carbon tetrabromide (7.30 g, 22.0 mmol) in pyridine (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction was partitioned between 1M hydrochloric acid and diethyl ether/ethyl acetate (1:1). The aqueous phase was extracted with diethyl ether. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate and brine, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 50-100% ethyl acetate/hexane afforded the title compound as an orange solid. 1H NMR (500 MHz, CD3OD) δ 5.46 (td, J=5.5, 2.2 Hz, 1H), 5.02 (t, J=5.3 Hz, 1H), 4.82 (dd, J=6.8, 2.7 Hz, 1H), 4.58 (d, J=5.1 Hz, 1H), 4.10 (d, J=10.7 Hz, 1H), 3.99 (dd, J=11.5, 2.1 Hz, 1H), 3.91 (dd, J=11.4, 5.2 Hz, 1H), 3.88 (dt, J=11.0, 2.4 Hz, 1H), 3.80 (d, J=2.7 Hz, 3H), 3.78 (d, J=2.7 Hz, 3H); LC-MS: m/z 300.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.Cl.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: O=S(=O)(NCc1ccc(Br)cc1)c1cccnc1
Yield: 83.7 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (300 mg, 1.69 mmol), and using 4-bromobenzylamine hydrochloride (342 mg, 1.54 mmol) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (422 mg) as a white solid. (Yield: 84%)