Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C[Si]([C:19]#[N:20])(C)C.O>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:19]([CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[OH:2])#[N:20]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(O)C#N)ccc1OC
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of methyl 5-formyl-2-methoxybenzoate (55.61 g) and zinc iodide (960 mg) in methylene chloride (560 ml) was added trimethylsilyl cyanide (48 ml) in an argon atmosphere under ice cooling and stirring, and the mixture was stirred for 6.5 hours as it was. The reaction mixture was poured into water and methylene chloride layer was separated. After washing with water, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved into 1,3-dioxolane (400 ml) and 2 N hydrochloric acid (200 ml) was added, which was allowed to stand for 1.5 hours at room temperature. The reaction liquor was poured into water and extracted with ethyl acetate. This was washed with water, brine and then dried over anhydrous sodium sulfate. This was concentrated to about 200 ml under reduced pressure and the crystals deposited were collected by filtration and dried to obtain 39.41 g (62%) of aimed compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[N:6][C:7]=1[C:8]#[C:9][Si](C)(C)C.C([O-])([O-])=O.[K+].[K+].O.CCOC(C)=O>CO>[NH2:1][C:2]1[N:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[N:6][C:7]=1[C:8]#[CH:9]
Reactant: CC(C)n1cc(-c2nc(C#C[Si](C)(C)C)c(N)nc2-c2ccccc2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C#Cc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
A mixture of 5-{5-amino-3-phenyl-6-[(trimethylsilyl)ethynyl]-2-pyrazinyl}-1-isopropyl-2(1H)-pyridone (300 mg) and sat. K2CO3 in MeOH (4.5 ml) was stirred at 25° C. for 3 hours. Water and EtOAc were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by short column (silica-gel; CH2Cl2) and recrystallized from EtOH to give 5-(5-amino-6-ethynyl-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2c(c1)-c1ccccc1C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc2c(c1)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A solution of 3-amino-9-fluorenone (1.95 g, 10 mmols), triethylamine (2.07 ml, 15 mmols), in 25 ml of dried dichloromethane, is cooled to 10° C. and a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml of dried dichloromethane is then added drop by drop. The resulting mixture is kept stirring for 1 hour at room temperature overnight. The mixture is washed with 2×30 ml of water, dried over sodium sulfate and evaporated. 2.63 g 2-Chloro-N-(9-oxo-9H-fluoren-3-yl)-acetamide (97%) are obtained.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[CH:40]=[CH:39][CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:4]1[N:3]([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1C(=O)Cn1nccn1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 56, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (70 mg, 55%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 7.80 (s, 2H), 7.58-7.51 (m, 2H), 7.48-7.39 (m, 2H), 7.35-7.25 (m, 2H), 7.23-7.15 (m, 2H), 7.06-6.91, (m, 4H), 5.50 (q, 2H), 4.56-4.48 (m, 1H), 3.92-3.81 (m, 1H), 3.44-3.36 (m, 1H), 2.94-2.73 (m, 3H), 2.28-1.86 (m, 2H). MS (EI) for C28H25ClFN5O3. found 533.9 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:23]>CC(N(C)C)=O.C(OCC)(=O)C.O>[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:25]=1)=[O:23]
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3cc(OC)ccc23)c2ccccc12
Temperature: 140 °C
Reaction time: 20 h

Procedure:
3.46 g (25 mmol) of potassium carbonate and 1.94 g (10 mmol) of 4-chloro-7-methoxyquinoline are added to 1.75 g (10 mmol) of 3-methoxycarbonyl-1H-indole in 50 cm3 of dimethylacetamide under an argon atmosphere. After stirring at a temperature in the region of 140° C. for 20 hours, the reaction mixture is cooled and diluted with 300 cm3 of ethyl acetate and 300 cm3 of water. The organic phase is separated off by settling and washed with three times 300 cm3 of water and 300 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 and then 7/3 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), 1.7 g of 3-methoxycarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole are obtained in the form of a yellow foam. Mass spectrum (EI): m/e 332 (M+•), m/e 301.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH2:11]1[O:12][C:13]2([CH2:18][CH2:17][C:16]([OH:19])([C:3]3[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=3)[CH2:15][CH2:14]2)[O:20][CH2:10]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Yield: 83.6 %

Procedure:
To a 500 ml round-bottom flask equipped with a mechanical stirrer, condenser and addition funnel were added magnesium turnings (3.50 g, 140 mmol) and enough THF to cover the Mg. A solution of 1-bromo-4-fluorobenzene (12.45 g, 70.43 mmol) in THF (90 ml) was added dropwise at such a rate that the reaction maintained a gentle reflux following reaction-initiation (the initiation may be accomplished by warming the flask). After the mixture was refluxed for an additional 2.5 h, a solution of 1,4-cylohexanedione monoethylene ketal (10.00 g, 64.03 mmol) in THF (75 ml) was added dropwise. The mixture was kept at refluxing for an additional 2 h before being quenched with saturated ammonium chloride solution (7 ml). After removal of the magnesium salts by filtration, the filtrate was concentrated to dryness. The residue was dissolved in CHCl3 and washed with water and brine. The organic layer was separated, dried over MgSO3, and concentrated. The residue was purified by flash chromatography (30% ether in petroleum ether) to afford the desired alcohol (13.50 g, 87%) as a colorless solid. mp 133-134° C. 1H NMR (500 MHz, CDCl3) δ1.69 (d, J=11.7 Hz, 2H), 1.79 (d, J=12.2 Hz, 2H), 2.05-2.18 (m, 4H), (m, 4H), 7.02 (t, J=8.3, 2H), 7.47-7.50 (m, 2H).
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]([C:39]3[N:44]=[C:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:42]=[C:41](C4C=CC=CC=4)[N:40]=3)[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)O1.[Cl-].[Li+].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.C(O)C.C1(C)C=CC=CC=1>[N:5]1[C:6]2[C:15](=[CH:14][CH:13]=[C:12]3[C:7]=2[N:8]=[CH:9][CH:10]=[CH:11]3)[C:2]([C:6]2[CH:7]=[C:12]([C:41]3[N:42]=[C:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:44]=[C:39]([C:26]4[CH:25]=[CH:24][CH:29]=[CH:28][CH:27]=4)[N:40]=3)[CH:13]=[C:14]([C:11]3[C:12]4[C:7](=[C:6]5[C:15](=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[N:5]5)[N:8]=[CH:9][CH:10]=3)[CH:15]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2cc(B3OC(C)(C)C(C)(C)O3)cc(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)c2)OC1(C)C
Reactant: Brc1ccnc2c1ccc1cccnc12
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4ccnc5c4ccc4cccnc45)cc(-c4ccnc5c4ccc4cccnc45)c3)n2)cc1
Temperature: 100 °C
Reaction time: 94 h

Procedure:
In a stream of argon, 1.42 g of 4-bromo-1,10-phenanthroline, 1.29 g 2-[3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,6-diphenyl-1,3,5-triazine, 515 mg of lithium chloride and 266 mg of tetrakis(triphenylphosphine)palladium were suspended in a toluene (52 mL)/ethanol (13 mL) mixed solvent. 9.2 mL of a 2.0 M aqueous sodium carbonate solution was added in the suspension, and the mixture was stirred at 100° C. for 94 hours. Then the reaction mixture was left to be cooled to room temperature and distilled under a reduced pressure to remove low-boiling point ingredients. The obtained crude product was purified by alumina column chromatography using a hexane/chloroform (1:1 to 0:1) mixed solvent as a developing solvent to give 955 mg of target 2-[3,5-bis(1,10-phenanthrolin-4-yl)phenyl]-4,6-diphenyl-1,3,5-triazine as a white powder (yield, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:16]2[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=2)=[O:8])=[C:4]([OH:11])[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(Cl)cc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1O
Yield: 55.8 %

Procedure:
Using 4-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C:33]([CH3:38])([C:34]([OH:36])=[O:35])[CH3:37])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CC(C)(N)C(=O)O
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: CC(C)(NCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1)C(=O)O

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 2-amino-2-methylpropanoic acid (100 mg; 0.97 mmol), to give Example 174 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 8.00 (2H, d, J=8.1 Hz), 7.94-7.87 (1H, m), 7.77-7.60 (5H, m), 7.55-7.47 (2H, m), 3.96 (2H, s), 1.36 (6H, s). LC/MS (Method C): 498 (M+H)+. HPLC (Method E) Rt 2.35 min (Purity: 98.9%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]([CH3:29])([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([CH3:29])([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:18][CH:19]=2)=[CH:30][CH:31]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(=O)C(C)(C)Oc2ccc(CCCO)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)C(C)(C)Oc2ccc(CCCOS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
A solution of 3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone (0.312 g, 0.73 mmol) in dry dichloromethane (15 ml) was cooled to 0-5° C. and treated with triethylamine (0.23 ml, 1.65 mmol) followed with methanesulfonyl chloride (0.10 ml, 1.29 mmol) added dropwise over 2 minutes. The reaction mixture was stirred at 0° C. for 45 minutes and then quenched by the addition of ethyl acetate and water. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution toluene-ethyl acetate, 85:15) to give 0.369 g (100%) of the title material as a clear oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH2:18]Br.[H-].[Na+].O>O1CCCC1.CN(C)C=O>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]#[N:12])[CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(OC(F)(F)F)cc2)CCC1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
A solution of 4-trifluoromethoxyphenylacetonitrile (38.9 g) and 1,3-dibromopropane (39.1 g) in tetrahydrofuran (50 ml) was added under argon to a stirred solution of 50% sodium hydride (19.2 g) in tetrahydrofuran (200 ml) and dimethylformamide (25 ml) at 25°-30° C. over 1 hour. The mixture was stirred at 20° C. for 1.5 hours, then at 30°-40° C. for 1 hour, then cooled and water added. The mixture was filtered and washed with ether. The organic layer was washed with water, dried over magnesium sulphate and the solvent removed by evaporation. The residue was distilled (b.p. 111°-117° C./10 mbar) to give 1-(4-trifluoromethoxyphenyl)cyclobutanecarbonitrile (30.98 g).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:1]([N:9]1[CH2:14][CH2:13][C:12]([S:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CN(C(=O)c2ccccc2)CCC1=O
Reactant: CCOC(=O)CS
Solvent: CCO
Product: CCOC(=O)CSC1=C(C(=O)OC)CN(C(=O)c2ccccc2)CC1
Reaction time: 5 h

Procedure:
A solution of 1-benzoyl-3-methoxycarbonyl-4-piperidone (12 g; 0.046 mole) in absolute ethanol (150 cc), cooled to -10° C, is saturated with dry hydrochloric gas. Ethyl mercapto-acetate (10.8 g; 0.092 mole) is added thereto and a slight stream of hydrochloric gas is further passed therethrough at -10° C during 5 hours. After leaving the reaction mixture aside at room temperature during 70 hours, it is evaporated to dryness and the residue is dissolved in ether. The organic phase is washed with a 5% sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting 1-benzoyl-4-ethoxycarbonylmethylthio-3-methoxycarbonyl-1,2,5,6-tetrahydro-pyridine is obtained as an oil (Yield: 100%) and used directly in the next step:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.O>CS(C)=O>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To the solution of 15.22 g (100 mmoles) of isovanilline in 125 ml of dimethylsulphoxide, 27 g of powdered anhydrous potassium carbonate are added. The suspension is stirred at 60° C. for 30 minutes and then 12.9 ml (120 mmoles) of cyclopentyl bromide are added at 60° C. during 60 minutes. Then the suspension is stirred at the same temperature 8 hours, cooled to 25° C. and poured into 500 ml of water. The aqueous emulsion is extracted four times with 100 ml of ether. The collected ethereal phases are washed twice with 20 ml of 1 N sodium hydroxide solution, dried over anhydrous magnesium sulphate and evaporated. To the oily residue 100 ml of benzene are added and the evaporation is repeated. The remained oil is fractionally distilled in vacuo to give 20.65 g (94%) of title compound, b.p. 136°-138° C./0.01 Hgmm.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[SH:39]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:39][C:33]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=2[Cl:31])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccc(Cl)cc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2,4-dichlorothiophenol yielded ((2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2,4-dichloro-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless oil. MS: 454.3 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:17]1.C(=O)([O-])[O-].[K+].[K+].CI>>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH3:17])=[O:11]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 97.1 %

Procedure:
N-(tert-Butoxycarbonyl)-L-proline (7.05 g, 0.0328 mol) was dissolved in THF (200 mL, 2 mol) and to this solution was added potassium carbonate (10.2 g, 0.0738 mol) and methyl iodide (5.0 mL, 0.08 mol). The resulting heterogeneous solution was heated to reflux for 16 h with vigorous stirring. The mixture was then filtered through a pad of diatomaceous earth and the filter pad was washed thoroughly with tetrahydrofuran (THF). The volatiles were removed in vacuo and the resulting residue was purified by CombiFlash chromatography using a 40 g column and eluting with EtOAc/hexanes (0-25%) to afford the desired product as a yellow oil (7.3 g, 97%). LC-MS: 130.2 (M−Boc+2H)+ and 252.1 (M+Na)+.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[CH:20][C:19]=1[F:30].CC(=O)OCC>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[CH:20][C:19]=1[F:30]
Reactant: C=C(c1ccc(F)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4ccc(F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.7 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (239 mg, 1.0 mmol) and 2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg, 1.07 mmol) in DMF (5 mL) at rt was added TEA (108 mg, 1.07 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound 5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (140 mg; yield 30.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.80-7.70 (m, 4H), 7.64-7.60 (m, 2H), 4.43 (d, J=18.4 Hz, 1H), 4.27 (d, J=18.4 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 96.0% at 220 nm and 96.4% at 254 nm; MS: m/z=428.1 (M+, ESI+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH3:18][C:15]([CH3:19])([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[C:16]#[CH:17]
Reactant: C#CC(C)(C)Cl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)(C)Oc1cc(C(=O)OC)ccc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (5.41 g), 3-chloro-3-methyl-1-butyne (10 ml), cesium carbonate (19.4 g), and DMF (54 ml) was stirred at 80° C. for one hour. 3-Chloro-3-methyl-1-butyne (5 ml) was further added to the mixture followed by stirring at 90° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and with a saturated saline and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 and 7/1) to give Compound IIao-a (2.31 g, 31%) as a brown oily substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1.[Cl-].[NH4+]>O.CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:20][CH:19]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
After addition of potassium carbonate (4.00 g, 29.0 mmol) and 2-bromomethyl-1,4-difluorobenzene (5.00 g, 24.2 mmol) to an N,N-dimethylformamide (120 ml) solution of 4-chlorobenzenethiol (3.86 g, 26.6 mmol), the resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture were added saturated ammonium chloride (50 ml) and water (20 ml), followed by extraction with diethyl ether. The extracts were combined, washed with water and brine, dried (over MgSO4), and concentrated. The residue thus obtained was purified by silica gel column chromatography (1% ethyl acetate-hexane) to give 2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (6.41 g, 98%) as a colorless oil.