Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1C2COCC3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[C:17]=3[C:11]=2[CH:10]=[CH:9][C:8]=1[O:28][CH3:29])(=O)=O.O.[SH-:33].[Na+].[C:35]([O:38][CH2:39][CH3:40])(=O)[CH3:36]>N1CCCC1=O>[CH3:29][O:28][C:8]1[CH:9]=[CH:10][C:11]2[C:17]3[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:40]=3[CH2:39][O:38][CH2:35][C:36]=2[C:7]=1[SH:33]
Reactant: [SH-]
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1OS(=O)(=O)C(F)(F)F)COCc1cc(OC)c(OC)c(OC)c1-2
Agent: O=C1CCCN1
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1S)COCc1cc(OC)c(OC)c(OC)c1-2
Temperature: 90 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-yl trifluoromethanesulfonate (Example 7, 85.2 mg, 0.183 mmol), sodium hydrosulfide hydrate (41.7 mg, 0.743 mmol) and 2-pyrrolidinone (0.4 mL, 0.005 mmol) in a sealed tube was sonicated (Branson 1510, output 70 W) for a period of 10 minutes and then stirred at an oil bath temperature of 90° C. for 1 hour, which afforded a pungent yellow solid. Column chromatography (petroleum ether 60-80°—ethyl acetate 1:1) gave the title compound as a yellow gum (50 mg, 78%); νmax/cm−1 (thin film) 2942, 2867, 2545, 1595, 1486; NMR Spectrum δH (400 MHz, CDCl3) 3.76 (3H, s, OCH3), 3.85 (1H, d, J 12.6 Hz, 5-H or 7-H), 3.92 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.05 (1H, d, J 12.6 Hz, 5-H or 7-H), 4.40 (1H, d, J 11.9 Hz, 5-H or 7-H), 5.15 (1H, d, J 11.9 Hz, 5-H or 7-H), 5.86 (1H, s, SH), 6.78 (1H, m, 8-H), 6.94 (1H, d, J 8.5 Hz, 2-H), 7.21 (1H, d, J 8.5 Hz, 1-H); NMR Spectrum δC (100 MHz, CDCl3) 56.44, 56.52, 59.65, 61.23, 61.52, 68.23, 109.17, 110.36, 121.23, 121.49, 126.85, 131.06, 131.56, 143.05, 143.80, 145.96, 151.07, 153.14; m/z (CI, NH3) no molecular ion; Rf (petroleum ether 60-80°—ethyl acetate 1:1) 0.32.
Reaction SMILES: [CH:1]1([CH:4]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)O)[C:5]([OH:7])=O)[CH2:3][CH2:2]1.[CH3:18][C@@H:19]([NH-:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:18][C@@H:19]([NH:26][C:5](=[O:7])[CH:4]([CH:1]1[CH2:2][CH2:3]1)[CH:8]([N:60]=[N+:61]=[N-:62])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]([NH-])c1ccccc1
Reactant: O=C(O)C(C1CC1)C(O)c1ccc(F)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)C(C1CC1)C(N=[N+]=[N-])c1ccc(F)c(F)c1)c1ccccc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
The appropriate diastereomer of 2-cyclopropyl-3-(3,4-difluorophenyl)-3-hydroxypropionic acid N-((R)-(α-methylbenzyl)amide (1.1 g, 3.18 mmol), triphenylphosphine (1.7 g, 6.48 mmol), and diphenyl-phosphoryl azide (1.37 mL, 6.36 mmol) were combined in THF (30 mL) and cooled to −78° C. under nitrogen. Diethyl azodicarboxylate (1.2 mL, 7.63 mmol) was added and the mixture was stirred 1 hour at −78, 1 hour at 0° C. and 16 hours at ambient temperature. The reaction mixture was washed with saturated sodium bicarbonate and brine, dried the over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified and separated by “flash” chromatography (98:2 of methylene chloride:ethyl ether). The product fractions were evaporated to dryness and the residue was reconcentrated from ethyl ether to yield the title compound as an oil.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]2[CH3:1])=[CH:17][C:18]=1[C:24]([F:25])([F:26])[F:27])#[N:21]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
A 4.46 g portion of t-butyl 3-methylpiperazine-1-carboxylate synthesized in Reference Example 2, 6.74 g of 4-fluoro-2-trifluoromethylbenzonitrile and 7.76 ml of diisopropylethylamine were stirred in 50 ml of DMF at 100° C. for 2 days. The reaction solution was diluted with water and extracted with ethyl acetate, the organic layer was washed and dried and then the solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to obtain 5.6 g of the title compound as white crystals.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:24])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[O:14][N:13]=1)C.Cl>O.O1CCOCC1>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[O:14][N:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:24])=[O:6])[CH:16]=1
Reactant: CCOC(=O)CCCCc1cc(-c2ccccc2O)on1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCc1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Add a solution of LiOH.H2O (2.87 g, 68.4 mmol) in water (60 mL) to a rapidly stirred solution of 5-[5-(2-hydroxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (3.96 g, 13.7 mmol) in dioxane (120 mL) and stir at room temperature overnight. After 1 hour, acidify to pH 1 with 5N HCl solution and concentrate to remove the majority of the dioxane. Add water to residue and place in refrigerator overnight. Filter out solids, wash with water, dry in a 50° C. vacuum oven for 6 hours to afford the title compound (3.11 g, 87%). MS (IS) 262 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([O:71][C:72](=[O:82])[CH2:73][CH2:74][CH2:75][NH:76][CH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1)[CH3:70]>CN(C=O)C>[CH2:69]([O:71][C:72](=[O:82])[CH2:73][CH2:74][CH2:75][N:76]([C:15](=[O:16])[C:14]1[CH:18]=[C:19]([Cl:21])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:13]=1)[CH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1)[CH3:70]
Reactant: CCOC(=O)CCCNC1CCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.300 g), TBTU (0.482 g) and HOBt (0.150 g) in DMF (5 ml) was added DIPEA (0.260 ml) followed by 4-cyclopentylamino-butyric acid ethyl ester (0.316 g) after 10 min. The reaction mixture was stirred at room temperature for 16 h and then further 4-cyclopentylamino-butyric acid ethyl ester (0.316 g) was added. After 24 h, the reaction mixture was concentrated under reduced pressure to give a viscous gum which was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with further water, aqueous saturated sodium bicarbonate solution, water and dried with brine and over sodium sulphate. The organic phase was concentrated under reduced pressure to give crude product as a black gum (0.420 g) which was purified by preparative hplc and the title compound (0.189 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)([CH3:10])[C:7]([OH:9])=[O:8].[CH:24]1C=CC=C[CH:25]=1>C(N(CC)CC)C>[CH3:10][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:14][CH:13]=1)([CH3:5])[C:7]([O:9][CH2:24][CH3:25])=[O:8]
Reactant: CC(C)(Oc1ccc(C2CCOCC2)cc1)C(=O)O
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.2 ml of thionyl chloride were added at 15° C to a mixture of 7 g of 2-methyl-2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoic acid, 70 ml of benzene and 3.5 ml of triethylamine and the mixture was stirred for 2 hours at room temperature and was then filtered. The filtrate was slowly added to 250 ml of 5.4N hydrochloric acid in ethanol and the mixture was stirred for 12 hours at room temperature and was then concentrated to dryness. The residue was added to 100 ml of ether and the solution was washed with a saturated sodium bicarbonate solution and then with water. The solution was dried and evaporated to dryness and the oily residue was distilled under reduced pressure to obtain 6.5 g of ethyl 2-methyl-2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoate with a boiling point of 138°-140° C at 0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[S:25][CH:26]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:23]=3)[CH2:28][CH2:29]2)=[O:15])[O:4][N:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)on1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)on1
Yield: 44.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (3-methylisoxazol-5-yl)carbamate (245 mg, 0.897 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.815 mmol) and diisopropylethylamine (0.156 ml, 0.897 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 135 mg (44.9%) of the desired product as a solid.
Reaction SMILES: CN(C=O)C.[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[OH:9].N1C=CN=C1.[CH2:34]([Si:36](Cl)([CH2:39][CH3:40])[CH2:37][CH3:38])[CH3:35]>CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCCC>[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[O:9][Si:36]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:34][CH3:35]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CI)ccc1OCc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 100.6 %

Procedure:
To a stirred DMF (65 mL) solution containing (R)-2-iodo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanol (12.7 g, 28 mmol), imidazole (5.25 g, 77 mmol), and 4-dimethylaminopyridine (0.30 g, 2.46 mmol) was added triethylsilyl chloride (5.0 mL, 29.8 mmol). After 15 minutes the completed reaction was diluted with EtOAc (200 mL) and heptane (70 mL). The organic phase was washed 1×100 mL H2O, 2×100 mL aq. sat. CuSO4, 1×100 mL H2O, 1×100 mL sat. brine, and dried over Na2SO4. The filtrate was concentrated in vacuo to give 15.81 g of tan solid which was dissolved in ~125 mL CH2Cl2 and diluted with 650 mL heptane. The mixture was concentrated in vacuo at 40°-42° C. until solids were seen (~105 mL distillate were collected), cooled to ~15° C. and filtered. The collected solids were washed with heptane and dried in vacuo at 45° C. to give 11.1 g (70%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:19][C:20]([NH2:22])=[S:21]>>[NH2:22][C:20]1[S:21][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=1
Reactant: CCOC(=O)/C(=N\OC1CCOCC1)C(=O)CBr
Reactant: NC(N)=S
Product: CCOC(=O)/C(=N\OC1CCOCC1)c1csc(N)n1
Yield: 70 %

Procedure:
Ethyl 4-bromo-(Z)-2-(tetrahydro-4H-pyran-4-yloxyimino)-3-oxobutyrate (0.52 g) was treated with thiourea as described in Example 4d. Crystallisation from diisopropyl ether gave the title compound as a pale yellow solid (0.34 g, 70%), m.p. 110.0°-110.5° C. [Found: C: 48.37, H: 5.99, N: 13.59. C12H17N3O4S requires C: 48.15, H: 5.72, N: 14.04%]. νmax (KBr) 3138, 1733, 1616, 1538 cm-1. δH (CDCl3) 1.39 (3H, t), 1.76 (2H, m), 2.01 (2H, m), 3.56 (2H, m), 3.88 (2H, m), 4.42 (2H, q), 4.53 (1H, m), 5.29 (2H, br s, exch. D2O), 6.73 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)(=[O:11])=[O:10])[O:4][N:3]=1.[H][H]>[Pd].CO>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:11])=[O:10]
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2N)c1C
Yield: 111.1 %

Procedure:
To a suspension of 135 mg of 10% palladium on carbon in 20 mL of methanol under argon, 0.9 g (3.03 mmol) of N-(3,4-dimethyl-5-isoxazolyl)-2-nitrobenzenesulfonamide (Example 9) in 20 mL of methanol was added. The solution was hydrogenated with a balloon filled with hydrogen for 90 minutes. The mixture was filtered through Celite® and the filtrate was concentrated to afford 0.9 g of a gum. This material was chromatographed on silica initially with 9:1 methylene chloride:methanol and then with 1:1 hexanes:ethyl acetate to provide 0.2 g (24%) of Example 10 as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:6]>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][Cl:3])[C:7]=2[CH2:5][CH3:6])=[CH:16][CH:17]=1
Reactant: CCc1c(CO)cccc1-c1ccc(OC)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1c(CCl)cccc1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 71 %

Procedure:
After thionyl chloride (4 ml) was added to a solution of (2-ethyl-4′-methoxy-1,1′-biphenyl-3-yl)methanol (4.39 g, 17.9 mmol) obtained in Example (90-3) in methylene chloride (18 ml) under ice-cooling, the mixture was stirred at room temperature for 7 hours. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3′-(chloromethyl)-2′-ethyl-1,1′-biphenyl-4-yl methyl ether (3.32 g, yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.Cl.[CH2:17](O)[CH3:18]>CN1CCNCC1>[OH2:9].[ClH:1].[CH3:5][N:4]1[CH2:18][CH2:17][N:7]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: CCO
Agent: CN1CCNCC1
Agent: Cl
Product: CN1CCN(c2cncc(C(=O)Nc3nnn[nH]3)n2)CC1
Product: O

Procedure:
To a suspension of 2.26 of 6-chloro-N-(1H-5-tetrazolyl) pyrazine-2-carboxamide in 30 ml of ethanol, 5.55 ml of N-methylpiperazine was added, and the mixture was refluxed for 6 hours. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 1. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 2.27 g of the desired compound as pale yellow crystals, m.p. 246°-250 ° C. (decomp.).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C)C=O.O.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>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[CH:4]=[N:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cnc(I)c3n2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
A mixture of 8-iodo-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.65 g, 3.61 mmol), trimethylsilylacetylene (0.9 mL, 6.5 mmol) and triethylamine (1.51 mL, 10.8 mmol) in N,N-dimethylformamide (10 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (0.76 mg, 0.11 mmol), PPh3 (57 mg, 0.22 mmol) and CuI (7 mg, 0.04 mmol) were added. Stirring was continued at 90° C. for 3.5 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), evaporated and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to give 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-8-trimethylsilanylethynyl-imidazo[1,5-a]pyrimidine (0.82 g, 53%) as a brown solid, which was dissolved in THF (10 mL) and MeOH (10 mL), while stirring at 0° C. potassium carbonate (26 mg, 0.19 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (50 mL) and extracted with TBME (2×100 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization from diethyl ether/hexane to give 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (0.54 g, 42%) as a brown solid. MS (EI) 355.1 [(M)+]; mp 163° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7]1[O:8][N:43]=[C:41]([CH3:42])[N:40]=1
Reactant: CC(=N)NO
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid (0.39 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added 1,1′-carbonyldiimidazole (0.24 g, 1.50 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, and N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The stirring was continued at ambient temperature for 6 hours, and another portion of N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The reaction mixture was heated for 23 hours at 110° C. and cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, and filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 15% yield (0.06 g): mp 163-164° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2 H), 7.41 (d, J=8.1 Hz, 2H), 4.55 (s, 2H), 4.15-4.09 (m, 2H), 3.51-3.45 (m, 2 H), 2.68 (s, 3H), 2.41 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 170.8, 167.3, 160.5, 155.3, 154.5, 139.6. 128.5, 125.9, 125.8, 122.1, 109.0, 47.6, 421 41.9, 17.5, 11.6: MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.ClS([N:25]=[C:26]=[O:27])(=O)=O.O>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[C:26]([NH2:25])=[O:27])[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCCc1c(O)cc2oc3cc(Cl)c(C(N)=O)n3c(=O)c2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To 100 mg (0.34 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 10 mL of toluene and 15 mL of CH2Cl2 was added 0.03 mL (0.34 mmol) of chlorosulfonylisocyanate at 0° C. After 15 min., the mixture was warmed to RT, stirred for 30 min., and then 2 mL of water was added. After 30 min, the solids were filtered, washed with ether and dried in vacuo to give 60 mg of the title compound: mp 250° C. dec.
Reaction SMILES: [O:1]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[Mg][CH2:10][CH:11]1[CH2:13][CH2:12]1>C1COCC1.C(OCC)(=O)C>[CH:11]1([CH2:10][CH:2]([OH:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12]1
Reactant: Br[Mg]CC1CC1
Reactant: CCOC(=O)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)CC1CC1
Reaction time: 48 h

Procedure:
Under argon and with ice cooling, a solution of 5.4 g (purity 50%, 26.7 mmol) of ethyl oxoacetate in 50 ml of THF was quickly added dropwise to 7.6 g (48 mmol, 1.8 eq.) of bromo(cyclopropylmethyl)magnesium. The reaction mixture was stirred for another 48 h, diluted with ethyl acetate and quenched with water. Celite was added, and the reaction mixture was stirred for 5 min and then filtered. After phase separation, the organic phase was washed once with water, dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 2.6 g (60% of theory)