Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:26])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[CH:10]=[CH2:11].[H][H]>[Ni].C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)([OH:26])[CH2:10][CH3:11]
Reactant: C=CC(O)(c1ccc(OCc2ccccc2)cc1)c1cc(C)ccc1C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cc(C)ccc1C

Procedure:
10.3 g. of 1-(2,5-dimethylphenyl)-1-(4-benzyloxyphenyl)-allyl alcohol are dissolved in 110 ml. of ethanol and the reaction mixture is hydrogenated under atmospheric pressure, in the presence of 3.5 g. of Raney nickel catalyst. After uptake of the calculated amount of hydrogen is complete, the catalyst is filtered off. Ethanol is distilled off under reduced pressure. As a residue 9 g. of the named compound are obtained as a viscous oil, boiling at 190°-192° C./26.6 Pa.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:17](=[O:32])[C:16]([CH:33]=O)=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:17](=[O:32])[C:16]([CH:33]=[CH2:1])=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cccc3c2c(=O)c(C=O)nn3Cc2ccccc2)c(C)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C=Cc1nn(Cc2ccccc2)c2cccc(-c3ccc(C)cc3C)c2c1=O
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a slurry of 0.081 g (0.72 mmol) of potassium tert-butoxide in 10 mL of ether was added 0.22 g (0.60 mmol) of methyl triphenylphosphonium bromide. The resulting ylide solution was stirred for 30 min then 0.11 g (0.30 mmol) of 1-benzyl-5-(2,4-dimethylphenyl)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde was added. The reaction mixture was stirred for 3 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography eluting with a 9% ethyl acetate/hexanes mixture to give 0.035 g (32%) of the title compound as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Na].[Cl:13][O-].[Na+].Cl>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH3:11])[C:2]=1[OH:1]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: Cc1c(C(=O)O)ccc(Cl)c1O
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 22.8 g of 3-hydroxy-2-methylbenzoic acid in 300 ml of water, cooled to 2° C., were added 55 ml of 3N sodium hydroxyde to adjust the pH to 10. To the clear solution were added within 20 minutes, at 2° to 6° C., 125 ml of 1.2N sodium hypochlorite solution, the pH being raised to 12.5. Then, 90 ml of 3N hydrochloric acid were added at once, a precipitate being formed immediately. The mixture was stirred at 0° C. for 30 minutes, and subsequently the precipitate was isolated by filtration and crystallized from diethylether/hexane to give 15.0 g of 4-chloro-3-hydroxy-2-methylbenzoic acid as white crystals of m.p. 191° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@@H:47]([CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])[C:48]([NH2:50])=[O:49].NC(C)(C)C(NCCO)=O>>[CH2:59]([O:58][C:56]([NH:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:47]([NH:46][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[C:32]([CH3:42])[CH:33]=1)[C:48](=[O:49])[NH2:50])=[O:57])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(=O)NCCO
Product: Cc1cc(OCCCN[C@@H](CCCCNC(=O)OCc2ccccc2)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 72 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-2-amino-6-(benzyloxycarbonylamino)hexanamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-[2-amino-2-(methyl)propionylamino]ethanol, respectively.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]12[CH2:14][CH2:13][C:10]([CH2:15][OH:16])([CH2:11][CH2:12]1)[CH2:9][CH2:8]2)=[O:6]>C1COCC1.CO>[OH:16][CH2:15][C:10]12[CH2:13][CH2:14][C:7]([C:5]([OH:6])=[O:4])([CH2:8][CH2:9]1)[CH2:12][CH2:11]2
Reactant: COC(=O)C12CCC(CO)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C12CCC(CO)(CC1)CC2
Reaction time: 16 h

Procedure:
Lithium hydroxide (2 N, 250 ml) is added to a mixture of 4-hydroxymethyl-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (XVI, Example 91) in a mixture of THF (50 ml) and methanol (75 ml). The resulting reaction mixture is stirred at 20-25° for 16 hr, and then concentrated. The residue is diluted with water (30 ml) and washed with methylene chloride (100 ml) and ethyl acetate (100 ml). The aqueous layer is acidified with concentrated hydrochloric acid pH about 0 and extracted with ethyl acetate (3×250 ml). The ethyl acetate layers are combined and washed with saline (3×50 ml), dried over anhydrous sodium sulfate and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 3.09, 1.72 and 1.29.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:27])[C@H:23]([CH2:25][OH:26])[NH2:24].C(N(CC)CC)C.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH3:20][O:21][C:22](=[O:27])[C@H:23]([CH2:25][OH:26])[NH:24][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g), L-serine methyl ester hydrochloride (0.78 g) and triethylamine (1.40 ml) are dissolved in dry chloroform (20 ml) and thereto is added 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (1.72 g) under ice-cooling. After allowing to stand overnight, to the mixture are added water and ethyl acetate. The ethyl acetate layer is washed and dried, and then the solvent is distilled off to give N-(N-benzyloxycarbonyl-L-prolyl)-L-serine methyl ester (1.4 g), melting point: 96°-100° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:7]=1.CCOC(C)=O.C(Cl)[Cl:29]>O.Cl.C(Cl)(Cl)Cl.[Cu]Cl>[Cl:29][C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:7]=1
Reactant: CCOC(=O)c1cn(-c2ncccn2)nc1N
Reactant: ClCCl
Agent: Cl[Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cn(-c2ncccn2)nc1Cl
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (1.0 g, 15.1 mmol) in 5.0 mL of water is added dropwise to a solution of ethyl 3-amino-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (2.7 g, 11.6 mmol) in 18 mL of conc. HCl at −5° C. with stirring. After 1 h at 0° C., the reaction mixture is added dropwise to a suspension of copper (I) chloride (1.8 g, 18.6 mmol) in 18 mL of CHCl3 at RT. After 1 h at RT, water (40 mL) and CHCl3 (40 mL) are added, and the layers are separated. The organic layer is washed once more with water (40 mL), dried (Na2SO4), filtered, and evaporated in vacuo to give a greenish/yellow solid. TLC analysis (70% EtOAc/CH2Cl2) of this crude solid reveals 2 products, which are separated by column chromatography (10% EtOAc/CH2Cl2) to afford ethyl 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (Rf≈0.7) as a white solid. The minor, more polar compound ethyl 5-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate, Rf≈0.5) is also isolated as a white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)=O.O=P(Cl)(Cl)Cl>C1COCC1>[N+:3]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)#[C-:1]
Reactant: CC(C)(C)OC(=O)c1ccc(NC=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: [C-]#[N+]c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To Intermediate 1A in THF (300 mL) was added TEA (33 mL, 238 mmol) and the after cooling to 0° C., POCl3 (7.3 mL, 79 mmol) was slowly added and the reaction was stirred at room temperature. After 24 h, the reaction was partitioned between EtOAc (200 mL) and aqueous NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL) and dried (MgSO4). Purification by normal phase chromatography afforded 10.4 g (64.6%) of Intermediate 1 as a green solid. 1H NMR (400 MHz, CDCl3) δ: 8.02 (d, J=8.59 Hz, 2H), 7.41 (d, J=8.34 Hz, 2H), 1.60 (s, 9H) ppm.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(C(C)C)CC)(C)C>O1CCOCC1>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([N:1]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])[C:3](=[O:13])[CH:4]=1
Reactant: Nn1c(=O)cc(O)c2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1n1c(=O)cc(O)c2ccccc21
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A mixture of the product of Example 350A (0.54 g, 3 mmol), phthalic anhydride (1.36 g, 2.2 eq.) and diisopropylethylamine (1.97 g, 5 eq.) in dioxane (20 mL) was heated at 100° C. for 2 hours, cooled to 25C and concentrated. The residue was triturated with water and ether. The resulting solids were filtered and dried in vacuum to give the title compound (0.6 g, 64% crude yield) which was used directly for the next step. 1H NMR (300 MHz, DMSO-d6) δ 5.95 (s, 1H), 7.37 (m, 1H), 7.6 (m, 2H), 7.95-8.1 (m, 5H), 12.18 (s, 1H). MS (DCI+) m/z 306 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:25].[K+]>C(O)(=O)C.O.C(OCC)(=O)C>[I:25][C:5]1[CH:7]=[CH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [I-]
Reactant: COc1cc(N)ccc1-c1ccccc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(I)ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
8 g of the product obtained in Stage B is dissolved at 40° C. in 60 ml of glacial acetic acid. Then a solution of 5 ml of concentrated sulphuric acid in 80 ml of water is added. The reaction medium is cooled down to 0° C. Then a solution of 2.77 g of sodium nitrite in 35 ml of water is added dropwise over one hour. Agitation is carried out for one hour at 0° C., and a solution of 13.33 g of potassium iodide, in 25 ml of water is added dropwise. The suspension obtained is maintained at 0° C. for one hour, brought to 10° C. over 40 minutes, maintained at 10° C. for one hour, and brought to 20° C. over 30 minutes. It is poured into water, and extraction is carried out with ethyl acetate. The organic phases are collected and washed (aqueous solution of NaHSO3 then NaHCO3). They are dried and evaporated under reduced pressure. The product obtained is chromatographed, eluting with a heptane-methylene chloride mixture (9-1) and 9.6 g of sought product is obtained, melting at 57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]I)[CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>O1CCCC1.C(O)(C)C.CO>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:3]=1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)O
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCN1CCCC1)c1ccccc1

Procedure:
A solution of the product from Example 1 step (c) (200 mg) and pyrrolidine (0.15 ml) in tetrahydrofuran (5 ml) was stirred for 2 days. The solvent was removed in vacuo and the residue dissolved in water and aqueous potassium carbonate and extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (Na2SO4) and evaporated to give an oil. To a solution of this amine in isopropanol (3 ml) was added a solution of oxalic acid (44 mg) in methanol (0.3 ml). The crystals that formed on cooling were collected and dried to afford the title compound as a white solid (163 mg). M.p. 157-158° C.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:22]([NH:24][N:25]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:22]([NH:24][N:25]([CH2:41][CH:42]([CH3:43])[CH3:44])[C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCN1C(=O)c2ccccc2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCN1C(=O)c2ccccc2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
A solution of 0.050 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(3-phthalimidopropionyl)valerohydrazide in 5 ml of methanol was treated with 0.005 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 1 hr at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.009 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(3-phthalimidopropionyl)valerohydrazide in the form of an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[C:5](=[O:18])[CH2:4][CH2:3]1.CC1(C)C2C(=CC=C([Si](C)(C)C)C=2)C(=O)C(C#C)C1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:18])[CH2:4][CH2:3][C:2]2([CH3:19])[CH3:1])#[CH:13]
Reactant: CC1(C)CCC(=O)c2ccc(C#C[Si](C)(C)C)cc21
Agent: C#CC1CC(C)(C)c2cc([Si](C)(C)C)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of 4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 12, 0.28 g, 1.03 mmol) in methanol (10 mL) was treated with potassium carbonate (0.74 g, 5.35 mmol) and stirred at ambient temperature for 4 h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with diethyl ether (×2). The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (0.19 g, 89%) as an oil that solidified on standing.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20].C[O-].[Na+]>CO>[CH3:2][N:3]([CH3:12])[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][S:19][C:17]1[N:16]=[C:15]([S:20][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N:3]([CH3:12])[CH3:2])[CH:5]=2)[C:14]([CH3:21])([CH3:13])[N:18]=1
Reactant: CC1(C)NC(=S)NC1=S
Reactant: CN(C)c1cccc(CCl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)c1cccc(CSC2=NC(C)(C)C(SCc3cccc(N(C)C)c3)=N2)c1

Procedure:
Initially, 3.1 g of 3-dimethylaminobenzylchloride hydrochloride was added to a mixture of 0.8 g of 5,5-dimethyl-2,4-dithiohydantoin and 1.34 g of sodium methoxide in 50 mL of methanol (MeOH). The reaction mixture was treated following the procedure used in Example 56, and purified by column chromatograph (CHCl3) to give the desired compound in the form of a syrup. The yield of this compound was 1.65 g with a yield ratio of 82.9%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].CN(C=O)C>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1c(C)cccc1C
Yield: 91.1 %

Procedure:
A solution of 2,6-dimethylphenol (0.87 g, 7.1 mmol), potassium carbonate (0.98 g, 7.1 mmol), 2-fluoro-5-nitrotoluene (1.0 g, 6.4 mmol) and DMF (20 mL) was stirred at 100° C. for 2 h. The reaction mixture was diluted with 100 mL water and extracted with 250 mL EtOAc. The organic layer was washed with brine, dried with sodium sulfate and concentrated to provide the crude titled compound (1.5 g, 92%). This material was used without purification: MS (ESI): mass calcd. for C15H15NO3, 257.3; m/z found, 258.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.16 (dd, J=2.8, 0.7 Hz, 1H), 7.92 (dd, J=9.1, 2.7 Hz, 1H), 7.18-7.07 (m, 3H), 6.33 (d, J=9.0 Hz, 1H), 2.50 (s, 3H), 2.09 (s, 6H).
Reaction SMILES: [CH3:1]Br.[Mg].[Br:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2=[O:16].Cl>O1CCCC1>[Br:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:1])[OH:16]
Reactant: CBr
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(Br)c(C)c2c1SCCC2(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 300-ml three-necked flask was charged with 55 ml (55 mmol, 3 equivalents) of a 1 M solution of magnesium methyl bromide (MeMgBr) and 100 ml of tetrahydrofuran (THF), and the mixture was cooled with ice under nitrogen current. To this mixture was dropwise added a solution of 5.0 g (18.4 mmol) of 6-bromo-5,8-dimethylthiochroman-4-one in 15 ml of THF, and the mixture was stirred at room temperature for 3 hours and then refluxed for 2 hours. To the reaction mixture was added 5% HCl, and the mixture was extracted with ethyl acetate. The resultant organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 5.2 g (yield 99%) of 6-bromo-4,5,8-trimethylthiochroman-4-ol.
Reaction SMILES: N(C(OCCOC)=O)=NC(OCCOC)=O.[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:28].[Br:29][C:30]1([Br:35])[CH2:32][CH:31]1[CH2:33]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:29][C:30]1([Br:35])[CH2:32][CH:31]1[CH2:33][O:28][C:19]1[CH:20]=[C:21]([CH3:27])[C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[CH3:17]
Reactant: OCC1CC1(Br)Br
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1(Br)Br
Yield: 36 %

Procedure:
0.85 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 0.47 g of 2,5-dimethyl-4-nitrophenol, 0.64 g of (2,2-dibromocyclopropyl)methanol (manufactured according to a reference document (R. Huwyler, A. Al-Dulayymi, M. Neuenschwander, Helv. Chim. Acta 1999, 82, 2336)), 0.87 g of triphenylphosphine and 30 mL of toluene at 0° C., and the mixture was stirred at 80° C. for 5 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.38 g of 1-[(2,2-dibromo-cyclopropyl)methoxy]-2,5-dimethyl-4-nitrobenzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][O:39][CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][O:39][CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COCCNS(=O)(=O)c1ccc(Br)cc1
Product: COCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.28) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (400 mg, 70%). MS (ISP) 569.1 [(M+H)+]; mp 185–187° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([N:21]=[C:22]=[S:23])[CH:20]=1>C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([NH:21][C:22](=[S:23])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:20]=1
Reactant: NCC(N)=O
Reactant: COc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of glycinamide hydrochloride (5.5 g), triethyl amine (5.05 g), 5-chloro-2-methoxyphenyl-isothiocyanate (9.95 g), and chloroform (500 mL) were heated at reflux for 3 hours. The mixture was then cooled to ambient temperature and washed with water (300 mL). The organic phase was separated. Precipitate formed upon standing. The solid was collected by filtration, washed with water, then with diethyl ether and air dried to give 2-[3-(5-chloro-2-methoxyphenyl)-thioureido]-acetamide (12.8 g), m.p. 166°-169° C. (dec.). This compound was used without further purification for the preparation of the title compound.