Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[H][H]>O1CCOCC1.[Pd]>[C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)OCc3ccccc3)cc2cc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)O)cc2cc1Cl

Procedure:
7-Butyryloxy-3-carboxymethylaminocarbonyl-6-chlorocoumarin was prepared as follows. 920 mg (2 mMol) 7-butyryloxy-3-benzyloxycarbonylmethylaminocarbonyl-6-chlorocoumarin were dissolved in 50 ml dioxane. 100 mg palladium on carbon (10%) and 100 microliters acetic acid were added to the solution and the suspension stirred vigorously in a hydrogen atmosphere at ambient pressure. After the uptake of hydrogen seized the suspension was filtered. The product containing carbon was extracted five times with 25 ml boiling dioxane. The combined dioxane solutions were let to cool upon which the product precipitated as a white powder. Reduction of the solvent to 20 ml precipitates more product. The remaining dioxane solution is heated to boiling and heptane is added until the solution becomes cloudy. The weights of the dried powders were 245 mg, 389 mg and 58 mg, totaling 692 mg (1.88 mMol, 94%) of white product. 1H NMR (dDMSO): 1.02 ppm (t, 3H, J=7.4 Hz, butyric methyl), 1.73 ppm (m, 2H, J1 J2=7.3 Hz, butyric methylene), 2.70 ppm (t, 2H, J=7.2 Hz, butyric methylene), 4.07 ppm (d, 2H, J=5.6 Hz, glycine methylene), 7.67 ppm (s, 1H, coumarin), 8.35 ppm (s, 1H, coumarin), 8.90 ppm (s, 1H, coumarin), 9.00 ppm (t, 1H, J=5.6 Hz, amide).
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].ClCCl>[CH3:1][C:2]1[NH:6][C:7]2[C:12]([C:3]=1[CH3:4])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C#CC(C)O
Reactant: Nc1ccccc1
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: ClCCl
Product: Cc1[nH]c2ccccc2c1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
3-Butine-2-ol (0.701 g, 10 mmol), aniline (0.931 g, 10 mmol), Ru3(CO)12 (32.0 mg, 0.05 mmol) and aniline hydrochloride (0.259 g, 2.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 120° C. for 12 hours. After cooling, dichloromethane (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby 2,3-dimethyl indole (1.31 g; 9.0 mmol; yield, 90%; purity, about 99%) was obtained.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[S:13][C:12](=[S:23])[N:11]=2)=[CH:6][CH:5]=1.[CH2:24]1[O:26][CH2:25]1.O>C(O)C.C(Cl)Cl>[OH:26][CH2:25][CH2:24][S:23][C:12]1[S:13][C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: C1CO1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
0.23 g of sodium are dissolved in 30 ml of ethanol under nitrogen. The solution is allowed to cool to room temperature, while stirring 3 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are added and, once dissolution is complete, ethylene oxide is introduced, the reaction temperature being maintained at 25°-30° by gentle cooling. After introducing the ethylene oxide for 30 minutes, it should not be possible to detect any more thione by thin layer chromatography. 10 ml of 2 N-ammonium chloride are then added, the ethanol is removed by distillation under reduced pressure, and the residue obtained by concentration by evaporation is shaken with a mixture of 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, then shaken with methylene chloride, dried over magnesium sulphate and concentrated to dryness by evaporation. The oily crude product is caused to crystallise by triturating with 20 ml of diethyl ether and dried under reduced pressure. 2-(2-Hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 82°-83° is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](OC)[C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(OC)c2c[nH]c3ncccc23)ccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncccc23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-[(4-Benzyloxy-3-methoxy-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (565, 0.9 g, 2.4 mmol) and acetonitrile (50 mL) were mixed with trifluoroacetic acid (0.360 mL, 4.7 mmol) and triethylsilane (0.746 mL, 4.7 mmol). The reaction was heated at 80° C. and stirred overnight. The reaction was concentrated. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography to give the compound (P-1613, 0.454 g 54.8%). MS(ESI) [M+H+]+=345.3.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([O:13]C)=[O:12])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1
Reactant: COC(=O)c1c2ccccc2nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc2ccccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To methyl 2-methylindazole-3-carboxylate (1.59 g, 8.36 mmol) were added THF (85 ml) and 0.25N NaOH (50 ml, 12.5 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added water, followed by the addition of 1N HCl (50 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 2-methylindazole-3-carboxylic acid (1.34 g, 91%) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-])=O>C1COCC1>[N:15]1([C:5]2[CH:6]=[C:7]([N:10]3[CH:14]=[CH:13][CH:12]=[N:11]3)[CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(-n2cccn2)cc1N1CCCCC1
Solvent: C1CCOC1
Product: Nc1ccc(-n2cccn2)cc1N1CCCCC1
Yield: 94 %

Procedure:
Using a procedure similar to Example 4, step (b), 1-(2-nitro-5-pyrazol-1-yl-phenyl)-piperidine (100 mg, 0.31 mmol, as prepared in the previous step) was allowed to react with TiCl3 (1.80 mL, 2.94 mmol) in 3 mL of THF to afford 72 mg (94%) of 2-piperidin-1-yl-4-pyrazol-1-yl-phenylamine, which was allowed to react in a manner similar to Example 3, step (d), with 5-cyano-furan-2-carbonyl chloride (67.5 mg, 0.43 mmol) in the presence of DIEA (111 μL, 0.6 mmol) to afford 52.7 mg (47%) of the title compound as a light yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.67 (s, 1H), 8.50 (d, 1H, J=8.8 Hz), 7.90 (d, 1H, J=2.4 Hz), 7.71 (d, 1H, J=1.5 Hz), 7.65 (d, 1H, J=2.4 Hz), 7.37 (dd, 1H, J=2.5, 8.8 Hz), 7.29 (d, 1H, J=3.8 Hz), 7.23 (d, 1H, J=3.7 Hz), 6.46-6.45 (m, 1H), 2.92-2.89 (m, 4H), 1.85-1.80 (m, 4H), 1.66 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C20H19N5O2 362.1 (M+H), found 362.2.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10](Cl)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:16]([NH2:18])[CH3:17]>C1COCC1>[CH2:16]([NH:18][S:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1)(=[O:12])=[O:11])[CH3:17]
Reactant: CCN
Reactant: O=S(=O)(Cl)Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCNS(=O)(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
[[4-(Trifluoromethyl)phenyl]methyl]sulfonyl chloride (0.60 g, 2.32 mmol) was added dropwise to a saturated solution of ethylamine in THF (10 mL). The mixture was stirred at room temperature for 1 h. It was evaporated and the residue was dissolved in DCM and the resulting mixture was washed with 5% HCl, dried and evaporated to give the title compound (0.49 g, 79%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.68 (d, 2H), 7.55 (d, 2H), 4.32 (s, 2H), 4.01 (bs, 1H), 3.08-3.14 (m, 2H), 1.19 (t, 3H); Mass Spectrum: M−H+ 265.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][NH2:19])[CH2:11][CH2:10]1.[O:20]1[C:24]2[CH:25]=[C:26]([C:29](Cl)=[O:30])[CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][NH:19][C:29]([C:26]2[CH:27]=[CH:28][C:23]3[NH:22][C:21](=[O:32])[O:20][C:24]=3[CH:25]=2)=[O:30])[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc2[nH]c(=O)oc2c1
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1N1CCN(C/C=C/CNC(=O)c2ccc3[nH]c(=O)oc3c2)CC1
Yield: 87.5 %

Procedure:
According to the method of Example 7, trans-4-[4-(2-methyloxyphenyl)piperazinyl]-2-buten-1-yl-amine and benzoxazolin-2-one-6-carbonyl chloride were subjected to acylation in the presence of sodium carbonate to obtain the product. Yield: 87.5%. mp: 200-202° C. 1HNMR (ppm, DMSO-d6) δ: 2.50 (m, 4H), 2.96 (s, br., 4H), 3.31 (m, 2H), 3.75 (s, 3H), 3.89 (t, 2H), 5.62-5.67 (m, 2H), 6.86 (m, 2H), 6.91 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.73-7.77 (m, 2H), 8.63 (t, J=5.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:20]=1.[S:21]([OH:25])([OH:24])(=[O:23])=[O:22].CS[C:28](=[NH:30])[NH2:29]>CN(C)C=O.O>[S:21]([OH:25])([OH:24])(=[O:23])=[O:22].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:28](=[NH:29])[NH2:30])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:20]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:28](=[NH:29])[NH2:30])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:20]=1
Reactant: CSC(=N)N
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCNCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)N1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 5-chloro-3-[(1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (3.0 g) in a mixture of N,N-dimethylformamide (30 ml) and water (5 ml) was added S-methylisothiourea sulfate (4.0 g). The mixture was stirred for 8 hours at 80° C. and then cooled. The precipitates formed were filtered and recrystallized from water (100 ml) to give 5-chloro-3-[(4-amidino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hemisulfate (2.63 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[C:15](Cl)(Cl)=[O:16].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][C:15](=[O:16])[NH:1][CH2:2]2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2CNC(=O)O2)cc1OC
Reaction time: 1 h
Yield: 75 %

Procedure:
100 mmol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol is dissolved in 100 ml. of chloroform. After cooling to 0°, a solution of 100 mmol of phosgene in 100 ml. of chloroform is added dropwise so slowly that the internal temperature does not rise above 5°. After one hour of agitation at 5°-10°, 200 mmol of pyridine in 100 ml. of chloroform is added dropwise to the reaction mixture, and the latter is stirred for 3 hours. After washing the organic phase in semisaturated NaCl solution, the mixture is concentrated by evaporation and recrystallized from methanol, thus obtaining in a 75% yield 5-(3,4-dimethoxyphenyl)-2-oxazolidinone, m.p. 114°-117°.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[I:8][C:9]1[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1.C1(=O)OC(=O)C=C1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[I:8][C:9]1[CH:15]=[CH:14][C:12]([N:5]2[C:4](=[O:6])[CH:3]=[CH:2][C:1]2=[O:7])=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C1C=CC(=O)N1
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1C=CC(=O)N1c1ccc(I)cc1

Procedure:
The title compound was prepared by standard maleimide procedures involving the reaction of p-iodoaniline with maleic anhydride and then subsequent cyclization with acetic anhydride and sodium acetate.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]([O:20][C:21](=[O:47])[CH:22]([N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[CH:23]1[NH:27][CH:26]([C:28]([OH:30])=[O:29])[C:25]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[S:24]1)([CH3:19])([CH3:18])[CH3:17].Cl>CN(C)C=O>[CH2:1]([O:30][C:28]([CH:26]1[C:25]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[S:24][CH:23]([CH:22]([N:36]2[C:40](=[O:41])[C:39]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]3[C:37]2=[O:46])[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:47])[NH:27]1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)O)C2(CCCCC2)S1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCCCC2)S1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 82.7 %

Procedure:
8.5 g. (0.05 mole) of benzyl bromide are first added all at once and then 3.43 g. (0.034 mole) of triethylamine are added to a solution of 12 g. (0.026 mole) of tert-butyl-4-carboxy-alphaphthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate in 130 ml. of anhydrous dimethylformamide. The reaction mixture is left to stand overnight at ambient temperature and then it is poured on to ice and 10 ml. of 6N hydrochloric acid are added followed by extraction with benzene. The organic phase is first washed with a 5% aqueous solution of sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate, filtered and finally evaporated to dryness. After recrystallization from a mixture of diethyl ether and hexane (50/50), 12 g. (0.0215 mole) of tert-butyl 4-benzyloxycarbonyl-alpha-phthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate are obtained. Yield: 82.7%. M.P. 165°-166° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C=[N+]=[N-])(C)C.CCOCC.[BH4-].[Na+]>CO.C(O)(=O)C>[OH:19][CH2:18][C:17]1[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:23]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(=O)O)cc(C(F)(F)F)n2)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-6-(trifluoromethyl)isonicotinic acid (1.4 g, 3.6 mmol, prepared by the method of Step 2) in methanol (70. mL) at 0° C. was added 2.0 M trimethylsilyldiazomethane in ether (18 mL, 36 mmol) dropwise until TLC indicated complete reaction. Excess reagent was discharged by dropwise addition of acetic acid to the mixture cooled in an ice bath. Solvent was removed by rotary evaporation. The residue was dissolved in ethanol (28 mL), cooled to 0° C., and sodium tetrahydroborate (0.26 g, 7.0 mmol) was added. The cooling was discontinued and the reaction was allowed to stir at room temperature for 30 minutes. It was re-cooled in an ice bath and an additional portion of Sodium tetrahydroborate (0.27 g, 7.2 mmol) was added. The reaction mixture was allowed to reach room temperature and stir until the reaction was complete as determined by analytical LCMS and TLC. The reaction was quenched by the addition of saturated ammonium chloride, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, using a 120 g silica gel cartridge and eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a colorless oil (0.90 g, 67%). 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 6.90 (s, 1H), 5.27 (tt, J=7.7, 3.7 Hz, 1H), 4.74 (d, J=2.5 Hz, 2H), 3.81-3.63 (m, 2H), 3.31 (ddd, J=13.4, 8.4, 3.7 Hz, 2H), 1.98 (ddt, J=13.5, 7.0, 3.8 Hz, 2H), 1.72 (dtd, J=12.5, 8.2, 4.0 Hz, 2H), 1.47 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −69.21 (s). LCMS (M-tBu+H)+: 321.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[C:19]([O:28][CH3:29])[CH:18]=2)=[O:15])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N1CCOCC1)C>ClCCl>[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[C:19]([O:28][CH3:29])[CH:18]=2)=[O:15])([CH3:10])[CH3:11])=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(N)cc2)ccc1-c1cnco1
Reactant: CC(=O)OC(C)=O
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(NC(C)=O)cc2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of 30 mg (0.074 mmol) of N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide, 8 mg (0.078 mmol) of acetic anhydride and 17 mg (0.15 mmol) of N-ethylmorpholine in 1 ml of dichloromethane was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue triturated with diethyl ether and collected by filtration to give 14 mg of N-[2-(4-acetamidophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 451 [M+H]+.
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.C(O[C@@H:12]1[C@H:17]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C:14](=[O:33])[CH2:13]1)[C@:26]1([CH3:27])[C:21]([CH:22]=[C:23]([O:31]C)[CH2:24][CH2:25]1)=[CH:20][CH2:19]3)(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:3]([C@:14]1([OH:33])[CH:13]=[CH:12][C@H:17]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:15]12[CH3:16])[C@:26]1([CH3:27])[C:21](=[CH:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)#[CH:4]
Reactant: [Li]CCCC
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h

Procedure:
Acetylene is introduced at 0° C. for 45 minutes into 200 ml of butyllithium solution (1.6 molar in hexane) in 600 ml of tetrahydrofuran. Then, 20.0 g of 15α-acetoxy-3-methoxyandrosta-3,5-dien-17-one in 400 ml of tetrahydrofuran is added thereto. After 2 hours, the mixture is gently combined with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried, and concentrated under vacuum. At room temperature, 14 ml of concentrated hydrochloric acid is added dropwise to the crude product in 400 ml of methanol and 50 ml of water. After 1.5 hours, the reaction mixture is stirred into ice/water. The thus-precipitated product is suctioned off, washed with water, dissolved in ethyl acetate, dried, and concentrated under vacuum. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, thus obtaining 9.5 g of 17α-ethynyl-17β-hydroxyandrosta-4,15-diene-3-one, mp 206.4° C. (from acetone/hexane).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:7]=2[CH:26]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=3[O-:35])[C:7]=2[CH:26]=1)#[N:2]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccccn2)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2cccc[n+]2[O-])[C@@H]1O
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(2-pyridylamino)-2H-1-benzopyran-3-ol (152 mg, 0.43 mmol) obtained in Example 42 was dissolved in dichloromethane (5 ml), and m-chloroperbenzoic acid (150 mg, purity 80%) was added under ice-cooling. The mixture was stirred for 1.5 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (methanol:chloroform=5:95) to give 94.5 mg of the title compound (59%).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: [C-]#[N+]CC(=O)N1CC[C@H](F)C1
Yield: 79.1 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 1.18 g, 11.9 mmol) was slowly added (S)-(+)-3-fluoropyrrolidine hydrochloride (97%, 1.5 g, 11.9 mmol), triethylamine (1.67 mL, 11.9 mmol) and MeOH (3 mL). The mixture was stirred for 15 h at RT and concentrated. The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-((S)-3-fluoropyrrolidin-1-yl)-2-isocyanoethanone VIB 01166 (1.47 g, 79% yield) as a brown oil which was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][NH:15][CH3:16].C1COCC1.C([BH3-])#N.[Na+]>O.[Cl-].[Cl-].[Zn+2].CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:15]([CH3:16])[CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNC
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)cc(CN(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-bromo-5-formylbenzoate (200 mg, 0.82 mmol), methanol (3 mL), 2.0 M dimethylamine solution in THF (0.3 mL, 6 mmol), zinc dichloride (30 mg, 0.22 mmol), and sodium cyanoborohydride (200 mg, 3.2 mmol) was stirred at 0° C. for 1 h. The mixture was diluted with water (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel chromatography to afford the title compound.