Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[C:15]2[N:16]=[C:17](N)[S:18][C:14]=2[CH:13]=[C:12]([F:20])[CH:11]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:17]1[S:18][C:14]2[CH:13]=[C:12]([F:20])[CH:11]=[C:10]([F:9])[C:15]=2[N:16]=1
Reactant: Cl
Reactant: Nc1nc2c(F)cc(F)cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Fc1cc(F)c2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution containing copper chloride (II) (0.87 g, 6.45 mmol) and tri(ethylene glycol)dimethyl ether (3 mL) in acetonitrile (50 mL) was added isoamyl nitrite (0.94 g, 8.06 mmol), and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 4,6-difluoro-1,3-benzothiazol-2-amine (1.0 g, 5.37 mmol) in tri(ethylene glycol)dimethyl ether (5 mL). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (200 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water and brine, filtered and concentrated down to afford 2-chloro-4,6-difluoro-1,3-benzothiazole (1.1 g, 99%). 1H NMR (400 MHz, DMSO-d6) 7.05 (m, 1H), 7.36 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][N:20](C(OCC2C=CC=CC=2)=O)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[CH3:29])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:40])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:61]=[C:62]([N:66]=[C:67]=[O:68])[CH:63]=[CH:64][CH:65]=1>C(Cl)Cl>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][CH2:19][C@H:13]([N:10]1[CH2:11][CH2:12][C@H:8]([NH:7][C:67]([NH:66][C:62]2[CH:63]=[CH:64][CH:65]=[C:60]([C:59]([F:69])([F:70])[F:58])[CH:61]=2)=[O:68])[C:9]1=[O:40])[C@@H:14]([OH:18])[CH2:15][CH2:16][CH3:17]
Reactant: CC#C[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)Nc2cccc(C(F)(F)F)c2)C1=O
Reaction time: 3 h

Procedure:
A solution of {(3S)-1-[(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pent-3-ynyl)]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1.16 g, 1.74 mmol, see procedure 1c above) was dissolved in CH2Cl2 (16 mL) and treated with TFA (8 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. A portion (0.22 mmol) of the product amine was dissolved in CH2Cl2 (4 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (0.16 mL, 0.88 mmol) and (meta-trifluoromethyl-phenyl)isocyanate (0.033 mL, 0.22 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (6 mL). The resultant solution was charged with 5% Pd/C, Degussa style (50 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder after lyopholization. MS found: (M+H)+=521.5.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCNc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21

Procedure:
A 3.32 g portion of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one and 4.31 ml of triethylamine were dissolved in 33 ml of dichloromethane and, with stirring on an ice bath, 4.59 g of p-nitrobenzoyl chloride was added to the resulting solution. The reaction solution was stirred at room temperature for additional 60 minutes. The reaction solution was then mixed with a saturated sodium bicarbonate aqueous solution and subjected to phase separation. The dichloromethane layer was separated and washed with a 1N hydrochloric acid aqueous solution and a saturated sodium chloride aqueous solution once for each. The thus washed layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was recrystallized from methyl alcohol to obtain 5.68 g of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=O)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].[OH-].[Na+].C.Cl>O.O1CCOCC1.N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[S:15])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc(NC(C)=O)cc1C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NC(C)=S)cc1C

Procedure:
185 g of 2-methyl-4-acetamino-anisole (prepared by procedures described by M. Heidelberg and W. A. Jacobs in J.A.C.S. 41 (1919) p. 1453), 100 ml of pyridine and 250 ml of anhydrous dioxane were poured into a 1 l. multi-neck flask mounted on an oil bath whose temperature was 100° C. After complete dissolution, 130 g of P2S5 were added thereto in small portions under stirring; after the addition, the solution thus obtained was stirred for another 45 minutes by maintaining the conditions of the reaction temperature. The reaction mixture was poured into a 5 l. of a very cold water solution of 45 g of NaOH; animal charcoal was added thereto and the whole stirred for 1 hour. After filtration, the solution was poured into a Keller flask, provided with a stirrer and externally cooled, cautiously acidified with concentrated HCl to pH=4-5, keeping the temperature lower than +5° C. After approximately 1 hour of stirring, the product, thus separated, was filtered with a Buchner and washed with water. The raw product was crystallized many times from ligroin in the presence of animal charcoal to reach a melting point of 88.5°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[C:9](OC2C=CC(F)=CC=2F)[C:8]([C:20](=O)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:7][N:6]=1.CCO.[NH2:34][NH2:35]>O1CCOCC1>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:34][N:35]=[C:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:8]2=[CH:7][N:6]=1
Reactant: CC(C)CC(=O)c1cnc(Oc2ccc(F)cc2F)nc1Oc1ccc(F)cc1F
Reactant: NN
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)Cc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 90 °C

Procedure:
1-[2,4-Bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-3-methyl-butan-1-one (0.427 g, 1.0 mmol) was dilloved in 10 mL of 10:1 dioxane:EtOH, and hydrazine (0.032 mL) was added. The reaction mixture was heated to 90° C. for four hours, then cooled and quenched by addition of 25 mL saturated aqueous ammonium chloride and 25 mL water. The aqueous mixture was extracted three times with 25 mL EtOAc, and the combined organic layers were washed with saturated aqueous brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was eluted through silica gel using 20% EtOAc in hexanes to yield 65 mg of 6-(2,4-difluoro-phenoxy)-3-isobutyl-1H-pyrazolo[3,4-d]pyrimidine as an oil. Mass Spec. M+H=305.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[N:12]([O-])=O.[Na+].S(=O)(=O)(O)O>CC(O)=O>[NH:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=[N:12]1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nn[nH]c2c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
3,4-diaminobenzoic acid (5 g, 32.8 mmol) was dissolved in AcOH (30 ml) and this mixture cooled to 5° C. To this mixture NaNO2 solution (2.7 g in 8 ml water) was added followed by 2 ml sulphuric acid. Reaction mixture was allowed to stir for 90 mins. After that, reaction mixture quenched with ice and solid that obtained was filtered and washed with water to obtain the title compound (4.5 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[N:14]([C:17]([CH:19]([CH2:21][CH2:22][CH3:23])[CH3:20])=O)=[N+]=[N-].CN(C)[CH:26]=[O:27]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:26]([NH:14][CH2:17][CH:19]([CH3:20])[CH2:21][CH2:22][CH3:23])=[O:27])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CN(C)C=O
Reactant: CCCC(C)C(=O)N=[N+]=[N-]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Product: CCCC(C)CNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 2 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (175 mg, 0.78 mmol) and the crude 2-azidocarbonyl pentane in 2 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (5 mg, 2%). LC-MS (m/z) 336.2 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[Li].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Agent: [Li]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-buryl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with (MgSO4). Solvent was removed in vacuo and the residue further 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)C1C=CC(NC([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=O)=CC=1)C.C(C1C=CC(C=CC(OC)=O)=CC=1)=O>>[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2nc3ccc(OC)cc3s2)cc1
Agent: COC(=O)C=Cc1ccc(C=O)cc1
Product: COc1ccc2nc(N)sc2c1
Yield: 93 %

Procedure:
The title compound 162 was obtained following the procedure described in J. Med. Chem., 1979, 22 (1), 28-32, starting from 2-amino-6-methoxybenzothiazole (93% yield). 1H NMR: (DMSO-d6) δ(ppm): 9.63 (bs, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.55-7.51 (m, 2H), 6.98 (d, J=8.8 Hz, 1H), 4.28 (q, J=6.8 Hz, 2H), 3.79 (s, 3H), 1.32 (t, J=7.2 Hz, 3H). m/z: 372.3 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)#[N:4].Cl[CH2:15][CH2:16][O:17][CH2:18]Cl>CN1CCCC1=O.C1COCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:5]2([C:3]#[N:4])[CH2:15][CH2:16][O:17][CH2:18]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: ClCCOCCl
Reactant: N#CCc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(C2(C#N)CCOC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a suspension of NaH (60% by weight, 1.2 g, 30 mmol) in 1-methylpyrrolidin-2-one (20 mL) was added a solution of 4-(cyanomethyl)benzonitrile (1.42 g, 10 mmol) and 1-chloro-2-(chloromethoxy)ethane (1.29 g, 10 mmol) in THF (10 mL) at −20° C. The mixture was allowed to warm to room temperature after completion of addition and stirred for 24 hours. The reaction was quenched by ice water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to afford the crude product which was purified by Prep-TLC (EtOAc/hexane=1:5) to provide the title compound as a yellow oil (345 mg, 17.4%). LC-MS: m/z 172 (M−CN).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([S:6](=[O:16])(=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][NH:2]1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:17][N:2]1[CH2:3][CH2:4][N:5]2[S:6](=[O:15])(=[O:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH:10]2[CH2:1]1
Reactant: O=S1(=O)c2ccccc2CC2CNCCN21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN2C(Cc3ccccc3S2(=O)=O)C1
Reaction time: 4.5 h
Yield: 78 %

Procedure:
To a solution of the title compound of Example 215 (23.0 mg, 0.0965 mmol) in dimethylformamide (0.75 mL) were added cesium carbonate (94 mg, 0.29 mmol) and methyl iodide (0.0072 mL, 0.12 mmol). After 4.5 h, the reaction was partitioned between dichloromethane (2 mL) and water (2 mL). The aqueous layer was extracted with dichloromethane (2 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was taken up in a minimum amount of 50% aqueous methanol and loaded onto a methanol-activated water-equilibrated 1-g SCX-type cation exchange column. The column was washed with water (6 mL) and 50% aqueous methanol (6 mL). The column was eluted with 2N methanolic ammonia (8 mL). This fraction was concentrated in vacuo to provide (−)-1,2,3,4,11,11a-hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine 6,6-dioxide as a white solid (19 mg, 79%): LCMS (pos. ion spectrum) m/z 253.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A mixture of cyclopentylmethanol (2.5 g, 25 mmol), 4-methylbenzene-1-sulfonyl chloride (5.23 g, 27.5 mmol) in CH2Cl2 (50 mL) at 0° C. was treated with triethylamine (4.17 mL, 30 mmol) and the mixture was allowed to warm to room temperature for 8 hours. The mixture was then washed with water, brine, dried with anhydrous MgSO4 and concentrated under reduced pressure to afford 6.5 g the title compound. MS (DCI/NH3) m/z 272 (M+NH4)+.
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=O)[CH3:21]>CCO.O.O>[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=[N:2][OH:3])[CH3:21]
Reactant: NO
Reactant: CC(=O)c1c(O)cccc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydroxylamine hydrochloride (756 mg, 10.9 mmol) and sodium acetate trihydrate (1.71 g, 12.6 mmol) dissolved in 23 ml of a mixture of EtOH/H2O (7/3) was added to a solution of 2′,6′-dihydroxyacetophenone (1.5 g, 9.9 mmol) in 12 ml of a 7/3 EtOH/H2O mixture. After refluxing and stirring under N2 for 2 hours, additional hydroxylamine hydrochloride (340 mg, 4.9 mmol) and sodium acetate trihydrate (570 mg, 4.19 mmol) dissolved in 7 ml of water were added and the reflux was continued for additional 30 minutes. After cooling down to room temperature, the volatiles were removed. Then water was added and the solid obtained was filtered, washed with water and dried. This afforded 1.3 g of the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH:2]1[CH:3]=[CH2:4].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>[Pd]>[N:6]1([C:5]([CH2:2][CH:3]=[CH:4][CH2:13][OH:14])=[O:1])[CH:10]=[CH:9][N:8]=[CH:7]1.[N:6]1([C:2]([CH:12]([CH2:13][OH:14])[CH:11]=[CH2:15])=[O:1])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: C1CCOC1
Reactant: c1c[nH]cn1
Reactant: C=CC1CO1
Agent: [Pd]
Product: C=CC(CO)C(=O)n1ccnc1
Product: O=C(CC=CCO)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 5 %
Yield: 95 %

Procedure:
Reaction of 3,4-epoxy-1-butene and imidazole 1.95 g (0.0286 moles) of imidazole and 2.0 g (0.0286 moles) of 3,4-epoxy-1-butene were dissolved in 25 ml of THF. 0.83 g of the polymer-bound palladium(0) catalyst of Example 2 was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure. The residue was distilled. The reaction Yielded about 95% 4-(1-imidazoYl)-2-buten-1-ol (1,4 adduct) and less than 5% 3-(1-imidazoyl)-1-buten-4-ol (1,2 adduct). The combined yield of products was 63%.
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O.CCCCCCC>CO>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCCCCCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 91.6 %

Procedure:
A stirred mixture of 29.3 kg of crude (3β,5α)-3-(benzoyloxy)cholest-8(14)en-15-one (6) (Example 3) in 190 liters of methanol in a 100-gallon glass-lined reactor was treated with 8 5 kg of potassium carbonate, the mixture was heated to gentle reflux and held at reflux for 3 hours. The methanol solution was cooled, then was treated with 130 liters of water and 80 liters of heptane with vigorous stirring. The agitation was stopped and the mixture was chilled to 0° C. to -5° C. for 16 hours The crystalline mass was broken up by agitation and the solid was filtered, washed with 100 liters of methanol at 15° C, then air-dried to yield 21.3 kg of the desired crude product. The crude product was recrystallized as follows: A solution of the crude product, 21.3 kg, in 180 liters of methanol at about 45° C. was filtered through a pad of diatomaceous earth using nitrogen pressure. The filtrate was added to 200 liters of heptane at 45°-50° C. Then the solution was treated by vigorous agitation with 100 liters of water preheated to 60° C. The mixture was agitated for 10 minutes, then cooled to 35° C. over a 3-hour period, followed by standing at 25° C. for 24 hours and finally the mixture was chilled to 3° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[CH3:11][O:12][CH2:13][CH2:14][C:15]1[S:19][C:18]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[N:17][C:16]=1[CH3:26]>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:20]([C:18]2[S:19][C:15]([CH2:14][CH2:13][O:12][CH3:11])=[C:16]([CH3:26])[N:17]=2)([OH:25])[C:21]([F:24])([F:23])[F:22])=[N:7][C:6]=1[CH3:10]
Reactant: COCCc1sc(C(=O)C(F)(F)F)nc1C
Reactant: COCCc1scnc1C
Solvent: CS(C)=O
Product: COCCc1sc(C(O)(c2nc(C)c(CCOC)s2)C(F)(F)F)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and 5-(2-methoxyethyl)-4-methyl-2-trifluoroacetylthiazole. M.p. 68°-69° C. 13C Nmr (d6 -DMSO) 14.6, 26.0, 57.7, 71.4, 77.0 (q, J 30 Hz), 123.1 (q, J 286 Hz), 131.4, 148.1 and 162.0 ppm.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[O:11][C:9](=O)[C:8](=C=O)[CH2:7]1.O.[NH2:15][NH2:16].[CH2:17]([OH:19])C>>[O:11]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:2]1[CH:3]([CH2:17][OH:19])[CH2:4][C:5](=[O:1])[NH:15][N:16]=1
Reactant: NN
Reactant: CCO
Reactant: O=C=C1CC(c2ccco2)OC1=O
Solvent: O
Product: O=C1CC(CO)C(c2ccco2)=NN1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4.7 g (0.026 mol) of 4-(2-furyl)-carbonyl-γ-butyrolactone and 1.5 ml (0.03 mol) of hydrazine hydrate are dissolved in 40 ml of ethanol at room temperature and stirred at 50° C. for 1 hour. After the mixture has been concentrated, the reaction product is subjected to fractionation by chromatography over a silica gel column using methylene chloride/methanol=9:1 as the mobile phase.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1Br)=[O:4].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(NC(C)C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1C#C[Si](C)(C)C
Yield: 57.3 %

Procedure:
React 3-bromo-5-(4-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester (0.66 g, 2.0 mmol) with (trimethylsilyl)acetylene (216 mg, 2.2 mmol), Pd(PPh3)2Cl2 (140 mg, 0.20 mmol), CuI (38.2 mg, 0.20 mmol), PPh3 (210 mg, 0.80 mmol) and diisopropyl amine (3.3 mL, 30 mmol) in DMF (1.0 mL) at 120° C. for 30 min in a microwave reactor. Treat the mixture with Et2O (15 mL), filter, pour into 0.1 M HCl (15 mL), and extract with Et2O (3×10 mL). Wash the combined organic layers with saturated NaHCO3 (20 mL) and water (20 mL). Purify the crude material by chromatography, eluting with 30% CH2Cl2/hexane to give 400 mg (57%) of the title compound. LC-MS/ES m/z (35Cl) 349.0 [M+H]+.