Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:17]=2)=[CH:8][C:7]=1[CH3:39].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:39][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:19]=[C:18]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:40])=[O:2]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccccc3)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccccc3)c2)ccc1OCC(=O)O
Temperature: 0 °C
Reaction time: 7.67 h

Procedure:
To a solution of (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-phenylethynylphenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester (70 mg, 0.13 mmol) in THF (1.25 ml) and methanol (0.25 ml) was added a ice-cold solution of LiOH (1 M, 1.25 ml). The reaction mixture was stirred at 0° C. for 460 min., after which water (10 ml) and aqueous HCl (1M, 1.75 ml) were added. The mixture was extracted with ethyl acetate (2×10 ml), and the combined organic phases were dried and evaporated to give the title compound in 68 mg (100%) yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([O-])=O.[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24].O>C1COCC1>[SH:24][C:23]1[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N:1]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(S)nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
In a test tube equipped with a septum, tert-butyl (2-nitro-4-trifluoromethyl-phenylamino)-acetate (Starting material 5-VIII, 80 mg, 0.25 mmol) is dissolved in dry THF (0.5 ml). Argon is allowed to bubble through this solution for 10 min. Then dry palladium on carbon (10% w/w, 26 mg, 10% mol) is added and the flask is set under H2 atmosphere. The resulting mixture is shaken vigorously at rt overnight. If necessary, another 8% mol of palladium on charcoal 10% w/w is added and the resulting suspension is stirred for another hour under H2 atmosphere. The crude mixture is then filtered over celite to remove any solid particle. The celite is rinsed once with dry THF. To the resulting light yellow solution is added, under argon, 1,1′-thiocarbonyldiimidazole (89 mg, 0.5 mmol, 2 eq.). The resulting orange solution is allowed to stir at rt for 5 h. Water is then added. The yellow solid formed is filtered over a fritted funnel, rinsed thoroughly with water and dried under high vacuum. This yields the title compound (60 mg) in 73% as a yellow solid: tR=1.10 min (LC-3), ESI-MS (pos.): m/z 332.99 [M+H]+, 331.13 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.41 (s, 9H, tBu), 5.06 (s, 2H, NHCH2CO2), 7.44 (s, 1H, Harom), 7.57 (s, 2H, Harom), 13.25 (br. s, 1H, SH).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]([N:40]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH3:41])=[O:39])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH2:24]([N:31]1[CH2:32][CH2:33][N:34]([CH2:37][C:38]([N:40]([C:42]2[CH:43]=[CH:44][C:45]([NH:46]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:47][CH:48]=2)[CH3:41])=[O:39])[CH2:35][CH2:36]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-[N-(4-benzylpiperazinomethylcarbonyl)-N-methylamino]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C@@H:19]([OH:23])[C:20]#[C:21][CH3:22])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:33]([O:37][C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:47]([O:50][C:51]([F:54])([F:53])[F:52])=[CH:46][C:42]=1[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:33]([O:37][C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:47]([O:50][C:51]([F:52])([F:53])[F:54])=[CH:46][C:42]=1[C:43]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C@@H:19]([OH:23])[C:20]#[C:21][CH3:22])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4])=[O:44])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cc(OC(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of benzyl (2S,3S)-2-[2-(tert-butoxycarbonylamino)acetamido]-3-hydroxyhex-4-ynylcarbamate (700 mg; see WO-02/50019 for preparation) in methylene chloride (12 mL) was cooled to 0° C. and charged with trifluoroacetic acid (4 mL). The mixture was allowed to warm to RT and stirred for 45 min before being concentrated in vacuo. The residue was dissolved in methylene chloride and the resultant solution concentrated; this was repeated twice more to afford the TFA salt of benzyl (2S,3S)-2-(2-aminoacetamido)-3-hydroxyhex-4-ynylcarbamate, MS found: (M+H)+=320.6. A solution of this amine in 1:1 CH2Cl2/DMF (10 mL) was charged successively with N,N-diisopropylethylamine (0.84 mL), 2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoic acid (322 mg, see WO-02/50019), and HATU (544 mg). The reaction was stirred for 14 h at RT before being partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (2S,3S)-2-(2-(2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzamido)acetamido)-3-hydroxyhex-4-ynylcarbamate (182 mg). MS found: (M+H)+=623.3.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>CCO.O>[N+:8]([C:7]1[C:2]([NH:17][C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@@H](Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Yield: 69.2 %

Procedure:
2-Chloro-3-nitropyridine (500 mg, 3.15 mmol) was dissolved in EtOH (12.5 ml), added potassium carbonate (435 mg, 3.15 mmol) and to this mixture (S)-2-aminopropanoic acid (561 mg, 6.3 mmol) in 2.5 ml water was added and refluxed for overnight. Reaction mixture cooled to 0° C. to obtain the solid. Then EtOH was removed on rotavapour and acidified with 2N HCl and solid filtered and dried on vacuum to obtain the title compound (460 mg) as an yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]2[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]2)[CH:12]=[C:11]([Cl:23])[C:10]=1[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH:24]([C:10]2[C:9]([Cl:8])=[CH:14][C:13]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]3)=[CH:12][C:11]=2[Cl:23])[C:25]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:26])=[CH:29][CH:30]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(c2ccc(Cl)cc2)c2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)CC1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a stirred mixture of 10 parts of 1-methylpiperazine in 45 parts of tetrahydrofuran was added dropwise a solution of 6.7 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetyl chloride in 45 parts of tetrahydrofuran during a period of 5 minutes. Upon complete addition, stirring was continued for 2 hours at room temperature. After evaporation in vacuo, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was boiled in acetonitrile. After cooling, the precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 4.8 parts (62.8%) of 1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]acetyl]-4-methylpiperazine: mp. 261.5° C. (intermediate 36).
Reaction SMILES: [CH:1]1([C:4]2[S:22][C:7]3[NH:8][C:9](=[O:21])[N:10]([CH2:13][CH2:14]N4CCOCC4)[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=C(C(Cl)(Cl)Cl)O[N:38]=2)=[CH:27][CH:26]=1.[C:46](=[O:49])([O-])[O-:47].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[S:22][C:7]3[N:8]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]5[NH:38][C:46](=[O:49])[O:47][N:41]=5)=[CH:29][CH:30]=4)[C:9](=[O:21])[N:10]([CH2:13][CH2:14][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:2][CH2:3]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2sc(C3CC3)cc2c(=O)n1CCN1CCOCC1
Agent: [K+]
Solvent: CC#N
Product: O=c1[nH]c(-c2ccccc2-c2ccc(Cn3c(=O)n(CCc4ccccc4)c(=O)c4cc(C5CC5)sc43)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.9 %

Procedure:
A mixture of 6-cyclopropyl-3-(2-morpholin-4-ylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.50 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.86 g), potassium carbonate (0.44 g) and acetonitrile (20 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 ml) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 84%).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.Br[CH2:27][CH2:28][CH2:29][C:30]#[N:31]>C(N(CC)CC)C>[C:30]([CH2:29][CH2:28][CH2:27][NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)#[N:31]
Reactant: N#CCCCBr
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCCCNc1cccc(/C=C/c2nc3ccccc3s2)c1
Yield: 40 %

Procedure:
To 50 ml of toluene were added 2.02 g of triethylamine and 5.04 g of 2-(trans-3-aminostyryl)benzothiazole at room temperature, and then 2.96 g of 4-bromobutyronitrile was added to carry out the reaction at 110° C. for 7 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. After evaporation of the solvent under reduced pressure, the residue was purified through silica gel column chromatography by use of ethyl acetate-ethyl ether-n-hexane (2:5:5) to give 2.55 g (yield 40%) of the title compound as colorless oily product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.C1C(=O)N([I:21])C(=O)C1>S(O)(C(F)(F)F)(=O)=O>[OH:1][CH2:2][CH2:3][C:4]1[C:13]([I:21])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OCc2cc(CCO)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2c1ccc(CCO)c2I
Product: O=C1OCc2cc(CCO)c(I)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (9.00 g, 50.6 mmol) in 100 mL of TfOH was added NIS (12.5 g, 55.6 mmol), then the mixture was stirred at 0° C. for 2 hrs and then poured into ice-water (500 mL). The solution was extracted three times with 500 mL of EtOAc and the combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (EtOAc Petrol Ether=1:5) to give the desired 5-(2-hydroxyethyl)-6-iodo-2-benzofuran-1(3H)-one and regioisomer by-product 5-(2-hydroxyethyl)-4-iodo-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 5.09 (s, 2H), 3.93 (q, J=6.3 Hz, 2H), 3.16 (t, J=6.3 Hz, 2H), 1.45 (t, J=5.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:13](B1OB(C=C)OB(C=C)O1)=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:13]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[CH2:14]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: O=C1NCCc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 7-bromo-3,4-dihydro-1(2H)-isoquinolinone (0.679 g, 3.004 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) in 1,2-dimethoxyethane (30 ml) was stirred at room temperature for 0.5 h before addition of triethenylboroxin.pyridine complex (295 mg, 1.218 mmol), K2CO3 (415 mg, 3.004 mmol) and water (10 ml). The reaction was heated at reflux for 1.5 h before cooling to room temperature and addition of water (50 ml). The mixture was extracted with 10% methanol/dichloromethane (3×100 ml), the organic layers were dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (456 mg, 88%).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[CH:24]=[C:23]2[C:18]([C@H:19]([OH:32])[C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][O:22]2)=[CH:17][CH:16]=1)C.[OH-].[Na+]>C(O)(C)C.O.C(OC(C)C)(C)C>[CH2:25]([C@@H:20]1[C@@H:19]([OH:32])[C:18]2[C:23](=[CH:24][C:15]([C:6]3[CH:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=[CH:10][C:5]=3[C:4]([OH:33])=[O:3])=[CH:16][CH:17]=2)[O:22][CH2:21]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
A mixture of (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl ester (897 9, 1.93 mol) and 10% aqueous sodium hydroxide (980 mL, 2.72 mol) in isopropyl alcohol (9 L) was heated at reflux for 6 hours, cooled to ambient temperature, and stirred for 12 hours. The reaction mixture was diluted with water (13.5 L), hexanes (9 L), and isopropyl ether (4.5 L). The aqueous layer was separated and extracted with hexanes (9 L) and isopropyl ether (4.5 L), adjusted to pH 2 with 2 N aqueous hydrochloric acid, and extracted with ethyl acetate (8 L and 4 L). The combined ethyl acetate extracts were washed with water (6 L), dried over magnesium sulfate, and concentrated in vacuo to a dark amber oil which was diluted with toluene (2 L) and concentrated again to an oil. The oil was dissolved in toluene (4.2 L) at 60° C., and hexanes (8.8 L) were added at a rate to maintain a temperature of greater than 50° C. The tan solids which precipitated upon slowly cooling to ambient temperature over several hours were filtered and washed with 2:1 hexane/toluene (2 L). These solids were dissolved in toluene (5 L) at 60 ° C., treated with Darco®G-60, filtered, washed with toluene, and concentrated in vacuo to approximately 4.0 L. This mixture was heated to 50-60 ° C., treated drop-wise with hexanes (8.6 L), cooled, and granulated at 5° C. for 1 to 2 hours. The resulting solids were filtered, washed with 2:1 hexanes/toluene (2 L), and the wet cake was stirred with hexanes (4 L) at reflux for 30 minutes. This mixture was cooled to ambient temperature, granulated for 1 hour, filtered, and the resulting solids were dried under vacuum overnight to provide 450 g (55%) of (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid as an off white solid: 1H NMR (400 MHz, CDCl3) 67 7.99 (d, J=8.1 Hz, 1H), 7.66 (dd, J=1.1, 8.1 Hz, 1 H), 7.63 (s, 1 H), 7.15-7.32 (m, 6H), 6.89 (dd, J=1.7, 7.9 Hz, 1 H), 6.85 (d, J=1.7 Hz, 1 H), 6.1 (bs, 2H), 4.50 (d, J=4.3 Hz, 1 H), 4.18 (dd, J=2.7, 11.2 Hz, 1 H), 3.94 (dd, J=4.6, 11.0 Hz, 1 H), 2.74 (dd, J=6.1, 13.8 Hz, 1 H), 2.51 (dd, J=9.4, 13.9 Hz, 1H), 2.22 (m, 1H); IR3454, 3218(br), 1699, 1431, 1337, 1299, 1275, 1258, 1191, 1178, 1135, 1123, 700 cm1; mp 142° C.
Reaction SMILES: [F:1][C:2]([F:31])([CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@@H:18]([CH2:19][C@H:20]([OH:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[C:3]([OH:6])([CH3:5])[CH3:4].[Br:32]NC(=O)C.C(OCC)(=O)C>C(O)(C)(C)C.O.Br>[Br:32][C@H:19]1[C:20](=[O:30])[CH2:21][CH2:22][C@@:23]2([CH3:24])[C@@H:18]1[CH2:17][CH2:16][C@@H:15]1[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][CH2:7][C:2]([F:31])([F:1])[C:3]([OH:6])([CH3:4])[CH3:5]
Reactant: CC(=O)NBr
Reactant: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4[C@@H](Br)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 800 mg of 24,24-difluoro-5β-cholestane-3α,25-diol (Va) in 32 ml of tert-butyl alcohol, 15 ml of water, 200 μl of 48% hydrobromic acid and 800 mg of N-bromoacetamide were added. After stirring at room temperature for 3 days, ethyl acetate was added to the reaction mixture, which was then washed sequentially with 0.5% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified through a short column (5 g of silica gel) to produce 950 mg of a crude product. The product was recrystallized from ether/hexane to produce 4β-bromo-24,24-difluoro-25-hydroxy-5β-cholestan-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[NH2:15][C:16]1[NH:20][N:19]=[CH:18][C:17]=1[C:21]#[N:22].[CH:23]1([N+:28]#[C-:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl(O)(=O)(=O)=O>CO>[CH:23]1([NH:28][C:29]2[N:20]3[N:19]=[CH:18][C:17]([C:21]#[N:22])=[C:16]3[NH:15][C:5]=2[C:4]2[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: [C-]#[N+]C1CCCC1
Reactant: N#Cc1cn[nH]c1N
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: COc1cc(OC)c(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 14.1 %

Procedure:
To a clear light brown solution of 2,4,5-trimethoxybenzaldehyde (600 mg, 3.06 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (331 mg, 3.06 mmol) in methanol (10 mL) in a 20 mL vial were added cyclopentyl isonitrile (294 mg, 342 μL, 3.06 mmol) and perchloric acid (61.4 mg, 54.9 μL, 0.612 mmol) at RT under nitrogen atmosphere. Then, the nitrogen line was disconnected and the resulting dark brown solution slowly became a suspension within few hours which was then stirred for 15 h at RT. The off-white solids were collected by filtration and washed with methanol and the solids were not the desired product. The filtrate was removed under vacuum and the resulting residue was purified using an ISCO (120 g) column chromatography eluting with 0-60% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to isolate 165 mg (14% yield) of 3-(cyclopentylamino)-2-(2,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as a dark brown solid. LC/MS calcd. for C20H23N5O3 (m/e) 381.434, obsd. 382.1 (M+H, ES+).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])=[CH:9][CH:8]=1)=[O:6].[H-].[Na+].[H][H].[CH3:23]I>CN(C)C=O>[CH3:18][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH3:23])[C:14](=[O:17])[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:6]
Reactant: [H][H]
Reactant: CI
Reactant: CCC(=O)Nc1ccc(C(=O)C=CN(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)N(C)c1ccc(C(=O)C=CN(C)C)cc1
Reaction time: 1 h

Procedure:
A soluton of 3.10 g of N-[4-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]propanamide in 25 ml dimethylformamide was stirred in an inert atmosphere and 0.60 g of sodium hydride (60% oil suspension) was added. After stirring for 1 hour, the liberation of hydrogen had ceased and a solution of 1.8 g of methyl iodide in 5 ml of dimethylformamide was added portionwise. After stirring for an additional hour, the system was evaporated to remove volatiles and then the reaction mixture was triturated 3 times with hexane (3×50 ml). The reaction mixture was carefully poured into cold water and extracted with methylene chloride. The methylene chloride solution was dried and evaporated to dryness at reduced pressure to yield a crystalline solid. Recrystallization from methylene chloridehexane gave a yellow crystalline solid, mp 76°-78° C.
Reaction SMILES: O=[C:2]1[N:7]2[CH2:8][CH2:9][S:10](=O)[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:17]([O:19][CH3:20])=[O:18])[CH:4]=[C:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(Cl)([Cl:29])=O>>[Cl:29][CH:9]1[CH2:8][N:7]2[CH2:2][C:3]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:4][C:5]([C:17]([O:19][CH3:20])=[O:18])=[C:6]2[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[S:10]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1S(=O)CC2
Product: COC(=O)C1=C2c3sccc3SC(Cl)CN2CC(c2ccccc2)=C1

Procedure:
(aa) 15.7 g of methyl 5,6-dihydro-8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate 4-oxide were added portionwise to 70 ml of thionyl chloride with the exclusion of moisture in such a manner that the temperature of the reaction solution is at about 35°. After completion of the addition, the mixture was stirred until the reaction was completed. The excess thionyl chloride was removed in vacuo and the residue was treated with 100 ml of water. The crystals were removed by filtration and dried, whereupon they were chromatographed on silica gel. By recrystallization from toluene, there was obtained methyl 5-chloro-5,6-dihydro-9-phenyl-8H-pyrido[1,2-d]thieno-[2,3-f][1,4]thiazepin-11-carboxylate as yellow crystals of m.p. 192°-196°.