Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:31][O:32][C:33]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C.ClP(C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C12CC(CC1)CC2)C12CC(CC1)CC2.[Pd].O>[CH3:31][O:32][C:33](=[O:34])[CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:12])([F:11])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:41][CH:42]=1
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)CCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1[PH](Cl)(C12CCC(CC1)C2)C12CCC(CC1)C2
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(-c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 26, Step 1, 100 mg, 0.2 mmol), 4-(2-methoxycarbonylethyl)phenyl boronic acid (53 mg, 0.24 mmol) and chloro-{2′-(dimethylamino)-2-biphenylyl}-(dinorbornylphosphin)-palladium (3 mg, 0.005 mmol) in dioxane (0.8 ml) was treated with water (0.22 ml) and K3PO4 (128 mg, 0.6 mmol) and stirred at 100° C. under argon for 3 h. To reaction mixture were added dioxane (0.5 ml), water (0.022 ml) and chloro-{2′-(dimethylamino)-2-biphenyl}-(dinorbornylphosphin)-palladium (2 mg). The mixture was stirred at 100° C. under argon for 6 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was dissolved in methanol (2 ml) and treated with thionylchloride (56 mg, 0.5 mmol) at 0° C. The reaction solution was stirred at r.t. for 5 h. The mixture was poured on ice-water and sat aq NaHCO3, extracted twice with AcOEt. The combined organic phases were washed with sat aq NaCl, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (10 g silica gel, heptane/AcOEt 3:1) to give the title compound as colorless
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([NH:15][C:16](NC)=[O:17])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:21])=[O:20].C(Cl)(Cl)=O>C1C(Cl)=CC=C(Cl)C=1>[CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:21])=[O:20]
Reactant: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)C2
Agent: O=C(Cl)Cl
Solvent: Clc1ccc(Cl)cc1
Product: CC1Cc2cccc(S(=O)(=O)N=C=O)c2OS1(=O)=O
Reaction time: 0.33 h
Yield: 116.4 %

Procedure:
14.3 g of N-(3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-methylurea are suspended in 143 ml of dry dichlorobenzene. 9.5 g of phosgene are introduced into the mixture over 75 minutes at 140° C. Dry nitrogen is subsequently blown through the reaction mixture for 20 minutes. With the exclusion of moisture, the solution is concentrated by evaporation at 90° C./20 mbar, affording 15.1 g of 3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl isocyanate in the form of an oil which is dissolved in warm absolute dioxane and, without further storage, is reacted in the subsequent step (c).
Reaction SMILES: Br[C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C@H:7]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:6][CH2:5][C:4]=2[CH:3]=1.[C:21](OC)(=[O:23])C>[Cu]Br.C[O-].[Na+]>[CH3:21][O:23][C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C@H:7]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(Br)c3c(c21)CCO3
Reactant: COC(C)=O
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Product: CCC(=O)NCC[C@@H]1CCc2cc(OC)c3c(c21)CCO3
Yield: 60.2 %

Procedure:
A solution of sodium methoxide (200 mL, 28% solution in methanol) was added dropwise into a mixture of (S)—N-(2-[4-bromo-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl)propionamide (5.00 g, 14.8 mmol), copper(I) bromide (2.12 g, 14.8 mmol) and methyl acetate (3.29 g, 44.3 mmol). The mixture was refluxed for 5 hours. The mixture was cooled, which was quenched with 1N HCl, followed by extracting with methanol-chloroform. The extracted solution was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography and recrystallized from ethyl acetate to afford the title compound (yield 2.58 g, 60%) as a white powder.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH2:10][O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C>[Si:1]([O:8][CH:9]([CH2:21][OH:22])[CH2:10][O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)OCC
Solvent: CC(=O)O
Product: CCOP(=O)(COCC(CO)O[Si](C)(C)C(C)(C)C)OCC
Yield: 44.8 %

Procedure:
A solution of diethyl 2,3-bis(t-butyldimethylsilyloxy)propoxymethylphosphonate (1 g, 2.13 mmol) in 80% aqueous acetic acid (20 ml) was stirred at 20° C. for 4 h. The solvent was evaporated in vacuo, co-evaporated with toluene and the residue chromatographed on silica, eluting with ethyl acetate-hexane 2:1, affording diethyl 2-t-butyldimethylsilyloxy-3-hydroxypropoxymethylphosphonate (340mg, 45%) as a clear liquid. νmax (film) 3400, 1460, 1390 and 1250 cm-1 ; δH (CDCl3), 0.05 (6H, s, CH3SiCH3), 0.83 (9H, s, (CH3)3CSi), 1.25 (6H, t, J6.9 Hz, 2×CH3CH2), 2.16 (1H, br.s, D2O exchangeable, OH), 3.50 (4H, m, CH2OH+CH2OCH2P), 3.72 (3H, m, CHOSi+CH2P), 4.05 (4H, m, 2×CH3CH2); m/z (FAB+ve Ion), 357 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C=O)cc1Cl
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a stirred solution of 3-chloro-4-hydroxybenzaldehyde (2.9 g, 18.412 mmol) in DMF (30 mL) was added K2CO3 (7.6 g, 55.238 mmol). CH3I (7.80 g, 55.238 mmol) was then added slowly at RT under an inert atmosphere. After addition was completed, the reaction mixture was brought to 80° C. and stirred for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography to afford 3-chloro-4-methoxybenzaldehyde (2.78 g, 93%) as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([O:12][CH3:17])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To a solution of (4R)-1-Boc-4-hydroxy-L-proline (8 g, 34.63 mmol) prepared in Step A in DMF was added K2CO3 (14 g, 101 mmol) and methyliodide (2.6 ml, 51.9 mmol). The reaction mixture was stirred at rt for 5 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (8.0 g, 95%).
Reaction SMILES: [NH3:1].[ClH:2].[I:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7](=[NH:11])OCC>C(O)C>[ClH:2].[I:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([NH2:11])=[NH:1]
Reactant: CCOC(=N)c1cccc(I)c1
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C(N)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ammonia gas was bubbled into an ice-cold suspension of the product (1.00 g, 3.21 mmol) from Step A in 20 mL of absolute ethanol for 20 min. The resultant clear solution was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was then concentrated under reduced pressure, and the residue was triturated with diethyl ether. The supernatant was decanted, and the residual gummy product was dried in vacuo to afford the title compound as white foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:4]([C:3]1[CH:8]=[C:9]([O:12][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O:6][CH3:7])=[O:5]
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2cccc(Cl)c2)ccc1O
Yield: 68.2 %

Procedure:
Eight grams (47.62 mmoles) of the above ester was treated with 6.3 ml (47.62 mmoles) of 3-chlorobenzyl bromide and 8 grams potassium carbonate in 70 ml acetonitrile under reflux for 4 hours. The mixture was diluted with 100 ml ethyl acetate, filtered, and stripped in vacuo. The residue was recrystallized from ethanol to give 9.5 g of 2-Carbomethoxy-4-(m-chlorophenylmethyloxy)-phenol (62% yield from 2,5-dihydroxybenzoic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[CH:11][C:6]2=[CH:5][CH:4]=1.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:14]1([S:20]([N:9]2[C:7]3=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]3[CH:11]=[CH:10]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2cc[nH]c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ccn(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To a mixture of 6-methoxy-1H-pyrrolo[2,3-b]pyridine (1.2 g, 8.1 mmol), sodium hydroxide (0.97 g, 24.3 mmol) and tetrabutylammonium bromide (78.4 mg, 0.24 mmol) in dichloromethane (50 mL) at 0° C. was added benzenesulfonyl chloride (2.14 g, 12.15 mmol) dropwise. The resulting mixture was stirred for 12 h at room temperature. The mixture was washed with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 100% dichloromethane) to afford 1-benzenesulfonyl-6-methoxy-1H-pyrrolo[2,3-b]pyridine (2.0 g, 85%): LC/MS m/e calcd for C14H12N2O3S [M+H]+ 290.33, observed 289.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH:21]([CH3:25])[CH2:22][CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH:21]([CH3:25])[CH2:22][C:23]([OH:28])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(-n2nc(C(C)CCO)cc2-c2ccc(Cl)cc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(-n2nc(C(C)CC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of compound 50 (0.65 g, 1.8 mM) in acetone (50 ml) was added Jones Reagent (1.85 ml, 3.7 mM) and the reaction stirred for 1.5 hr, the acetone decanted and the chromium residues washed exhaustively with acetone. The combined acetone layers were then evaporated in vacuo, the residue dissolved in EtOAc (100 ml), washed (H2O), dried (Na2SO4) and concentrated to give an oil which was chromatographed on Silica (EtOAc/MeOH, 30% as eluent) to afford 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-3-methylpropanoic acid (0.62 g, 92%) as a yellow semi-solid which was used without further purification and following the procedure of Example 11 was converted to the title hydroxamic acid 51 as a yellow foam (92%); NMR (CDCl3) δ 1.50 (d, 3H, J=7Hz, C3 --CH3); MS, m/e 399 (M+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[O:10].[OH:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>CC(C)=O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[CH2:8][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: O=C(Nc1cccc(O)c1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1C(=O)COc1cccc(NC(=O)c2ccccn2)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 55.3 %

Procedure:
According to Scheme 2: K2CO3 (2.33 mmol, 323 mg) and 2-bromo-1-(2-methoxyphenyl)ethanone (0.47 mmol, 107 mg) were added sequentially to a solution of N-(3-hydroxyphenyl)picolinamide (0.47 mmol, 100 mg) in acetone (3 mL). The reaction mixture was stirred at 50° C. for 14 hours. After filtration and evaporation, the crude product was diluted with water and with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was triturated with Et2O to obtain N-(3-(2-(2-methoxyphenyl)-2-oxoethoxy)phenyl)picolinamide (0.26 mmol, 94 mg, 55%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][CH:7]([NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:15]([NH:14][CH:7]1[CH2:8][C:9]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[C:11]([CH2:12][CH3:13])[CH:10]=2)[CH2:6]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCc1cc2c(cc1CC)CC(NC(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc2c(cc1CC)CC(NCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 6 h

Procedure:
N-(5,6-Diethyl-indan-2-yl)-benzamide (3.30 g) is dissolved in dry THF (100 mL). Lithium aluminium hydride, 1M in THF (22.52 ml) is then added dropwise. The reaction mixture is stirred at 50° C. The reaction is shown to be complete by TLC after 6 hours. The reaction mixture is allowed to cool, poured slowly into ice-water (200 mL) and extracted with diethyl ether (2×150 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 2:1 Rf=0.20).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:14][C:15](=O)[C@@H:16]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][CH2:46]2)[C@:42]2([CH3:43])[C:37]([CH2:38][C@@H:39]([O:56][CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)[CH2:40][C@@H:41]2[O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[CH:36][CH2:35]3)[CH2:32][CH2:31]1)[CH2:17][CH2:18][C@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])C>CCOCC>[O:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH:50]1[O:49][C@@H:41]1[C@@:42]2([CH3:43])[C:37](=[CH:36][CH2:35][C@@H:34]3[C@@H:44]2[CH2:45][CH2:46][C@@:47]2([CH3:48])[C@H:33]3[CH2:32][CH2:31][C@@H:30]2[C@H:16]([CH2:15][OH:14])[CH2:17][CH2:18][C@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])[CH2:38][C@@H:39]([O:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)[CH2:40]1
Reactant: CCOC(=O)[C@H](CC[C@H](F)C(C)(C)OC(C)OCC)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 0.028 g. (0.00074 mole) of lithium aluminum hydride in 1 ml. of tetrahydrofuran at 0° C. was added 0.200 g. (0.00027 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-oic acid ethyl ester in 3 ml. of tetrahydrofuran. The mixture was stirred at 50° C. for 1.5 hr, recooled to 0° C. and diluted with 12 ml. of ether. The mixture was then quenched with the dropwise addition of 0.06 ml. of water and 0.05 ml. of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 0.5 hr and was filtered. The solids were triturated with ether and filtered. Evaporation of solvent afforded [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol.
Reaction SMILES: N#CN.C(O)(=O)C.C(O)(=O)C.C(N)=N.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[N+:25]([O-])=O>[Ni].CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[NH2:25]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: N#CN
Agent: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Cl)c(N)c1
Reaction time: 1 h

Procedure:
1.5 g of cyanamide, 1.5 g of acetic acid, 2 g of Raney nickel (60%, aqueous), and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. Under a hydrogen pressure of 4 bar and a temperature of 25° C., the cyanamide is hydrogenated quantitatively to the formamidine acetate. 40.8 g of 1-chloro-2,4-dinitrobenzene are then added to the autoclave, and the hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 1 hour. 1-Chloro-2,4-diaminobenzene, 97.5% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:22]#[N:23])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][CH:4]=1)=[O:2].CC(=CC)C.Cl([O-])=[O:30].[Na+].O.OP([O-])(O)=O.[Na+].[Cl-].[NH4+]>C1COCC1.C(O)(C)(C)C.O>[C:22]([C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]([OH:30])=[O:2])=[CH:4][NH:5]2)=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:16][CH:17]=1)#[N:23]
Reactant: [O-][Cl+][O-]
Reactant: N#Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(OCCO)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2[nH]cc(C(=O)O)c2cc1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 7.8 %

Procedure:
To a solution of crude 3-formyl-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-6-carbonitrile (110 mg, assume 0.2 mmol) in a mixture of THF (1.5 mL) and tert-butanol (1.5 mL) was added 2-methyl-2-butene (0.638 mL, 6.0 mmol) followed by a solution of sodium chlorite (169 mg, 2.0 mmol) and sodium phosphate monobasic monohydrate (284 mg, 2.06 mmol) in water (1.1 mL) via glass pipet at room temperature. The mixture was stirred at room temperature for 15.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×8 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in DMSO (1.8 mL) and half of this solution was purified by reverse phase prep-HPLC to give the title compound (5 mg). MS (ES−) 321.1 (M−H)−. Retention time: 0.90 min Waters Xbridge dC18 5 um 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Li+].[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:38]>C(COC)OC>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[C:20]([OH:38])=[O:22])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2F)C(=O)O1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccccc1F)C(=O)O

Procedure:
In analogy with Example 1i), 4.5 g (10.8 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(o-fluorophenyl)methyl]dihydrofuran-2-(3H)-one in 170 ml of dimethoxyethane are hydrolysed with 43.5 ml of a 1M lithium hydroxide solution. The evaporation residue of the reaction mixture is poured onto a mixture of ice, 120 ml of sat. ammonium chloride solution and 240 ml of 10% citric acid solution, and this mixture is then extracted with 3 portions of methylene chloride. The organic phases are washed with water and saline, dried over Na2SO4 and evaporated: tRet (II)=14.5 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])=[CH:18][CH:17]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a mixture of methyl 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]acetate (0.57 g), tetrahydrofuran (3.0 mL) and methanol (3.0 mL) was added a 1N aqueous sodium hydroxide solution (2.4 mL) and the mixture was stirred at 50° C. for 1.5 hrs. 1N Hydrochloric acid (2.4 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.51 g, 96%) of 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.