Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[CH3:2][Si:3]([CH3:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)Cl.[SiH3][Li].[F:14][C:15](F)=[CH2:16]>C1COCC1>[F:14][C:15]([Si:3]([CH3:11])([CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:16]
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: C=C(F)F
Agent: [Li]
Agent: [Li][SiH3]
Solvent: C1CCOC1
Product: C=C(F)[Si](C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 4.4 g of lithium wire cut into small pieces in 200 mL of anhydrous THF stirred under argon and cooled on ice (internal temperature <10° C.) was added dimethylphenyl-chlorosilane in 5 mL portions over 1 hour. The deep red color of the silyl lithium reagent appeared after approximately 0.75 hour. The mixture was stirred on ice for an additional 5 hours (internal temperature remained between 5° C. and 10° C.). The mixture was cooled on a dry ice/acetone bath and 1,1-difluoroethylene was introduced by filling a balloon connected to the reaction mixture and the reagent cylinder using a three-way valve. The balloon was filled with 1,1-difluoroethylene and emptied into the reaction mixture 10 times. The mixture was allowed to warm to room temperature (effervescence observed, probably from unreacted 1,1-difluoroethylene). The mixture was diluted with 200 mL of hexanes and filtered through a cotton wool plug. The filtrate was washed with water, dried, filtered, and concentrated in vacuo. Four fractional distillations under vacuum through a Vigreux column gave 4.6 g of product.
Reaction SMILES: [C:1](OC(N1CCC(O)CC1)=O)([CH3:4])([CH3:3])[CH3:2].[C:15](=[O:18])([O-:17])[O-:16].[Cs+].[Cs+].C[N:22](C=O)C>FC1C=CC(C(F)(F)F)=CC=1>[C:15]([O:17][NH2:22])([O:16][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C([O-])[O-]
Agent: Fc1ccc(C(F)(F)F)cc1
Agent: [Cs+]
Product: CC(C)(C)OC(=O)ON
Yield: 81 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-4-piperidinol (5.00 g, 2.48 mmol), 4-fluorobenzo-trifluoride (3.46 mL, 2.73 mmol), and cesium carbonate (12.1 g, 3.72 mmol) in DMF (60 mL) was heated at 120° C. under N2 for 2 days. The mixture was concentrated, diluted with H2O, and extracted with ethyl acetate. The organic layer was washed with H2O and brine, dried with MgSO4, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided the BOC-aminoether as a white solid (6.97 g, 81%); Anal. calculated. for C17H22NO3F3: C, 59.12; H, 6.42; N, 4.06. Found: C, 59.29; H, 6.47; N, 3.99.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:6]1[N:7]=[CH:8][C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)=[CH:4][CH:5]=1
Reactant: CSc1ccc(C#N)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 30.3 %

Procedure:
5-Cyano-2-methylthiopyridine (2.26 g, 15.0 mmol) and methyl thiosalicylate (5.05 g, 30.0 mmol) were dissolved in toluene (100 ml), and triethylamine (6.3 ml, 45.0 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated. The residue was recrystallized from ethanol to give the titled compound (1.30 g, 31%) as pale yellow crystals.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OC(C)(C)C)(=O)C>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][C:6]([CH3:11])([CH3:7])[CH3:2])=[O:4]
Reactant: O=C(O)C(Br)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7.9 g (44.1 mmol) of bromo-phenylacetic acid in tert-butyl acetate (100 ml) was cooled in an ice/water bath. 0.5 ml of perchloric acid was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was slowly added to a saturated aqueous sodium bicarbonate solution (200 ml), and the organic phase was separated off. The aqueous phase was extracted twice with 60 ml of ethyl acetate each time, the combined organic phases were washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 8.41 g (84%) of colorless oil
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH:19]=[CH:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH2:19][CH2:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCCC(F)C(O)C=CC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCC(F)C(O)CCC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Yield: 94 %

Procedure:
To 1.1 g of platinum in 50 ml of ethyl acetate was added a solution of 11 g of (0.028 mol) of [3aR-[3a alpha,4alpha(1E,3R*,4S*),5beta,6a alpha]]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxy-1-octenyl)hexahydro-2H-cyclopenta[b]furan-2-one in 110 ml of ethyl acetate. The mixture was then hydrogenated until the theoretical uptake of hydrogen was complete and then filtered through a bed of Celite. The solvent was then removed under reduced pressure and the residue chromatographed over 250 g of silica gel (toluene -.varies. 30% by volume ethyl acetate/70% by volume toluene) to afford 10.7 g of [3aR-[3a alpha,4alpha(3R*,4S*),5beta,6a alpha)]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxyoctyl)hexahydro-2H-cyclopenta[b]furan-2-one (94% yield) as a colorless oil.
Reaction SMILES: [CH2:1](C(O)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([OH:17])(=[O:16])[CH2:14][OH:15].C(N(CC1C=CC=CC=1)C(=NC(C)C)O)(C)C>C1COCC1>[C:13]([O:17][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])[CH2:14][OH:15]
Reactant: O=C(O)CO
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: CC(C)N=C(O)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: O=C(CO)OCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Construction of Benzyl-glycolic Acid. Glycolic acid (5.89,100 mmol) is added to N,N'-diisopropylbenzylisourea (23.3 g, 100 mmol) with stirring for 1 hour. The volume is then increased to 200 mL with THF, and the mixture stirred for 48 h at room temperature. After cooling the mixture to -15° C., the diisopropylurea is removed by filtration and the THF evaporated under reduced pressure. The resulting product is pumped under high vacuum for 24 h to give benzyl glycolate which may be used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:27][CH3:28])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.CO>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:27][CH3:28])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:46])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2CC)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2CC)c1ccccn1
Yield: 85 %

Procedure:
Prepared analogously to Example 25d from 1-ethyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 85% of theory, C28H31N7O3 (513.6) Rf value: 0.21 (silica gel; dichloromethane/methanol=5:1) ##EQU55##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[CH:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:5]=[CH:6][CH:7]=1.[B-](F)(F)(F)[F:28].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C.O>>[F:28][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:9]=1[CH:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18]
Reactant: F[B-](F)(F)F
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2cccnc2n1-c1cccc(F)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1c(F)c2cccnc2n1-c1cccc(F)c1
Temperature: 50 °C
Yield: 15.3 %

Procedure:
A mixture of tert-butyl {1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl}carbamate (0.10 g, 0.28 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (0.10 g, 0.28 mmol) in acetonitrile (1.5 mL, 29 mmol) and water (0.15 mL, 8.3 mmol) was heated at 50° C. overnight. The reaction was cooled and extracted with dichloromethane. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-20% EtOAc/hexane) to give the desired product (16 mg, 15%). LCMS calculated for C20H22F2N3O2(M+H)+: m/z=374.2. Found: 374.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[I:13])(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>[Ni]>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:7][C:6]=1[I:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Reactant: NNC(N)=S
Agent: [Ni]
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1I

Procedure:
lodination of 4-aminobenzonitrile 30 with ICI produces 4-amino-3-iodobenzonitrile 31. Acetylatation of 4-amino-3-iodobenzonitrile 31 results in compound 32, which can be reduced with Raney nickel to form 4-acetamido-3-iodobenzaldehyde 33. Reaction of compound 33 with thiosemicarbazide yields 4-acetamido-3-iodobenzaldehyde thiosemicarbazone 34, as illustrated below.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]([CH3:12])[N:5]=2)[CH2:3][CH2:2]1.C1(C2N(C)N=CC=2C(O)=O)CC1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:33]=[C:34]([CH:51]=[CH:52][CH:53]=1)[O:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([N:42]=[C:43]([NH:45][C:46]([CH:48]3[CH2:50][CH2:49]3)=[O:47])[N:44]=2)[CH:41]=1>O1CCCC1.CN(C)C=O.O>[CH:1]1([C:4]2[C:8]([C:9]([NH:31][C:32]3[CH:53]=[CH:52][CH:51]=[C:34]([O:35][C:36]4[CH:37]=[CH:38][C:39]5[N:40]([N:42]=[C:43]([NH:45][C:46]([CH:48]6[CH2:49][CH2:50]6)=[O:47])[N:44]=5)[CH:41]=4)[CH:33]=3)=[O:11])=[CH:7][N:6]([CH3:12])[N:5]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1cc(C(=O)O)c(C2CC2)n1
Agent: Cn1ncc(C(=O)O)c1C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a mixture of 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid and 5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid (430 mg, 2.59 mmol) in tetrahydrofuran (7 mL) were added oxalyl chloride (338 μL, 3.87 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (400 mg, 1.29 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=70/30→0/100), and then by column chromatography (silica gel, ethyl acetate/methanol=95/5) and recrystallized from ethyl acetate to give the title compound (120 mg, 20%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[NH:18])[CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[Cl:13])=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1Cl
Reactant: Nc1ccc(Br)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N=C(Cc1ccccc1Cl)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
4-Bromoaniline (6.4 g, 37 mmol) was placed into a three-neck reactor, and the reactor was flushed with argon for 20 min. 60 mL anhydrous toluene was added. After cooling to 0° C., trimethylaluminum (28 mL, 2.0M solution in toluene, 56 mmol) was added slowly to keep the inner temperature below 20° C. Over 0.5 h, the addition was completed. Ice bath was removed, and the reaction mixture was warmed to room temperature and then stirred for additional 2.5 hrs. A solution of 2-chlorobenzyl cyanide (8.4 g, 55 mmol) in 35 mL anhydrous toluene was added, and the reaction mixture was heated to 80° C. After 18 hrs, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in CHCl3/MeOH (4/1, 400 mL). After stirring for 30 min, the mixture was filtered and the residue was washed with a mixture of CHCl3/MeOH (4/1). The combined filtrates were concentrated in vacuo, and the resulting solid was washed with hexane to give a light pink solid (5.78 g, 48% yield).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH:23]4[CH2:27][O:26]C(C)(C)[O:24]4)=[O:20])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].CC(O)=O>O>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH:23]([OH:24])[CH2:27][OH:26])=[O:20])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(-c3ccc(C(=O)NCC4COC(C)(C)O4)cc3)n2n1
Solvent: CC(=O)O
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)NCC(O)CO)cc3)n2n1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
To 150 mg (0.355 mmol) of 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-benzamide was added 15 ml of AcOH and 5 mL of water and heated to 60° C. for 1.5 hr. It was concentrated and the crude was purified on the acetic PREP HPLC to yield 107 mg (79%) of the titled compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.00 (t, J=7.39 Hz, 3H) 1.42-1.55 (m, 2H) 1.66-1.76 (m, 2H) 3.40 (t, J=7.17 Hz, 2H) 3.43-3.52 (m, 1H) 3.56-3.65 (m, 3H) 3.84-3.93 (m, 1H) 7.24 (d, J=9.92 Hz, 1H) 7.96 (d, J=9.92 Hz, 1H) 8.00-8.05 (m, 2H) 8.23-8.28 (m, 2H) 8.30 (s, 1H); LRMS (ESI) m/e 384.0 [(M+H)+, calcd for C20H25N5O3 383.0]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CCN(CC)CC.CS([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:15][C:12]1[CH:11]=[N:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][CH:13]=1
Reactant: OCc1cnc(Nc2ccc(Cl)cc2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
A suspension of (2-(4-chlorophenylamino)pyrimidin-5-yl)methanol (0.15 g, 0.636 mmol) and Et3N (0.177 ml, 1.273 mmol) in DCM (6.4 mL) was cooled to 0° C. and methanesulfonyl chloride (0.099 mL, 1.273 mmol) was added. The reaction was stirred for 1.5 h while warming to room temperature. The mixture was diluted with DCM and quenched with sat. NaHCO3. The organic layer was isolated and dried over Na2SO4, then concentrated to give crude 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine as a yellow solid (0.1 g, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (2H, s), 7.58 (2H, d, J=8.78 Hz), 7.31 (2H, d, J=8.78 Hz), 7.25 (1H, br. s.), 4.53 (2H, s).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C[C@H]1[C@@H](C(C)C)OC(=O)C2N(CCC=2)C(=O)C2=COC(=N2)CC(=O)C[C@H](O)C=C(C)C=CCN[C:12](=[O:13])[CH:11]=C1>N1C=CC=CC=1>[CH3:2][C:1]([O-:4])=[O:3].[CH3:11][C:12]([CH2:6][C:5]([OH:4])=[O:7])=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)C=CC(=O)NCC=C1
Agent: CC1=C\[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)/C=C/C(=O)NC\C=C\1
Solvent: c1ccncc1
Product: CC(=O)CC(=O)O
Product: CC(=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (45 ml) was added to a stirring solution of Virginiamycin M1 (6.5 g) in anhydrous pyridine (45 ml) at room temperature. After 30 minutes, ice-cold methanol (85 ml) was added in portions. Stirring was continued for 20 more minutes followed by flash evaporation to dryness at room temperature. The residue was partitioned between dichloromethane (3×300 ml) and saturated NaCl (aq, 300 ml). The organic layers were pooled, dried over anhydrous Na2SO4, flash evaporated to dryness (dry weight=8.1 g) and purified over E. Merck silica gel 60 column in hexane/acetone mixtures to give 1.0 g of the monoacetate and 1.58 g of the diacetate.
Reaction SMILES: [CH:1]1([CH:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O.O>[CH:1]1([CH:4]([NH:8][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: COCC(N)C1CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCC(NC(=O)OCc1ccccc1)C1CC1
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H); LRMS (ESI) m/e 250.3 [(M+H)+, calcd for C14H20NO3 250.1].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]([F:26])([F:25])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([CH2:21][C:22](O)=[O:23])[N:13]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C>[F:26][C:11]([F:10])([F:25])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([CH2:21][C:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[O:23])[N:13]=1
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccsc1NC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 120 °C
Yield: 1.7 %

Procedure:
2-aminothiophene-3-carboxamide (23 mg, 0.16 mmol) and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid (40 mg, 0.16 mmol) were dissolved in DCM/DMF (2 mL/50 μL) and polymer supported carbonyldiimidazole (264 mg, 1.2 mmol/g, 0.32 mmol) added. The reaction mixture was heated at 120° C. for 10 min in a Biotage SmithCreator microwave. The reaction mixture was filtered washing with MeOH (10 mL), EtOAc (10 mL), and MeCN (10 mL). The filtrate was concentrated in vacuo to give a yellow gum. Purification by preparative reverse phase HPLC gave desired product (1 mg, 2%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][CH:5]=1)=[O:2].[H-].[Na+].CI.[C:14](OCC)(=O)C>CN(C)C=O.O>[CH:1]([N:3]([C:4]1[N:8]([CH3:9])[N:7]=[CH:6][CH:5]=1)[CH3:14])=[O:2]
Reactant: Cn1nccc1NC=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(C=O)c1ccnn1C
Reaction time: 1 h

Procedure:
To a solution of 5-formamido-1-methylpyrazole in N,N-dimethylformamide (50 ml) was sodium hydride (1.6 g) under ice-cooling. Then, to the mixture was added methyl iodide (2.5 ml) at the same condition. The mixture was stirred for 1 hour under ice-cooling. To the reaction mixture was added a mixture of ethyl acetate (500 ml) and water (100 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml×2). The organic solution was dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to a column chromatography on silica gel using a mixture of ethyl acetate and diisopropyl ether (3:1) as an eluent. Fractions containing the object compound were collected and evaporated in vacuo to give 5-(N-formyl-N-methylamino)-1-methylpyrazole (2.5 g).
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C>CO>[CH:23](=[C:19]1[C:20](=[O:21])[C:4]2([CH3:3])[CH:17]([CH:16]3[CH:7]([CH2:6][CH2:5]2)[C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[CH2:14][CH2:15]3)[CH2:18]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Reaction time: 4 h

Procedure:
Potassium hydroxide (1.0 g) was added to a solution of estrone (1.350 g, 5.0 mmol) and benzaldehyde (1.0 g, 9.4 mmol) in methanol (50 ml) at room temperature. The resulting orange solution was stirred at this temperature for 4 h. Then glacial acetic acid (ca. 5 ml) was added with stirring. The colour changed to light yellow and a white solid precipitated. The solid was filtered off and washed with water (50 ml), methanol (20 ml), diethyl ether (50 ml) and hexane and dried under high vacuum. Yield 1.578 g (88%). H-NMR (CDCl3, 400 MHz), δ: 1.00 (s, 3H), 1.40-1.77 (m, 5H), 2.04-2.12 (m, 2H), 2.26-2.34 (m, 1H), 2.38-2.45 (m, 1H), 2.50-2.60 (m, 1H) 2.86-3.03 (m, 3H), 4.76 (s, 1H, —OH), 6.60 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.34-7.45 (m, 3H), 7.48 (s, 1H), 7.54-7.59 (m, 2H). LRMS (FAB+): 359.2 (100, [M+H]+). LRMS (FAB−): 357.2 (100, [M−H]−). HRMS (FAB+) 359.202332 C25H27O2 requires 359.201105
Reaction SMILES: CCCC[CH:5]1[C:10](=[O:11])[N:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]1=[O:7].[C:25](Cl)(=[O:27])[CH3:26]>C(O)(=O)C>[C:19]1([N:8]2[C:6](=[O:7])[CH2:5][C:10](=[O:11])[N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:25](=[O:27])[CH3:26])=[CH:14][CH:13]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccc(O)cc2)C1=O
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(N2C(=O)CC(=O)N2c2ccccc2)cc1

Procedure:
First, 1-Phenyl-2-(4'-acetyloxyphenyl)-3,5-pyrazolidinedione was prepared as follows. Oxyphenbutazone (1.00 g, 3.1 mmole) was suspended in 4 ml of glacial acetic acid and allowed to react with 2 ml of acetyl chloride at room temperature overnight. The solution was concentrated in vacuo at 86° C. to give a white residue (mp 126°-130° C.). The residue was crystallized from chloroformheptane (6:50) with cooling to give 0.81 g (mp 132°-134° C., 71% yield, lit., R. Pfester and F. Hafliger, Helvetica Chemica Acta, 40, 395 (1957) mp 135°-137° C. from methanol) of 1-phenyl-2-(4'-acetyloxyphenyl)-3,5-pyrazolidinedione.