Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2S)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[OH-].[Na+]>[N+]([O-])(O)=O>[F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2c(-n3ccnc3S)c(F)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(-n3ccnc3)c(F)ccc2n1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 16.2 g (0.0625 mole) of 6-fluoro-5-(2-mercaptoimidazol-1-yl)-2-methylquinoline was added with stirring 300 ml of 20% nitric acid. After stirring for 30 minutes, the mixture was heated on a steam bath for an additional 30 minutes. The solution was allowed to cool to about 20° C., then made basic (pH 8 to 10) by adding 50% aqueous sodium hydroxide while cooling with an ice bath. The solid precipitate was separated by filtration, washed with water and dried. Recrystallization from aqueous ethanol provided 6-fluoro-5-(imidazol-1-yl)-2-methylquinoline, m.p. 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[C:12]([CH3:16])=[C:13]([CH3:15])[NH:14][C:7]=12.[CH3:22][O:23][CH2:24]Br>>[ClH:1].[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]([CH2:22][O:23][CH3:24])[C:7]=12
Reactant: COCBr
Reactant: Cc1[nH]c2c(OCc3ccc(Cl)cc3Cl)ccnc2c1C
Product: COCn1c(C)c(C)c2nccc(OCc3ccc(Cl)cc3Cl)c21
Product: Cl
Yield: 58.9 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 33, except for using 7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine prepared in Step 2 and bromomethyl methyl ether, the titled compound was obtained as a white solid. (Yield: 58.9%)
Reaction SMILES: [CH2:1]([N:3]([C:5]1[C:6]2[N:7]([CH:15]=[N:16][C:17]=2[C:18]([O:20]CC)=O)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4])[CH3:2].[CH:23]1([C:26](=[N:28]O)[NH2:27])[CH2:25][CH2:24]1.[H-].[Na+].ClCCl>CN(C=O)C>[CH:23]1([C:26]2[N:28]=[C:18]([C:17]3[N:16]=[CH:15][N:7]4[C:8]5[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:14]=[C:5]([N:3]([CH2:1][CH3:2])[CH3:4])[C:6]=34)[O:20][N:27]=2)[CH2:25][CH2:24]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)c1ncn2c1c(N(C)CC)nc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(C)c1nc2ccccc2n2cnc(-c3nc(C4CC4)no3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A mixture of ethyl 4-(N-ethyl-N-methylamino)-imidazo[1,5-a]quinoxaline-3-carboxylate (1.2 g, 4 mmol), cyclopropanecarboxamidoxime (1.4 g, 14 mmol), crushed 4 Å molecular-sieves (0.5 g), and sodium hydride (0.1 g, 60% in mineral oil) in dry DMF (20 ml) was stirred at ambient temperature for 1 h. Dichloromethane (25 ml) was added and the mixture was filtered through celite. The filtrate was evaporated and the residue was brought to crystallize by the addition of 10 ml of ethyl acetate and cooling to 0° C. The crystals was collected by filtration, rinsed with ethyl acetate and dried to give 0.58 g of the title compound, m.p. 96°-97° C. An additional amount (0.22 g) of the product was obtained from the mother liquour. (Compound 6).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:30]#[N:31])=[N:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[CH2:27][O:28][CH3:29])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH3:29][O:28][CH2:27]/[CH:26]=[CH:25]/[C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:30]=2[NH2:31]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: COC/C=C/c1cnc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: COC/C=C/c1cnc2c(N)nc3ccccc3c2c1
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH®, system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-2-(3-methoxyprop-1-enyl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (dmso-d6): δ 9.24 (d, 1H), 9.18 (d, 1H), 8.54 (d, 1H), 7.52-7.58 (m, 2H), 7.31 (m, 1H), 7.11 (bs, 2H), 6.86-7.00 (m, 2H), 4.18 (d, 2H), 3.36 (s, 3H). LRMS [M+H]=266.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.[C:21]([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]([CH3:30])[CH3:29].O>CN(C=O)C>[CH2:21]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12]1)[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: CC(C)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and isobutyl bromide were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 332.2, found 332.3.
Reaction SMILES: [CH:1]1([CH:7]([OH:27])/[CH:8]=[CH:9]/[CH:10]2[CH2:17][CH2:16][CH:15]3[CH:11]2[CH2:12]/[C:13](=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])/[C:14]3=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].CO>O>[C:23]([CH2:22][CH2:21][CH2:20]/[CH:19]=[C:13]1/[C:14](=[O:18])[CH:15]2[CH:11]([CH2:12]/1)[CH:10](/[CH:9]=[CH:8]/[CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[OH:27])[CH2:17][CH2:16]2)([OH:25])=[O:24]
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)C3CCCCC3)CCC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCC/C=C1\CC2C(/C=C/C(O)C3CCCCC3)CCC2C1=O
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 6-[(E)-3-cyclohexyl-3-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (12.7 mg), prepared as described in Example 1 and in the form of (±)-6β-[(E)-3-cyclohexyl-3α-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)methyl(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate, lithium hydroxide (21.5 mg), methanol (2 ml), and water (0.7 ml) was left to stand at the ambient temperature for 1 hour. The mixture was then diluted with water (5 ml) and washed with dichloromethane. The aqueous layer was separated and acidified to pH 3 by treatment with aqueous hydrochloric acid (2N). The acidic solution was extracted with dichloromethane, and this extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to give 3-[(E)-4-carboxybutylidene]-6-[ (E)-3-cyclohexyl-3-hydroxyprop-1-enyl]bicyclo[3,3,0]octan-2-one (6.6 mg), in the form of (±)-3-[(E)-4-carboxybutylidene]-6β-[(E)-3-cyclohexyl-3α-hydroxyprop-1-enyl]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:15]2=[O:17]
Reactant: O=C(O)c1cccc(OCc2cc3ccccc3o2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cc5ccccc5o4)c3C2=O)C(=O)N1
Yield: 65 %

Procedure:
A mixture of 3-(benzofuran-2-ylmethoxy)-phthalic acid (0.55 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.30 g, 1.8 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in CH2Cl2 (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL) and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the title compound at 95:5 CH2Cl2-methanol, 0.46 g, in 65% yield; mp 234-236° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.16 (98.58%); 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.43-2.61 (m, 2H), 2.81-2.95 (m, 1H), 5.08 (dd. J=12.7 Hz, J=5.3 Hz, 1H), 5.55 (s, 2H), 7.14 (s, 1H), 7.23-7.37 (m, 2H), 7.50 (d, J=7.0 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 23.9, 30.9, 48.8, 63.1, 107.4, 111.3, 115.9, 116.7, 120.2, 121.6, 123.1, 125.0, 127.5, 133.3, 137.0, 152.0, 154.6, 155.0, 165.2, 166.7, 169.9, 172.7; Anal. Calcd for C22H16N2O6.0.15H2O: C, 64.91; H, 4.04; N, 6.88. Found: C, 64.89; H, 3.99; N, 6.84.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)=[C:6]([C:16](=[O:18])[CH3:17])[CH:5]=[C:4]([Cl:19])[C:3]=1[CH3:20].N1C=CC=CC=1.Cl[CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32].CC(C)([O-])C.[K+]>C(Cl)Cl.O1CCCC1>[C:16]([C:6]1[C:7]([C:8]2[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=2)=[C:2]([N:1]2[CH2:28][CH2:29][CH2:30][C:31]2=[O:32])[C:3]([CH3:20])=[C:4]([Cl:19])[CH:5]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cc(F)cc(F)c1
Reactant: O=C(Cl)CCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.34 mmol) and pyridine (0.041 mL, 0.51 mmol) in methylene chloride (2 mL) was added 4-chlorobutanoyl chloride (0.042 mL, 0.37 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated to dryness under reduced pressure. The resulting residue was treated with 1.0 M potassium tert-butoxide in tetrahydrofuran (0.84 mL, 0.84 mmol) in tetrahydrofuran (2 mL) at room temperature for 2 hours. The reaction was quenched with aq. NH4Cl, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to give the desired product (15 mg, 12%), LCMS calculated for C19H17ClF2NO2 (M+H)+: m/z=364.1. found: 364.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C1COCC1.CC(C)([O-])C.[K+]>O>[O:24]=[C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:17]1[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2
Reactant: O=C(Cl)CCCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(N3CCCCC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
To tert-butyl-5-amino-1-indolinecarboxylate (1.90 g, 8.2 mmol) was added 5-bromovaleryl chloride (1.4 mL, 9.0 mmol) and 18 mL of THF. After stirring for 5 min at rt under N2, potassium tert-butoxide (9 mL, 9 mmol; 1.0 M in THF) was added in one portion, and the resulting brown solution was stirred under N2 for 30 min. A second portion of potassium tert-butoxide (9 mL) was added, and the resulting brown suspension was stirred for 15 min. An additional 0.10 mL-portion of 5-bromovaleryl chloride and a 4.5 mL-portion of potassium tert-butoxide were added, and the mixture was stirred for 30 min. The reaction was then poured into H2O (80 mL). The aqueous layer was washed with EtOAc (3×50 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the resulting residue was purified by radial chromatography (50% EtOAc in hexanes) to afford tert-butyl 5-(2-oxo-1-piperidinyl)-1-indolinecarboxylate as a pink solid (1.30 g, 50%). LRMS (AP+): 317.2 (M+H)+. 1H NMR (CDCl3) δ 7.40-7.80 (br m, 1H), 7.01 (s, 1H), 6.97 (d, 1H), 3.94 (t, 2H), 3.55 (br m, 2H), 3.09 (t, 2H), 2.49 (br m, 2H), 1.91 (br m, 4H), 1.52 (s, 9H).
Reaction SMILES: Br.C([O:4][P:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([P:22]([O:27]CC)(=[O:26])[O:23]CC)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])[O:6]CC)C.O>C(O)(=O)C>[C:16]1([C:13]2[CH:14]=[CH:15][C:10]([P:5]([OH:6])(=[O:4])[OH:9])=[CH:11][CH:12]=2)[CH:17]=[CH:18][C:19]([P:22]([OH:26])(=[O:23])[OH:27])=[CH:20][CH:21]=1
Reactant: CCOP(=O)(OCC)c1ccc(-c2ccc(P(=O)(OCC)OCC)cc2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=P(O)(O)c1ccc(-c2ccc(P(=O)(O)O)cc2)cc1
Temperature: 80 °C
Yield: 0.1 %

Procedure:
66 ml of HBr at 33% by weight in acetic acid are added to 4.9 g (11.5 moles) of 4,4'-biphenyl-diphosphonic acid tetra-ethyl ester and the mixture is heated at 80° C. for 4 hours. After cooling to ambient temperature, 150 ml of H2O are added under agitation and the precipitate obtained is filtered, washed with water and vacuum dried (20 mm Hg) at 45° C. for one night. 2.29 g of 4,4'-biphenyl-diphosphonic acid, with a molar yield of 66% are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:3][CH2:2]1
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 2 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
10 kg tetrahydropyran-4-ol are dissolved in a mixture of 50 L toluene and 10.4 kg triethylamine. 11.55 kg methanesulfonyl chloride in 100 ml toluene are added while maintaining the internal temperature below 20° C. by cooling, and the addition funnel is rinsed with 50 ml toluene. The stifling is continued for one hour. The precipitate is filtered and the filter cake is washed twice with 20 L toluene each. The filtrate is concentrated by vacuum evaporation (60 L were distilled of), seeding crystals and 50 L methylcyclohexane are added. The suspension is cooled to 2° C. After 1 h the product is isolated by filtration, washed with 30 L methylcyclohexane and dried at 30° C. 16.6 kg of the product are obtained as a white solid. Yield: 94%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (2H, m), 1.92-2.00 (2H, m), 3.19 (3H, s), 3.42-3.49 (2H, m), 3.77-3.83 (2H, m), 4.80-4.88 (1H, m).
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([O:41]C)=[O:40])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[F:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:29]([NH:28][CH:12]2[C:11](=[O:43])[N:10]([CH2:9][C:7]([C:2]3[C:1]([CH3:44])=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:13]2)=[O:30])=[CH:33][C:34]=1[C:39]([OH:41])=[O:40]
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1ccc(F)c(C(=O)O)c1)CN2C(=O)C(C)(C)C
Yield: 64.2 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-fluorophenyl)urea (510 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (178 mg) solution (12 ml) and tetrahydrofuran (12 ml) was added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 320 mg of the titled compound.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]1[C:19]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:18][S:17](=[O:25])(=[O:24])[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>CO>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[S:17](=[O:25])(=[O:24])[NH:18][C:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]=2[CH2:14][NH:5][CH2:4][CH2:3][F:2])=[CH:31][CH:30]=1
Reactant: O=S1(=O)NC2(CCCC2)C(CBr)=C1c1ccc(Cl)cc1
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=S1(=O)NC2(CCCC2)C(CNCCF)=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-fluoroethylamine hydrochloride (1.08 g, 10.9 mmol; prepared as described in J. Med. Chem. 9 (1966), 892-911) in 30 mL of absolute MeOH was treated with triethylamine (2.50 mL, 1.76 g, 17.4 mmol) at 0° C. Solid 4-bromomethyl-3-(4-chlorophenyl)-2,2-dioxo-2-thia-1-aza-spiro[4.4]non-3-ene (1.64 g, 4.35 mmol; described during the preparation of Intermediate 6) was added. The resulting mixture was stirred for 16 h at ambient temperature and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol as eluent to yield the title intermediate. Yield: 1.00 g (64%); MS (IS): 359.1 [M+H]+.
Reaction SMILES: [Na].[N:2]([C@@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C@H:11]([O:23]C(C2C(C3C=CC=CC=3)=CC=CC=2)=O)[C@@H:10]([CH2:38][O:39][Si:40]([C:53]([CH3:56])([CH3:55])[CH3:54])([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:9][C@H:6]1[S:7][CH3:8])=[N+:3]=[N-:4]>CO.C1COCC1>[N:2]([C@@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C@H:11]([OH:23])[C@@H:10]([CH2:38][O:39][Si:40]([C:53]([CH3:56])([CH3:55])[CH3:54])([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[O:9][C@H:6]1[S:7][CH3:8])=[N+:3]=[N-:4]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium (89 mg) was reacted in dry MeOH (50 mL) then a solution of methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D glucopyranoside (11) (3 g, 3.88 mmol) in THF (25 mL) was added. The reaction mixture was stirred at 40° C. for 30 minutes, then cooled to room temperature. The solution was neutralized by Amberlite IR 120 (H+) ion exchange resin. The suspension was filtered, the filtrate was evaporated. The residue was purified by chromatography using EtOAc—hexane 1:4 as the mobile phase to give methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D glucopyranoside (10) (2.1 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:16][CH2:17][NH:18][C@:19]23[CH2:63][CH2:62][C@@H:61]([C:64]([CH3:66])=[CH2:65])[C@@H:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:60])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:40])([CH3:39])[C:28]([C:41]3[CH2:59][C:43]5([CH2:46][C:45]([C:53]([O:55]C(C)C)=[O:54])([C:47]([O:49]C(C)C)=[O:48])[CH2:44]5)[CH:42]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[N:6][CH:7]=1.[OH-].[Na+].Cl>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:16][CH2:17][NH:18][C@:19]23[CH2:63][CH2:62][C@@H:61]([C:64]([CH3:66])=[CH2:65])[C@@H:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:60])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:39])([CH3:40])[C:28]([C:41]3[CH2:59][C:43]5([CH2:46][C:45]([C:53]([OH:55])=[O:54])([C:47]([OH:49])=[O:48])[CH2:44]5)[CH:42]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccc(Cl)cn3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccc(Cl)cn3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
Step 4 for example A3 was carried out in a similar manner: To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(N-(5-chloropyridin-2-yl)-1,1,1-trifluoromethylsulfonamido)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (32 mg, 0.033 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 50° C. for 3 h. The mixture was neutralized by 1N HCl (1 mL) to pH ˜6 and solids formed were collected by filtration. The crude product was purified by preparative HPLC using method 14 to give 6-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-((2-(N-(5-chloropyridin-2-yl)-1,1,1-trifluoromethylsulfonamido)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid in 47% yield as a solid. MS: m/e 876.5 (M+H)+, 2.56 min (method 4). 1H NMR (400 MHz, METHANOL-d4) δ 8.53 (d, J=2.3 Hz, 1H), 8.00 (dd, J=8.7, 2.6 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 5.92 (s, 1H), 5.54 (dd, J=6.4, 1.9 Hz, 1H), 4.71 (d, J=1.3 Hz, 1H), 4.60 (s, 1H), 4.34-4.17 (m, 2H), 2.76-2.65 (m, 6H), 2.62-2.53 (m, 2H), 2.43-2.33 (m, 1H), 2.15 (dd, J=17.9, 6.7 Hz, 1H), 1.86 (quin, J=10.6 Hz, 1H), 1.79-0.94 (m, 20H), 1.68 (s, 3H), 1.16 (s, 3H), 1.09 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.88 (s, 3H). 19F NMR (376 MHz, METHANOL-d4) 6-75.55 (s., 3F).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)CCl.[CH3:18][NH2:19]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH3:18])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CNC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (3.00 g, 16.2 mmoles) was dissolved in dichloromethane (100 mL) and cooled in an ice bath to 0–5° C. EDC (3.73 g, 19.5 mmoles) was added followed by dropwise addition of methylamine solution (8.1 mL, 16.2 mmoles, 2.0 M solution in THF). The mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was then diluted with ethyl acetate and washed successively with 1 M HCl, saturated aqueous NaHCO3 and brine. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to leave 4-fluoro-3-nitro-N-methylbenzamide as a yellow solid (2.94 g, 91%) which was used directly in the next step.