Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CC3)N=C(N)OCC2(F)F)nc1
Yield: 27 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-cyanopicolinic acid yielded the title compound (27% yield) as an off-white solid. MS (ISP): m/z=384.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH:14]1([CH2:19][C:20](=O)[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.[Cl-].[Na+].O>[CH:14]1([CH2:19]/[C:20](/[CH3:21])=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)CC1CCCC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C(\C)CC1CCCC1
Temperature: 0 °C
Yield: 99 %

Procedure:
To a suspension of sodium hydride (956 mg, 60% in oil, 23.9 mmol) in THF (60 mL) cooled at 0° C. was added dropwise trimethyl phosphonoacetate (3.87 mL, 4.35 g, 23.9 mmol). The mixture was stirred for 20 mn at 0° C. and cyclopentylacetone (2.22 mL, 2.00 g, 15.9 mmol) was added dropwise. The solution was warmed to 25° C., then refluxed for 2 h, and poured in a solution of brine (100 mL). The reaction mixture was extracted with ethyl acetate (2×50 mL) and the combined organic phase was dried over sodium sulfate and concentrated to give the ester (2.87 g, 99%) as a mixture of E and Z isomers 3:1. MS (m/z) 182 (M).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24]=O)=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:11][O:10][C:8]([C:7]1[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:24]=[N:27][OH:28])[NH:3][C:2]=1[CH3:1])=[O:9]
Reactant: NO
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C=NO)=C(C(=O)OC)C1c1ccccc1C#N
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
A mixture of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.4 g), hydroxylamine hydrochloride (539.3 mg) and sodium acetate (752.3 mg) in acetic acid (15 ml) was stirred at room temperature for 55 minutes to form dimethyl-2-methyl-4-(2cyanophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5dicarboxylate. To the reaction mixture was added acetic anhydride (2.375 g), and the mixture was heated at 110° C. for 4 hours with stirring. The reaction mixture was concentrated and treated with water (30 ml). The resultant acidic solution was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride solution, and evaporated to dryness under reduced pressure. The residue was kept overnight in a refrigerator for crystallization. The resultant crystals were collected by filtration and washed with small portion of cold methanol to give crystals of dimethyl 2methyl-4-(2-cyanophenyl)-6-cyano-1,4-dihydropyridine-3,5dicarboxylate (1.71 g). Additional crop (0.9 g) was recovered from the mother liquor. The combined crystals (2.61 g) were recrystallized from methanol to give pure crystals (1.2 g), m.p. 166°-166.5° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:29])=[CH:14][C:15]([O:27][CH3:28])=[CH:16][C:17]=3[C:18]32[C:24](=S)[S:23][C:22](=S)[NH:21]3)=[CH:9][CH:8]=1>CCO>[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:29])=[CH:14][C:15]([O:27][CH3:28])=[CH:16][C:17]=3[C:18]32[C:24]2=[N:5][CH2:1][CH2:2][CH2:3][N:4]2[C:22](=[S:23])[NH:21]3)=[CH:9][CH:8]=1
Reactant: NCCCN
Reactant: COc1cc(F)c2c(c1)C1(NC(=S)SC1=S)c1cc(Br)ccc1O2
Solvent: CCO
Product: COc1cc(F)c2c(c1)C1(NC(=S)N3CCCN=C31)c1cc(Br)ccc1O2
Temperature: 65 °C
Yield: 23.3 %

Procedure:
Propane-1,3-diamine (4.12 mL, 47.8 mmol) and 7′-bromo-4′-fluoro-2′-methoxyspiro[thiazolidine-4,9′-xanthene]-2,5-dithione (4.23 g, 9.56 mmol) were combined in 50 ml of EtOH and heated to 65° C. for 30 minutes. The solution was then concentrated. The product was purified via silica gel column chromatography (RediSep 330 g column) using 0-50% EtOAc in hexane to afford 7′-bromo-4′-fluoro-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthene]-6(7H)-thione (1.0 g, 2.231 mmol) as an off white solid. MS m/z=448.0 [M+H].
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][NH+:5]=1.[CH3:12][C:13]1[NH:20][C:18](=[S:19])[NH:17][C:15](=[O:16])[CH:14]=1>>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][S:19][C:18]2[NH:17][C:15](=[O:16])[CH:14]=[C:13]([CH3:12])[N:20]=2)=[N:5][CH:6]=1)[CH3:11]
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: CCc1ccc(CCl)[nH+]c1
Agent: [Cl-]
Product: CCc1ccc(CSc2nc(C)cc(=O)[nH]2)nc1
Yield: 51 %

Procedure:
The title compound is prepared from 2-chloromethyl-5-ethylpyridinium chloride (m.p.: 126°-128° C.) and 6-methyl-2-thiouracyl by using the process described in Example 12. After recrystallization from ethanol the title compound is obtained as a white crystalline product in a yield of 51%, m.p.: 127°-128° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22]OS(C)(=O)=O)[O:19][C:18]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:22][C@@H:20]1[O:19][C:18](=[O:28])[N:17]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:21]1)=[N+:30]=[N-:31]
Reactant: CCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Temperature: 80 °C
Yield: 93.8 %

Procedure:
(5R)-3-(3-Fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)-oxazolidin-2-one (950 mg) was dissolved in dry DMF (30 ml) and sodium azide (893 mg) was added. The mixture was heated at 80° C. for 5 hours, and then evaporated to dryness. The residue was dissolved in ethyl acetate and the resulting solution washed with water and dried (MgSO4). The crude product so obtained was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 6% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-5-azidomethyl-3-(3-fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one (777 mg).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1(/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-phenyl-acrylic acid.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:6][C:7](=[O:15])[CH2:8]2)=[O:4]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)CBr)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromoacetyl chloride (14.17 g) in methylene chloride (30 ml) is added dropwise to a stirred suspension of oxindole (6 g) and AlCl3 (13.31 g) in methylene chloride (200 ml). The reaction mixture is refluxed for 4 hours, cooled to RT, poured with stirring into an ice/water mixture, stirred for 30 minutes, filtered and washed with methylene chloride yielding the desired product as a solid which is recrystallized from isopropanol.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25](C4CCCCO4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.I[CH2:35][CH2:36][O:37]C(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[NH:27][CH:26]=[N:25][N:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([O:10][CH2:35][CH2:36][OH:37])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C(OCCI)c1ccccc1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn2ccc(OCCO)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A mixture of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (73 mg, 0.16 mmol) produced in Example 31-B(i), (2-iodoethyl)benzoate (88 mg, 0.32 mmol), potassium carbonate (44 mg, 0.32 mmol) and N,N-dimethylformamide (3 mL) was stirred at 60° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70→100/0). The obtained solution was concentrated under reduced pressure. 1N Hydrochloric acid (2 mL), methanol (2 mL) and tetrahydrofuran (2 mL) were added to the obtained residue, and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added methanol (1 mL) and tetrahydrofuran (1 mL), and the mixture was stirred at 60° C. for 2 hr. To the reaction mixture was added 2N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give the title compound (54 mg, 81%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-4-fluoronitrobenzene (2 g, 9.1 mmol) in tetrahydrofuran (30 ml) was added triethylamine (1.9 ml, 13.6 mmol), trimethylsilylacetylene (1.9 ml, 13.6 mmol), triphenylphosphine (60 mg, 0.23 mmol) and dichlorobis(triphenylphosphine)palladium(II) (319 mg, 0.46 mmol). After stirring at room temperature for 20 minutes copper(I) iodide (17 mg, 0.09 mmol) was added and the mixture left to stir for 18 hours at room temperature. The reaction mixture was quenched into isohexane (150 ml) and filtered through a plug of silica using isohexane as eluent. The solvent was removed ex vacuo to leave (2-fluoro-5-nitrophenylethynyl)trimethylsilane as a brown solid: δH (360 MHz, CDCl3) 0.10 (9H, s), 7.02 (1H, dd, J 8 and 1), 7.97-8.02 (1H, m), 8.17 (1H, dd, J 6 and 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O1CCCC1.[CH3:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([CH3:20])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
1-Chloro-4-isocyanato-2-(trifluoromethyl)benzene (9.97 g, 45.0 mmol) was stirred in a solvent of tetrahydrofuran (100 mL). The reaction solution was added with 4-methyl-3-nitroaniline (6.52 g, 42.9 mmol), followed by stirring for about 6 hours at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated solid was added with a mixed solution of ethyl acetate/hexane (1/5), followed by stirring for 2 hours or more. The resulting solid was filtered under reduced pressure, and washed with diethyl ether. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (14 g, 87%).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:16][C:17]#[N:18]>CN(C)C=O>[C:17]([CH2:16][O:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][N:10]=1)#[N:18]
Reactant: N#CCCl
Reactant: O=C1CC(c2ccccc2)NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2ccccc2)[nH]n1

Procedure:
In an analogous manner to the method described in Example 1B, 40 g 5-phenylpyrazolin-3-one in 120 ml dimethyl formamide were first deprotonated by reaction with 5.6 g of an 80% oily sodium hydride preparation and subsequently reacted with 11 ml chloroacetonitrile to form 3-cyanomethoxy-5-phenylpyrazole. Melting point: 143° C.
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5].CN(C=O)C.[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:26])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-β-Ala-Ile-Ala-Leu SEQ ID NO: 117 (24.34 g, 0.04 mol) is added into a round bottom flask with DMF (350 mL) and a magnetic stirrer. After the tetrapeptide is dissolved, benzyl bromide (4.76 mL, 0.04 mol), followed by cesium carbonate (13.04 g, 0.04 mol), is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then the reaction mixture is slowly poured into a flask with 450 mL of iced water. A large amount of white solid precipitates out which is collected by suction filtration. The product is washed with water (2×200 mL) and placed in a vacuum desiccator.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[CH2:23]([NH:26][CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8]([N:26]([CH2:27][CH:28]=[CH2:29])[CH2:23][CH:24]=[CH2:25])([N:26]([CH2:27][CH:28]=[CH2:29])[CH2:23][CH:24]=[CH2:25])=[O:9])[CH3:2]
Reactant: C=CCNCC=C
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Solvent: CCOCC
Product: C=CCN(CC=C)P(=O)(CN(CC(=O)OCC)C(=O)SCc1ccccc1)N(CC=C)CC=C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (12 g.; 0.031 mol.) dissolved in 150 ml. of diethyl ether was added to a solution containing diallylamine (12.15 g.; 0.125 mol.) in 150 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with 3% ammonium hydroxide, 5% hydrochloric acid and then water. The ether layer was separated, then dried and concentrated in vacuo to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis(diallylamino)phosphinylmethyl]-glycinate, hemi-hydrate (10.1 g.) as an oil (nD25 =1.5373) having the following analysis:
Reaction SMILES: C1(S([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]34[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]3[C@@H:18]3[C@@:31]([CH3:34])([CH2:32][CH2:33]4)[C@@:30]4([CH3:35])[C@@H:21]([C@:22]5([CH3:47])[C@@H:27]([CH2:28][CH2:29]4)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]4[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=4)=[CH:24][CH2:23]5)[CH2:20][CH2:19]3)[CH2:9][CH2:8]2)(=O)=O)CC1.[C:54](Cl)(=[O:56])[CH3:55]>>[C:54]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]2[C@@H:18]2[C@@:31]([CH3:34])([CH2:32][CH2:33]3)[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:45][CH:46]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:9][CH2:8]1)(=[O:56])[CH3:55]
Reactant: CC(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(C)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)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)benzoic acid using acetyl chloride as the reagent in Step 1. The product was isolated as a white solid (5.4 mg, 35%). LCMS: m/e 684.67 (M+H)+, 2.27 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 5.33 (d, J=4.8 Hz, 1H), 4.82 (s, 1H), 4.72 (s, 1H), 4.09-3.89 (m, 1H), 3.85 (br. s., 3H), 3.68 (br. s., 4H), 3.53-3.14 (m, 4H), 2.92-2.66 (m, 1H), 2.28-1.01 (m, 22H), 2.17 (s, 3H), 1.73 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:22][C:23]([F:25])([F:24])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCC(F)(F)c2ccccc2)C1
Temperature: 180 °C
Yield: 40.9 %

Procedure:
The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), (2-bromo-1,1-difluoro-ethyl)-benzene (1 mmol), and K2CO3 (1 mmol) in acetonitrile (3 mL) was heated at 180° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (90 mg). To this compound was added CH2Cl2 (20 mL) and CF3COOH (3 mL). The mixture was stirred at rt for 4 h and concentrated to give the title compound (50 mg). MS (ESI): mass calcd. for C17H16ClF2NO2, 339.1; m/z found, 340.0 [M+H]+. 1H NMR (MeOD): 7.66-7.46 (m, 5H), 7.02-6.83 (m, 3H), 5.05-4.95 (m, 1H), 4.50 (t, J=12.7 Hz, 2H), 4.30-4.20 (m, 2H), 4.10-3.98 (m, 2H).
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[OH:11])[CH2:2]1)[CH2:8]2.[Cl:13][C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:14]([O:11][CH:4]1[CH:5]2[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][CH:3]1[CH2:2]3)[CH2:6]2)=[O:16]
Reactant: OC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Temperature: 0 °C

Procedure:
A solution of 1,4-adamantanediol (210 mg, 1.25 mmol) in dry pyridine (3 mL) and dry CH2Cl2 (6 mL) was cooled in an ice bath and a solution of triphosgene (122 mg, 0.41 mmol) in dry Ch2Cl2 (3 mL) was added dropwise over 5 min. The mixture was stirred in the ice bath for 3 h to afford a 0.1 M solution of 1-hydroxy-4-adamantyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16].[CH3:17]C(C)=O.C([O-])([O-])=O.[K+].[K+].IC>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16]
Reactant: CC(C)=O
Reactant: COc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To the phenol 1-7 (10.4 g, 39.1 mmol) in HPLC grade acetone (150 mL) was added K2CO3 (15 g, 108.5 mmol) and iodomethane (5 mL, 80.3 mmol). The reaction was heated to 60° C. for 22 h. The flask was cooled and then H2O (40 mL) was added and the mixture stirred for 30 min. The volatiles were removed in vacuo and the residue was taken up in CH2Cl2 and H2O. After extracting into CH2Cl2 (×3), the combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated to give the methyl ester 2-2 as an orange oil (9.92 g, 91% yield). 1H NMR (400 MHz, d6-DMSO) δ 0.95 (s, 3H), 8.22 (s, 1H).