Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(=O)(=O)C.ClCCl.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([O:18][CH2:19][CH3:20])(=O)C>>[CH2:11]([C:10]1[CH2:13][CH:12]2[CH2:11][CH:10]([CH2:9][C:19](=[O:18])[CH2:20]2)[CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Product: CCCCC1=CC2CC(=O)CC(C1)C2
Yield: 41 %

Procedure:
This reaction was performed in a manner similar to that described for the preparation of IIc, starting from mesylate IV (X=--CH2 --; R=n--C4H9) (13.6 g, 47.2 mmol), silica gel (14 g) and dichloromethane (140 ml). The residue obtained was subjected to column chromatography on silica gel (120 g) using hexane/ethyl acetate mixtures of increasing polarity as eluent. On elution with 95:5 hexane/ethyl acetate, the ketone IIe (3.7 g, 41% yield) was obtained. Continuing the elution with 90:10 hexane/ethyl acetate, alcohol V (X=--CH2 --; R=n--C4H9) (2.8 g, 28% yield) was obtained.
Reaction SMILES: [CH2:1]([C:3]1([C:8]([O:10]CC)=[O:9])[CH2:7][CH:6]=[CH:5][CH2:4]1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH:6]=[CH:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1(CC)CC=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1(C(=O)O)CC=CC1
Yield: 65.4 %

Procedure:
A solution of ethyl 1-ethylcyclopent-3-enecarboxylate (3.5 g, 20.8 mmol) and aqueous sodium hydroxide solution (20.8 mL, 2 mol/L) in methanol (30 mL) was stirred at 80° C. for 2 h and then concentrated. The residue was poured into water, and extracted with ether (3×100 mL). The water layer was acidified with 4 mol/L aqueous hydrochloric acid solution to pH<3, and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave the crude product, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford the title compound (1.9 g, 13.6 mmol, 65.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 5.61 (s, 2.91 (d, J=14.8, 2H), 2.32 (d, J=14.4, 2H), 1.78-1.72 (m, 2H), 0.92-0.88 (t, J=7.4, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>O1CCOCC1.O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: CCOC(=O)c1ccc(N)c2c1OCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(Cl)c(N)c2c1OCCO2
Reaction time: 8 h
Yield: 98.8 %

Procedure:
37 g (0.165 mol) of ethyl 8-amino-2,3-dihydro-1,4-benzodioxine-5-carboxylate dissolved in 370 ml of dioxane are introduced into a 1 l round-bottomed flask, 23.2 g (0.174 mol) of N-chlorosuccinimide are added, at room temperature and with magnetic stirring, and the mixture is stirred overnight. It is diluted with water, extracted with ethyl acetate and, after the usual processing of the organic phase, 42 g of compound are obtained, which product is recrystallized from a mixture of diethyl ether and diisopropyl ether.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:13][S:14][CH3:15])=[CH:3]1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:13][S:14]([CH3:15])=[O:24])=[CH:3]1
Reactant: CSCc1cn(C)c2ccccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(CS(C)=O)c(=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of the above 1-methyl-3-methylthiomethyl-4-quinolone (4.86 g.) in dichloromethane (220 ml.) at -20° was added a solution of 3-chloroperbenzoic acid (85%, 4.86 g.) in dichloromethane (220 ml.) during 1 hour. The solution was allowed to warm to room temperature and extracted with saturated aqueous sodium bicarbonate until free of per-acid. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give a solid product. The product was crystallized from acetone to give the novel 1-methyl-3-methylsulphinylmethyl-4-quinolone, m.p. 93°-95°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[C:19]([O:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OCCCBr
Reactant: CCCCOc1c(O)c2c(O)cccc2oc1=O
Product: CCCCOc1c(O)c2c(OCCCOC(C)=O)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-butoxy-4-hydroxy-5-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[F:38])=[O:29])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]=O)=[O:18])[CH:13]=2)[CH:7]=1.[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[F:38])=[O:29])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:43]3[CH2:44][CH2:45][CH:40]([OH:39])[CH2:41][CH2:42]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2F)c1
Reactant: OC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCC(O)CC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide (150 mg, 0.29 mmol) in 10 ml of anhydrous DMF were added 4-hydroxypiperidine (59 mg, 0.58 mmol) and acetic acid (10 mg, 0.17 mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60 ml, 0.60 mmol) and stirring was continued for another 60 minutes. The mixture was poured into 50 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 20% of MeOH in CHCl3 to give 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[3-(4-hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide as white solid. Yield: 110 mg, 63%.
Reaction SMILES: Cl.Cl.[C:3]([C:11]1[CH:41]=[CH:40][C:14]([CH2:15][N:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:22]3[N:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:24][CH:23]=3)[CH2:17]2)=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:48][NH2:49].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>CN(C)C=O.O>[C:3]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30](=[O:31])[NH:49][O:48][CH:43]4[CH2:44][CH2:45][CH2:46][CH2:47][O:42]4)=[CH:26][N:27]=3)[C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:17]2)=[CH:40][CH:41]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(Cc2ccc(C(=O)c3ccccc3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(Cc2ccc(C(=O)c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a mixture of (2E)-3-{6- [[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (93 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine (27 mg.), and 1-hydroxybenzotriazole (31 mg) in N,N-dimethylformamide (1.6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (36 mg) at 4° C. The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (2 mL) and water (8 mL), and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (35 mg)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[C:20]([C:26]([O:28][CH3:29])=[O:27])#[C:21][C:22]([O:24][CH3:25])=[O:23].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])/[C:21](/[CH:11]([P:6]([O:8][CH2:9][CH3:10])([O:5][CH2:3][CH3:4])=[O:7])[P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[CH:20]\[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(/C(=C/C(=O)OC)C(=O)OC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
In a suspension of 1.33 g of sodium hydride (60% in oil) in 120 ml of toluene are added dropwise 10 g of bis(diethoxyphosphoryl)methane dissolved in 20 ml of toluene. The reaction mixture is kept at room temperature under stirring for 1 hour, then it is cooled to 0° C. and added dropwise with a solution of dimethyl acetylenedicarboxylate (5.17 g) in 20 ml of toluene. After 1 hour under stirring the reaction mixture is added with ethyl acetate until dissolution of the formed gummy solid occurs and it is washed firstly with 1 N hydrochloric acid (30 ml) then with water (2×30 ml). The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure, to give a residue (12.9 g) which, after purification by silica gel chromatography (300 g; eluent:petroleum ether/isopropanol 7:3) furnishes 9.6 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[C:17]([NH:20][C:21](=[O:38])[CH:22]=[CH:23][CH2:24][N:25]([CH2:30][C:31]([O:33][C:34]([CH3:37])(C)[CH3:35])=[O:32])C[C@@H](O)C)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[C:17]([NH:20][C:21](=[O:38])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:35][C@H:34]([CH3:37])[O:33][C:31](=[O:32])[CH2:30]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC(=O)O1

Procedure:
A mixture of 700 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-[(tert.butyl-oxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-1-yl)-amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline and 228 mg of p-toluenesulphonic acid hydrate in 20 ml of acetonitrile is refluxed for five hours. Then a further 200 mg of p-toluenesulphonic acid hydrate are added and the mixture is again refluxed for five hours. For working up the reaction mixture is evaporated to dryness. The flask residue is distributed between ethyl acetate and saturated sodium carbonate solution. The organic phase is separated off, washed with saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The oily residue is brought to crystallisation by stirring with 15 ml diethyl ether.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]([P:28](=[O:33])([OH:32])[O:29][CH2:30][CH3:31])#[C:23][CH2:24][CH2:25][CH2:26][CH3:27].[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[CH:39]>[Au].ClC(Cl)C>[CH2:30]([O:29][P:28]1(=[O:32])[CH:22]=[C:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:39]=[C:38]([CH2:37][CH2:36][CH2:35][Cl:34])[O:33]1)[CH3:31]
Reactant: C#CCCCCl
Reactant: CCCCC#CP(=O)(O)OCC
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCCCC1=CP(=O)(OCC)OC(CCCCl)=C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
Method 2—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen hex-1-ynylphosphonate (57.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-n-butyl-6-3-chlorpropyl-1,2-oxaphosphorin 2-oxide (56.1 mg, 64%) which is a title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:18](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH3:18])[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC)c1

Procedure:
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into the corresponding tert-butoxycarbonylamino derivative by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at N and deprotected again to yield the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([Br:14])[C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].CI.CC(=O)OCC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[C:4]([Br:14])[C:3]=1[O:15][CH3:16]
Reactant: Oc1c(Br)cc(S(F)(F)(F)(F)F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(Br)cc(S(F)(F)(F)(F)F)cc1Br
Yield: 107.1 %

Procedure:
450 mg of 2,6-dibromo-4-pentafluorosulfanylphenol, 329 mg of K2CO3 and 186 mg of CH3I were stirred at RT in 5 ml of anhydrous DMF for 24 hours. Subsequently, the reaction mixture was poured onto 100 ml of EA and extracted 3 times with 30 ml each time of water. Drying was effected over MgSO4 and the solvent was removed under reduced pressure to obtain 500 mg of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].BrBr.S(Cl)([Cl:29])(=O)=O>C(O)(=O)C>[Cl:29][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Cl
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-(p-chlorophenyl)-5-(trifluoromethyl)-pyrrole-3-carbonitrile (8.12 g, 0.03 mol) and sodium acetate (0.25 g, 0.003 mol) in acetic acid at 70° C. is treated dropwise with bromine (0.48 g, 0,003 mol). When the color disappears, the reaction is treated dropwise with sulfuryl chloride (6.1 g, 0.045 mol) over a 1 hour period, held at 70° C. for 1 hour, concentrated in vacuo and diluted with water. The reaction mixture is filtered, the filter cake is washed with water and dried to yield the title product as white solid, 7.7 g (84% yield), mp 242°-243° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.CCCCCC.CCOCC>C1COCC1.Cl>[C:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][OH:8])[CH2:11][CH2:12]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 2 h

Procedure:
LAH (3.8 g, 100 mmol) was added portionwise to a solution the ester 2-3c (20.3 g, 83.5 mmol) in THF (300 mL) at 0° C. under argon. After the addition was complete, the mixture was stirred for 2 hours then poured onto ice, IN HCl was added and the slurry extracted 3× EtOAc. The organic layer was washed with water then brine, dried (MgSO4) and concentrated to give a white solid. The solid was swished with hexane/ether 9:1 and filtered to provide the alcohol 2-3.
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: C1COCCO1
Solvent: CO
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: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH3:33])[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:11])[CH3:10].[BH4-].[Na+]>CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH:11][CH:9]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH3:33])[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:23]2)=[CH:16][CH:17]=1)[CH3:10]
Reactant: CC(=O)c1ccc(N2CCC(N(C)CCc3ccccc3)CC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(N2CCC(N(C)CCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
10.4 g (0.32 mol) of the product from Example 12 (as base) were dissolved in 500 ml of methanol and, at 10° C., 18.0 g (0.475 mol) of sodium borohydride were added a little at a time. The mixture was stirred at room temperature for 16 hours and then evaporated in a rotary evaporator. The residue was partitioned between methylene chloride and water, and the organic phase was dried and evaporated in a rotary evaporator. The resulting oil was crystallized as the fumarate. 16.4 g of 1-(4-(1-hydroxyethyl)phenyl)-4-(N-methyl-N-(2-phenylethyl)amino)piperidine difumarate were obtained. Melting point 124°-129° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1.[H-].[Na+].C1(NS(C(F)(F)F)(=O)=O)C=CC=CC=1.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>CN(C=O)C.CCOC(C)=O>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=2)[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: COc1ccc2c(c1)c(O)cc(=O)n2C
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(Nc2cc(=O)n(C)c3ccc(OC)cc23)CC1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
To a suspension of 4-Hydroxy-6-methoxy-1-methyl-1H-quinolin-2-one (1.8 g, 10 mmol) in DMF (30 mL) was added sodium hydride (385 mg, 10 mmol, 60% dispersion in mineral oil). After stirring for 5 minutes, N-phenyltrifluoromethanesulfonamide (3.4 g, 10 mmol) was added and the reaction was stirred and monitored by TLC to completion (20 minutes). 4-amino-piperidine-1-carboxylic acid ethyl ester was then added and the reaction mixture was heated at 60° C. over night. The reaction mixture was then diluted up with EtOAc and washed with water, NaHCO3, and brine. The organic portion was dried over MgSO4 and evaporated to afford a residue which was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the title compound (445 mg, 12%). 1H NMR (300 MHz, CDCl3) δ 1.27 (2H, t, J=7.11 Hz), 1.22-1.35 (2H, m), 1.40-1.55 (2H, m), 2.10-2.20 (2H, m), 2.90-3.05 (2H, m), 3.50-3.70 (1H, m), 3.64 (3H, s), 3.87 (3H, s), 4.14 (2H, q, J=7.10), 4.50 (1H, br d, J=7.3 Hz), 5.29 (1H, s), 6.95 (1H, d; J=2.31 Hz), 7.17 (1H, dd, J=2.31, 9.03 Hz), 7.30 (1H, d, J=8.94 Hz).