Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=O)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
To a solution of vanillin (500 mg), phenylboronic acid (1.60 g) and copper(II) acetate (712 mg) in methylene chloride (10 mL) were added molecular sieve 4A (750 mg) and triethylamine (665 mg), and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed successively with 0.5M aqueous hydrochloric acid solution, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-methoxy-4-phenoxybenzaldehyde (440 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15](F)[CH:14]=2)[N:8]=1.[C@H:23]1([NH2:30])[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:29][C@H:26]3[CH2:27][CH2:28][C@H:23]([NH2:30])[CH2:24][CH2:25]3)[CH:14]=2)[CH:10]=[N:11][CH:12]=1
Reactant: Fc1cccc(CNc2cncc(-c3ccnc(F)c3)n2)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCc4cccc(F)c4)n3)ccn2)CC1
Temperature: 105 °C

Procedure:
To N-(3-fluorobenzyl)-6-(2-fluoropyridin-4-yl)pyrazin-2-amine (30 mg, 0.101 mmol) was added DMSO (0.6 ml) and trans-cyclohexane-1,4-diamine (115 mg, 1.006 mmol). The reaction mixture then was stirred at 105° C. until completion as indicated by LCMS, about 40 hours. To the crude reaction mixture, after cooling to room temperature mixture was added 0.75 ml of DMSO, the resulting mixture filtered and purified by prep LC. After lyphilization, 34 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 393.2 (MH+), retention time=0.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[O:12][C:11](=[O:13])[C:10]([O:14]CC3C=CC=CC=3)=[C:9]2[OH:22])=[CH:4][CH:3]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:23])[O:12][C:11](=[O:13])[C:10]([OH:14])=[C:9]2[OH:22])=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC1(c2ccc(Cl)cc2)OC(=O)C(O)=C1O
Yield: 45.8 %

Procedure:
Hydrogenolysis of 330 mg of 5-(4-chlorophenyl)-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3 ,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 110 mg (46% yield) of 5-(4-chlorophenyl)-3,4-dihydroxy-5-methyl-2(5H)-furanone a light tan solid: mp 154-155° C. dec.(benzene/hexanes) 1H NMR (acetone-d6) δ 7.52-7.34 (m, 4H), 1.82 (s, 3H). 13C NMR (acetone-d6) δ 169.0, 156.6, 139.8, 134.3, 129.2, 127.8, 117.9, 80.8,24.6. Anal Calcd for C11H9ClO4: C, 54.90; H, 3.77. Found: C, 54.74; H. 4.08.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:21]>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][CH2:20][CH3:21])=[CH:24][CH:25]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOc1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1OC
Product: CCOc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(OC)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with 4-ethoxyaniline gave N4-(3,4-dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (bs, 1H), 7.37 (dd, 2H, J=2.4 and 6.3 Hz), 7.21 (d, 1H, J=2.4 Hz), 7.03 (dd, 1H, J=2.4 and 8.1 Hz), 6.86–6.80 (m, 4H), 6.65 (bs, 1H), 4.00 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 3.75 (s, 3H), 1.39 (t, 3H, J=6.9 Hz); 19F NMR (CDCl3): −47501; LCMS: ret. time: 22.69 min.; purity: 98%; MS (m/e): 385 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[C:8]1=O)[CH2:14]2.[Si:18]([O:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[C:29]([O:31][CH2:32][CH2:33][Cl:34])=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(OCC)(=O)C>C1COCC1.CCCCCC.[Cl-].[Cl-].[Cl-].[Ti+3]>[Cl:34][CH2:33][CH2:32][O:31][C:29](=[C:8]1[CH:9]2[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][CH:7]1[CH2:14]3)[CH2:10]2)[C:28]1[CH:35]=[CH:36][CH:37]=[C:26]([O:25][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:27]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCl)c1
Agent: [Ti+3]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCCl)=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A three neck flask was purged with argon and charged with 400 mL of anhydrous THF. Titanium trichloride (48 g, 0.3 mol) was added with stirring and the flask was cooled in an ice bath. Lithium aluminum hydride (6.0 g, 0.16 mol) was added in small portions causing a brief exothermic reaction. After all of the LAH was added, the cooling bath was removed and the mixture warmed to room temperature. Triethylamine (30 mL) was added and the black mixture was refluxed for 1.5 hours under argon. A solution of adamantanone (14 g, 93 mmol) and 2-chloroethyl 3-t-butyldimethylsilyloxybenzoate (10 g, 31 mmol) in 50 mL of dry THF was added dropwise while reflux was continued. After an additional 10 min, TLC (5% ethyl acetate in hexane) indicated conversion of the ester to new material so the mixture was cooled and diluted with 3 L of hexane. The hexane was decanted, filtered through filter paper and evaporated leaving an oil which was purified by column chromatography on silica gel, eluting with 0-3% ethyl acetate in hexane yielding 8.68 g of alkene (65% based on ester); 1H NMR (CDCl3) δ0.195 (s,6H), 0.983 (s,9H), 1.78-1.98 (m,12H), 2.65 (br s,1H), 3.334 (br s,1H), 3.55 (t,2H), 3.66 (t,2H), 6.85-7.29 (m,4H). ##STR14##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([OH:30])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([O:30][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 118.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.07 g, 6.81 mmol) and 3-(1-cyano-1-methylethyl)-N-(4-ethyl-3-hydroxyphenyl)benzamide (2.0 g, 6.48 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.34 g, 9.72 mmol), and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed with water (150 mL), 5% aqueous sodium hydrogen carbonate solution (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70). The obtained solution was concentrated under reduced pressure to give the title compound (3.3 g, quantitative) as a yellow amorphous substance.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH:9]1[C:36]2[C:31](=[C:32]([Br:37])[CH:33]=[CH:34][CH:35]=2)[C:11]2([CH2:16][CH2:15][N:14]([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:13][CH2:12]2)[CH2:10]1.CCN(C(C)C)C(C)C.[CH3:47][N:48]=[C:49]=[O:50]>C(Cl)Cl>[Br:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[C:11]1([CH2:16][CH2:15][N:14]([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:27])([F:28])[F:29])[CH2:13][CH2:12]1)[CH2:10][CH:9]2[NH:8][C:49]([NH:48][CH3:47])=[O:50]
Reactant: CN=C=O
Reactant: NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A vial equipped with a flea stirbar was charged with (±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one TFA salt (9 mg, 0.015 mmol), i-Pr2NEt (0.01 mL) and CH2Cl2 (1 mL). MeNCO (0.05 mL, 0.085 mmol) was added. The mixture was stirred at rt for 3 h and evaporated to dryness. The residue was purified by prep HPLC to afford (±)-(E)-1-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-3-methylurea (2.9 mg, 59%). LC-MS Method 1 tR=1.77, min, m/z=536, 538.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C:11](O)=[O:12])=[C:4]([N+:14]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:9][CH2:10][C:11](=[O:12])[NH:14]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: O=C1CNc2cc(F)c(Cl)cc2N1
Temperature: 25 °C

Procedure:
A suspension of N-(4'-chloro-5'-fluoro-2'-nitrophenyl)glycine sodiumsaltand N-(2'-chloro-5'-fluoro-4'-nitrophenyl)glycine sodium salt (0.175 g, 0.704 mmol) and tin (II) chloride dihydrate (0.475 g, 2.11 mmol) in ethanol (3.5 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (10 mL) and the pH was adjusted with saturated NaHCO3 (3.0 mL) to pH~8. The resulting white suspension was extracted with ethyl acetate (30 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield 0.041 g (29%) pure (1H NMR) title compound as a light yellow powder; mp 217-219° C. (dec); 1H NMR (DMSO-d6) δ 3.75 (s, 2H), 6.37 (s, 1H), 6.59 (d, 1H, J=10.5 Hz), 6.74 (d, 1H, J=7.2 Hz), 10.33 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:21]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:20][N:19]=[C:18]([S:31][CH3:32])[N:17]=2)=[C:6]1[CH3:33].[OH-].[Li+]>O1CCCC1>[C:25]1([S:22]([C:21]2[C:16]([CH2:15][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[N:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]=3[CH3:33])=[N:17][C:18]([S:31][CH3:32])=[N:19][CH:20]=2)(=[O:23])=[O:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)Cn1c(C)c(Cc2nc(SC)ncc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ncc(S(=O)(=O)c2ccccc2)c(Cc2c(C)n(CC(=O)O)c3ccc(F)cc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of [3-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.23 g) and tetrahydrofuran (30 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.93 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a yellow solid (0.20 g).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH:38]([CH3:40])[CH3:39])[CH2:36][OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH:35]([CH2:36][OH:37])[CH:38]([CH3:40])[CH3:39])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CC(C)C(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: CC(C)C(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-3-methyl-1-butanol using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.38 (1H, d, J=9 Hz), 8.55 (1H, s), 8.14 (1H, s), 7.40 (2H, dd, J=6, 9 Hz), 7.13 (2H, t, J=9 Hz), 4.87 (1H, t, J=5 Hz), 4.30-4.50 (2H, m), 4.16 (2H, s), 3.79-3.87 (1H, m), 3.32-3.60 (7H, m), 1.89-2.04 (2H, m), 1.71-1.81 (2H, m), 0.90 (6H, dd, J=7, 9 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]([CH3:23])([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:13][OH:14].C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[CH3:11][C:12]([CH3:23])([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH:13]=[O:14]
Reactant: CC(C)(CO)COC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)COC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
DMSO (2.69 mL, 50.97 mmol) was added dropwise to a solution of oxalyl chloride (2.87 mL, 33.98 mmol) in dichloromethane (85.0 mL) at −78° C. After several minutes, neat 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.2 g, 16.99 mmol) was added dropwise and after stirring for 1 h at −78° C., triethylamine (9.5 mL, 68.0 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 30 min. Sat. NH4Cl was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and washed with brine. The organic layers were combined, dried over Na2SO4 and concentrated to give a pale liquid. The crude liquid was passed through a short silica gel column and eluted with 50% ethyl acetate in hexanes to provide 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionaldehyde (3.09 g, 97%) as a pale liquid after removal of solvents under reduced pressure.
Reaction SMILES: Cl([O-])=[O:2].[Na+].[F:5][C:6]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][NH:8][C:9]1[C:10]([F:19])=[C:11]([CH2:16][CH:17]=[O:18])[C:12]([Cl:15])=[CH:13][CH:14]=1.Cl>O.CS(C)=O>[F:26][C:6]([F:5])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[C:10]([F:19])=[C:11]([CH2:16][C:17]([OH:2])=[O:18])[C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: O=CCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of sodium chlorite (692 mg, 6.11 mmol) in H2O (6.1 mL) was added over a period of 30 minutes to a stirred mixture of 2{-3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}ethanal (1.43 g, 4.37 mmol), as prepared in the preceding step, in DMSO (4.5 mL) and of NaH2PO4 (141 mg, 1.18 mmol) in H2O (1.7 mL). After the addition, the mixture was stirred at ambient temperature overnight, acidified with 10 M HCl to pH 1, and extracted with DCM (3 times). The extracts were combined, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was flash chromatographed on silica gel eluting with MeOH/DCM (0, 2, and 4%) to give the title compound (0.77 g, 51% yield) as a pale brown solid. 1H-NMR (400 MHz, CD3OD) δ 7.53-7.51 (m, 2H), 7.44-7.41 (m, 3H), 6.93 (dd, J=8.9, 1.8 Hz, 1H), 6.62 (t, J=9.1 Hz, 1H), 3.80 (t, J=13.7 Hz, 2H), 3.74 (d, J=2.2 Hz, 2H). Mass spectrum (LCMS, ESI) calc'd for C16H14ClF3NO2 (M+H): 344.1. Found: 344.4.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4][CH:3]=1.[CH:34]([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:17])[CH3:18])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH:26]([CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1c(Sc2ccccc2)c2cc(C(C)C)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1c(Sc2ccccc2)c2cc(C(C)C)ccc2n1Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 6, Step 1, but using ethyl 1-(p-chlorobenzyl)-3-phenylthio -5-(i-propyl)-indole-2-acetate (Example 10, Step 1) as the starting material, lithium diisopropylamide as base, and tetrahydrofuran as solvent, ethyl 1-(p-chlorobenzyl)-α-methyl-3-phenylthio-5-(i-propyl)-indole-2-acetate was prepared.
Reaction SMILES: C(N(CC)CC)C.NCCN[C@H]1C[CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[OH:31])[CH2:13]1.FC(F)(F)C([O:36][CH2:37][CH3:38])=O>CO>[OH:31][C@H:21]1[CH2:20][CH2:19][C@H:18]2[C@H:17]3[C@H:26]([CH2:25][CH2:24][C@:22]12[CH3:23])[C@:27]1([CH3:28])[C@H:14]([CH2:13][C:37](=[O:36])[CH2:38][CH2:30]1)[CH2:15][CH2:16]3
Reactant: CCOC(=O)C(F)(F)F
Reactant: C[C@]12CC[C@H](NCCN)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 22 h
Yield: 21.2 %

Procedure:
Triethylamine (TEA) (3.0 mL, 21.5 mmol, 15.5 equiv.) was added to 1.39 mmol of crude 3β-[N-(2-aminoethyl)-amino]-17β-hydroxy-5α-androstane in 8.0 mL dry methanol, followed by 3.21 mL (27.0 mmol, 19.4 equiv.) of ethyl trifluoroacetate (Aldrich). After stirring for 22 h at room temperature, the reaction was concentrated on a rotary evaporator. The residue was partitioned between methylene chloride and aqueous 1N hydrogen chloride (HCl), shaken, and separated. The organic layer was washed with water, saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on a 20 mm column using one column volume of methylene chloride, one column volume of 5% methanol in methylene chloride, and then one column volume of 10% methanol in methylene chloride, as eluants. Isolation and concentration of the product afforded 155 mg (21.2% yield over two steps from 17β-hydroxy-5α-androstan-3-one) of pure product.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]3)[N:17]=[C:16]([NH:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:15]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.CO.C(OCC)(=O)C.C(O)(=O)C>[OH-].[OH-].[Pd+2]>[F:26][C:22]1([F:25])[CH2:23][CH2:24][N:20]([C:18]2[N:17]=[C:16]([NH:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:15]=[C:14]([CH:12]3[CH2:11][CH2:10][CH2:9][N:8]([CH3:1])[CH2:13]3)[CH:19]=2)[CH2:21]1
Reactant: FC1(F)CCN(c2cc(C3=CN(Cc4ccccc4)CCC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCCC(c2cc(Nc3cc(C(F)(F)F)ccn3)nc(N3CCC(F)(F)C3)c2)C1
Reaction time: 48 h
Yield: 2.2 %

Procedure:
A suspension of 4-(1-benzyl-3,4-dihydro-2H-pyridin-5-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (250 mg, 0.4850 mmol) and palladium hydroxide on activated charcoal (85 mg, 0.25 equiv., 0.1212 mmol) in methanol (20 ml, 500 mmol) and ethyl acetate (20 ml, 204 mmol) was charged with H2 balloon. The reaction was kept stirring for 48 h, while LCMS indicated olefin was reduced. The catalyst was filtered off, and new portion of catalyst was refilled, followed by addition of acetic acid (0.556 mL, 20 equiv., 9.699 mmol). The reaction was stirred with H2 balloon overnight. LCMS showed both m/z 442 and 456. The catalyst was filtered off, and the solvent was evaporated to dryness. The residue was submitted for HPLC purification to yield 4.7 mg (4.4%) off-white powder. LCMS: m/z 442 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:38][CH:37]=2)[CH2:13][CH:12]1[CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC(O)CC1Cc1c[nH]c2ncccc12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OC1CC(Cc2c[nH]c3ncccc23)N(C(=O)OCc2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution containing 72 (1.99 g, 5.66 mmol), p-nitrobenzoic acid (1.23 g, 7.36 mmol), and Ph3P (2.07 g, 7.92 mmol) in THF (35 mL) at 0° C. was added DIAD (1.6 mL, 8.2 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hat which point TLC analysis revealed complete consumption of 72 [EtOAc, Rf(72)=0.2; Rf(73)=0.6]. The solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7 g of crude 73 which was purified by flash silica gel chromatography (20% EtOAc/hexanes) to obtained 2.68 g of 73 (95%) as a white solid 1H NMR (CDCl3, 300 MHz): δ8.3 (d, J=35 Hz, 2H), 7.6 (d, J=35 Hz, 2H), 7.2 (m, 5H), 7.0 (s, 1H), 5.2 (s, 2H), 4.4-3.2 (m, 3H), 3.0-2.9 (m, 1H), 2.2 (s, 2H), 1.9 (s, 2H) ppm.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24](=[O:25])[C:23]2[N:26]3[C:16](=[CH:17][N:18]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH2:15]1)=O)(C)(C)C.[ClH:27]>C(O)C>[ClH:27].[ClH:27].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24](=[O:25])[C:23]2[N:26]3[C:16](=[CH:17][N:18]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCCCCN1Cc2cnc3cccc(n23)C1=O
Agent: Cl
Solvent: CCO
Product: NCCCCCN1Cc2cnc3cccc(n23)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.24 g (6.25 mmol) of 4,5-dihydro-4[5-(tert-butoxycarbonylamino)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylen-5-one in 20 ml of ethanol was added 20 ml of conc. HCl. The mixture was stirred for 1.5 hour at room temperature. The solvent was distilled off to leave 2.05 g of the desired compound (quant. a pale brown solid). This product was used in the subsequent reaction without further purification. NMR(200 MHz,D2O)δ: 1.28-1.90(6H,m), 2.94(2H,t,J=7.2 Hz), 3.60(2H,t,J=7.2 Hz), 5.16(2H,s), 7.75(1H,s), 7.82-7.95(3H,m).