Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=1.C(N(CC)CC)C>C1COCC1>[F:12][C:9]([F:10])([F:11])[CH:8]([OH:13])[CH:2]([NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([F:14])=[CH:16][C:17]=1[C:24]([F:27])([F:25])[F:26])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)C(O)C(F)(F)F
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.7 g (8.5 mmol) of ethyl 2-amino-4,4,4-trifluoro-3-hydroxybutyrate were dissolved in THF, and initially 1.8 g of 4-fluoro-2-trifluoromethylbenzoic acid and 2.6 g (25.4 mmol) of triethylamine and then, at 5° C., 1.9 g (8.5 mmol) of bis(2-oxo-3-oxazolinidylphosphoryl chloride were added. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated, and the residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed. This gave 3.1 g (93% of theory) of the title compound as a colorless residue.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:67])[C:55]4[C:59]([CH:60]=3)=[N:58][N:57](C3CCCCO3)[CH:56]=4)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:67][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccccc1
Reaction time: 0.08 h

Procedure:
Benzoic acid (10 mg, 0.08 mmol) in DMF (0.2 mL) was treated with HATU (27 mg, 0.07 mmol) in DMF (0.2 mL) and DIPEA (30 μL, 0.24 mmol). The reaction mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.2 mL). Reaction mixture was shaken for five minutes and left to stand at 22° C. for 18 hrs. Solvent was removed in vacuo and the product re-dissolved in methanol (1 mL) prior to application on to an SCX cartridge (1 g). Product was eluted after 1 hr with 2M ammonia in methanol (2×3 mL), fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method D) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:32])[C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].N1CCCCC1.C([OH:41])C>CCOCC>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([C:19](=[O:41])[CH2:18][C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:2]([Cl:1])[CH:3]=2)=[O:32])=[CH:25][CH:24]=1
Reactant: CCO
Reactant: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2)cc1Cl
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc(NC(=O)CC(=O)c2ccc(-c3ccccc3)cc2)cc1Cl
Reaction time: 8 h

Procedure:
0.16 g (0.36 mmol) of 3-biphenyl-4-ylpropynoic acid-[3-chloro-4-(2-diethylaminoethoxy)phenyl]amide (educt XII.1) is dissolved in 10 mL of aqueous ethanol and 0.10 mL (1.0 mmol) of piperidine is added. The mixture is stirred for 8 hours at reflux temperature. After cooling, the solvent is eliminated, and the residue is suspended in ether and filtered off. The residue is dried in vacuo at 50° C. Yield: 75 mg (45% of theory); Rf value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01); m.p. 148° C.-151° C.; C27H29ClN2O3; EII mass spectrum: m/z=465/467 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
1 g of 2-Fluoro-5-Nitro benzotrifluoride (4.78 m.moles) was dissolved in 3 ml of DMF. To this solution was added 640 mg (5 m.moles) of 2-chloro-phenol and 2.76 grams of potassium carbonate. The reaction mixture was heated for 4 hours at 100° C. The reaction was cooled to room temperature and 200 ml of water added. It was then extracted 4 times with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent evaporated to yield a pale yellow oil. It was purified using silica-gel column chromatography (1:3 ethyl acetate hexane) to yield 1.15 g (87.5% yield) of pure 1-Chloro-2-[4-Nitro-2-(Trifluoromethyl)phenoxy]benzene as product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH2:15][CH2:14]1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: OCC1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2cc(OCC3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a suspension of 6-hydroxy-1-tetralone (2.0 g, 12.4 mmol), tetrahydropyran-4-methanol (1.7 g, 14.8 mmol) and triphenylphosphine (6.5 g, 24.7 mmol) in THF (40 mL) was added DEAD (4.3 g, 24.7 mmol) at 0° C. The reaction was stirred at rt overnight. The solution was concentrated and purified by silica gel chromatography (PE:EtOAc=12:1) to give 3.2 g (100%) of the title compound as a yellow oil. [M+H] Calc'd for C16H20O3, 261. Found, 261.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=1)=O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH2:24][C:26]2[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=2)=[CH:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1ccc(C=O)cc1
Reactant: Clc1ccc2ccn(C(c3ccccc3)c3ccccc3)c2c1
Product: O=C(O)COc1ccc(Cc2cn(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc1

Procedure:
This compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and methyl 2-(4-formylphenoxy)acetate according to the procedure in Example 117 Step 1.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1cccc([C@@H]2COc3cc(OC)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1

Procedure:
Thus (±)-cis-7-methoxy-3-(3-methoxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane was de-methylated by heating with pyridine hydrochloride to give the racemic mixture, (±)-cis-7-hydroxy-3-(3-hydroxyphenyl)-4-(4-(2-pyrrolidinoethoxy)-phenyl)chromane. The title compound was then separated from this racemic mixture by means of preparative chiral HPLC {Chiradex 5 μm, 250×25 mm column; flow=20 ml/min; 40% methanol, 60% buffer (0.2% aqueous triethylammonium acetate, pH 3.5) eluent, 220 nm UV detection}. The title compound was the more rapidly eluted enantiomer, Rt=22-34 min.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2F)CCCC1=O
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
40% Methanolic Triton B (2.82 mL, 6.2 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (1.27 g, 5.22 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-fluorobenzyl bromide (1.19 g, 6.2 mM) was added and the resultant mixture stirred at room temperature for 17 days. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.00 g (55%) of the 9-[(2-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.4-7.2 (m, 4H), 7.1 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 5.65 (s, 2H), 3.8 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.45 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1652, 1464, 1441, 1288 and 1120. MS (ES) m/e 350, 352.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:4][CH:3]=1.[Cl-].ClC=[N+:19](C)C.[OH-].[NH4+]>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH2:19])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C[N+](C)=CCl
Reactant: O=C(O)c1csc(-c2ccc(O)cc2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1csc(-c2ccc(O)cc2)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
2-(4-Hydroxyphenyl)-1,3-thiazole-4-carboxylic acid (0.835 g, 3.77 mmol) was dissolved in 20 ml of dry tetrahydrofuran and cooled to 0° C. (Chloromethylene)dimethylammonium chloride (0.58 g, 4.53 mmol) was added in one portion. The mixture was stirred at 0° C. for 5 h. 28% Ammonium hydroxide aqueous solution (5 ml) was added, and the reaction mixture was stirred for 15 h at the room temperature. The organic solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated sodium carbonate solution. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give the title compound as beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:18](OC)=[O:19])=[N:16][CH:17]=3)=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:8](=O)[C:7]=2[CH:31]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH2:18][OH:19])=[N:16][CH:17]=3)=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:8][C:7]=2[CH:31]=1
Reactant: COC(=O)c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(CO)nc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate (0.314 g, 0.718 mmol) in THF (5.98 mL) at 0° C. was added LAH (1.0 M in THF, 2.153 mL, 2.15 mmol) dropwise and the reaction was stirred at 0° C. for 1 h. Upon completion the reaction was quenched with water and sat. aq. potassium sodium tartrate and the resulting mixture was stirred for 30 min and then extracted with EtOAc (3×). The organic layers were combined, passed through a phase separator and concentrated in vacuo to afford crude (5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)methanol which was used without further purification. LC/MS (m/z, MH+): 394.2.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Oc1ccc(F)cc1
Product: Nc1nnc(Oc2ccc(F)cc2)c(-c2ccccc2)n1
Yield: 7.8 %

Procedure:
6-(4-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 4-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[IH:21]>O>[I:21][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: I
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(I)ncnc32)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
[5 g. 16.2 mmol] of 4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine was added in small portions, to 100 mL of cold stirring 47% stabilized hydriodic acid at 0° C. and stirred for one hour cold; the temperature was then allowed to warm to ambient temperature and stirred an additional 5 hrs. The reaction mixture was diluted with water and the solid was isolated via suction filtration, the solid being washed with additional water. The crude solid was dissolved in dichloromethane and washed twice with saturated sodium hydrogen carbonate solution, brined, dried (Na2SO4) and the solvent was removed under reduced pressure and triturated with a 2:1 mixture of hexanes/MTBE to yield 5.7 g of a white material (88%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:18])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: Cc1ccc2ccc(=O)n(CC3OCCO3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.37 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methylquinolin-2(1H)-one, 3.7 mL of a 90% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The residue thus obtained was added with ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and an extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.32 g of a brown oily substance, (7-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:57][CH3:58])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([O:49][Si](C)(C)C)[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:59])=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([OH:49])[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:57][CH3:58])=[CH:31][C:30]=2[CH3:59])=[CH:27][CH:28]=1
Reactant: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.166 mL, 0.166 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 125-(4); 19.3 mg, 0.033 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (11.6 mg, 69%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=3)[N:25]([CH3:36])[N:24]=2)[CH2:16]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:15]1[CH2:16][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=3)[N:25]([CH3:36])[N:24]=2)[CH2:18]1
Reactant: Cn1nc(NCC(=O)NC2CN(C(=O)OC(C)(C)C)C2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as colorless oil from TFA treatment of 3-[2-(1-Methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester using the procedure described in Step D of Example 1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9](=[CH2:29])[CH2:10][C:11]1([C:24]([O:26]CC)=[O:25])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1>ClCCl>[CH3:8][C:9]1([CH3:29])[CH2:10][C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:24](=[O:26])[O:25]1
Reactant: C=C(C)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC2(CCNCC2)C(=O)O1
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Trifluoroacetic acid (50 mL) was added to a solution of 1-(1,1-dimethylethyl) 4-ethyl 4-(2-methyl-2-propenyl)-1,4-piperidinedicarboxylate (Description 89, 10.86 g, 35 mmol) in dichloromethane (10 mL) and the mixture was stirred at 50 C for 8 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Ether (50 mL) was added and the mixture was extracted with hydrochloric acid (1M, 3×50 mL). The combined aqueous fractions were washed with ether (2×50 mL), adjusted to pH 12 with aqueous sodium hydroxide (4M) and the mixture was extracted with ethyl acetate (6×50 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (50 mL), cooled in ice and and ethereal hydrogen chloride (1M, 35 mL) was added slowly. The solvent was evaporated under reduced pressure, ethanol (75 mL) was added and the mixture was heated under reflux for 15 minutes. The mixture was cooled and the solid was collected and dried in vacuo to give the title compound as a colorless solid (5.59 g, 73%), m.p.>280° C. m/z (ES+) 184 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([OH:12])([CH3:11])[CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:6]2[CH2:7][C:8]3([CH3:11])[CH2:9][CH2:10][CH:5]2[C:3](=[O:2])[O:12]3)(=[O:14])=[O:15])=[CH:17][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CCC(C)(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC12CCC(C(=O)O1)N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Temperature: 90 °C
Yield: 82.1 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-5-methyl-piperidine-2-carboxylic acid methyl ester (0.047 g, 0.11 mmol), p-toluenesulfonic acid (0.010 g, 0.05 mmol) and toluene (2.0 mL) was heated to 90° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo, giving 0.035 g of 5-(4-Benzyloxy-benzenesulfonyl)-1-methyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one as a colorless oil:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:26][CH:25]=2)(O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:28][CH:29]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(Cc1ccccc1)(c1ccc(OCCCCCl)cc1)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: ClCCCCOc1ccc(C(=Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethanol (1.0 g, 21.0 mmol) and methanol (2 mL). Add aqueous 2M hydrochloric acid solution (4 mL). Heat to reflux. After 2 hours, concentrate at 65° C. to remove most of the methanol. Cool to ambient temperature and extract with dichloromethane. Dry the organic layer over MgSO4, filter, and dry in vacuo to give 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethylene: Rf =0.50 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: O[Li].O.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]2[CH2:19][C@H:20]([CH2:30][C:31]([O:33]C)=[O:32])[C:21](=[O:29])[N:22]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:23][C:17]=2[CH:16]=1>C1COCC1.O>[O:29]=[C:21]1[C@@H:20]([CH2:30][C:31]([OH:33])=[O:32])[CH2:19][C:18]2[CH:35]=[CH:36][C:15]([O:14][CH2:13][CH2:12][CH2:11][NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=3)=[CH:16][C:17]=2[CH2:23][N:22]1[CH2:24][C:25]([F:28])([F:26])[F:27]
Reactant: COC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Reaction time: 18 h
Yield: 61.5 %

Procedure:
LiOH.H2O (25 mg, 0.6 mmole) was added to a solution of methyl (R)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.25 g, 0.54 mmole) in THF (5 mL) and H2O (2 mL) at RT. After 18 hr, the reaction was concentrated to dryness and the residue was dissolved in H2O (4 mL). The solution was carefully brought to pH≈4 with 3.0 N HCl. The precipitate was collected and dried in high vacuum at 40-45° C. to afford the title compound (0.15 g, 62%) as an off-white solid: MS (ES) m/e 452.1 (M+H)+. Anal. Calcd for C22H24F3N3O4. 0.5 H2O: C, 57.38; H, 5.47; N, 9.12. Found: C, 57.72; H, 5.24; N, 8.92.