Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH:33]=[CH:34][C:35]=1[CH:36]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[CH:31][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(C=O)c(F)c2)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(-c2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c(F)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-fluoro-4′-methoxy-biphenyl-4-carbaldehyde according to the procedure of Example 66. MS (ESI) m/z 593.
Reaction SMILES: [S:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:10]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=32)[CH2:3][CH2:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[CH:7]=[C:6]2[S:1][CH2:2][CH2:3][N:4]3[C:12](=[O:13])[C:11](=[O:14])[C:10]([CH:9]=1)=[C:5]23
Reactant: O=C1C(=O)N2CCSc3cccc1c32
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1C(=O)N2CCSc3cc(Br)cc1c32
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a solution of 2,3-dihydropyrrolo[1,2,3-de]-1,4-benzothiazine-5,6-dione (2.05 g) in acetic acid (40 ml) was added bromine (0.5 ml) in acetic acid (10 ml) dropwise. The mixture was stirred for 5 hours at room temperature and poured into ice water (200 ml) and the resultant precipitate was collected by filtration, washed with water and dried to yield the title compound (2.10 g, 73.9%). The compound was recrystallized from acetonitrile to give dark red needles, mp 196° C.
Reaction SMILES: C(OC([N:8]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Cl:45])[CH:43]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=2[O:31][Si](C(C)(C)C)(C)C)[C:9]1=[O:46])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:45][C:42]1[CH:43]=[C:44]2[NH:8][C:9](=[O:46])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[OH:31])[C:39]2=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cc(I)ccc1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Racemic (2′R,3R,4′S)-2′-[2-(tert-butyl-dimethylsilanyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)-2,6′-dioxo-spiro[3H-indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (200 mg, 0.25 mmol) was dissolved in 30% TFA/CH2Cl2 (5 mL) and the solution was stirred at rt for 2 h. The solvent was removed and the residue was partioned between water and methylene chloride. The organic layer was separated and dried with sodium sulfate and concentrated. The residue was chromatographed to give a white solid which was directly used for next step. MS (H+), 579.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][NH:27][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN
Reactant: CCCCc1ccc(C#Cc2ccccc2C=O)cc1
Product: CCCCCCNCc1ccccc1C#Cc1ccc(CCCC)cc1
Yield: 11.7 %

Procedure:
The title compound was prepared following procedure described in example 19, step b) from 2-[(4-butylphenyl)ethynyl]benzaldehyde (1.12 g, 4.28 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and n-hexylamine (Aldrich, 294 μl, 5.13 mmol). Purification of the crude product by flash chromatography on silicagel (DCM/MeOH/NH4OH 98/2/1) gave 174 mg (12%) of the title compound. HPLC, Rt: 4.39 min purity: 91.6%). LC/MS, M+(ESI): 348.4. 1HNMR (CDCl3) δ: 0.82 (t, J=6.8 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.23-1.40 (m, 8H), 1.46-1.64 (m, 4H), 2.25 (m, 1H), 2.62 (t, J=7.5 Hz, 4H), 4.00 (s, 2H), 7.15 (d, J=8.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.39 (m, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.50 (dd, J=7.3, 1.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][NH:12][C:11](=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(CCCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: O=S(=O)(O)O
Product: Clc1ccc(C2(CCCOC3CCCCO3)CCNC2)cc1Cl

Procedure:
Prepare according to the method of example 1.3.2 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one (3 mmol), LiA1H4 (18 mmol) H2SO4 (99.999%) (9 mmol). Purify to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]>C(O)(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(OC(=O)C(F)(F)F)C(F)(F)F

Procedure:
Epoxidation of the 21-methoxy compound (7) with hexafluoroacetone trihydrate and 30% hydrogen peroxide produce a 2:1 mixture of 5α,10α- and 5β,10β-epoxides (8) as evidenced by NMR. As attempts to isolate pure 5α,10α-epoxide (8) were unsuccessful, the crude mixture was used directly on to the copper (I) catalyzed Grignard reaction, to obtain the 11β-[4-(N,N-dimethylamino)phenyl] derivative (9). Hydrolysis with trifluoroacetic acid restored the 4,9-diene-3,20-dione structure (10). Acetylation of the 17α-hydroxy compound (10) with the mixed anhydride formed from trifluoroacetic anhydride and acetic acid afforded the desired 19-norprogesterone compound (11).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[NH2:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[NH:20][C:1](=[O:3])[CH3:2])=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: Nc1ccccc1Oc1ccc2[nH]ncc2c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Acetic anhydride (0.04 ml) was added to a solution of the 2-(1H-indazol-5-yloxy)aniline (34 mg, 0.151 mmol) obtained in Example 476 in pyridine (1 ml) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C. and a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in a mixed solution of tetrahydrofuran (1 ml) and methanol (1 ml), followed by adding thereto 1N aqueous sodium hydroxide solution (1 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was added to a saturated aqueous sodium chloride solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (chloroform/methanol) to obtain N-[2-(1H-indazol-5-yloxy)phenyl]acetamide (32 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].Br[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.O.[OH-].[Li+]>CN(C=O)C.C(OCC)(=O)C.O>[C:24]([O:23][C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C

Procedure:
Under argon, 1.25 g (4.73 mmol) of the compound of Example 24A were combined with 1.46 g (6.2 mmol) of tert-butyl (3-bromopropyl)carbamate and 4.62 g (14.2 mmol) of caesium carbonate in 25 ml of DMF and stirred at RT until the reaction had gone to completion. The reaction was then acidified with 4 M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 25 ml of THF and 12 ml of water and, after addition of 596 mg (14.2 mmol) of lithium hydroxide monohydrate, stirred at 40° C. for 4 h. After the reaction had ended, water and ethyl acetate were added and the mixture was adjusted to pH 2 with 1 M hydrochloric acid. The organic phase was separated off, dried over magnesium sulphate, filtered and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC (Method 19). This gave 1.64 g (92% pure, 76% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[I:27]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:27])=[N:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: II
Reactant: COC(=O)c1ncoc1-c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(I)oc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a round bottom flask were added methyl 5-(2-chlorophenyl)-1,3-oxazole-4-carboxylate (2.25 g, 9.5 mmol) and THF (50 mL). The mixture was cooled to −78° C. LiHMDS (1M in hexane, 12.3 mL, 12.3 mmol) was added dropwise. The mixture was allowed to stir at −78° C. for 1 h. Iodine (3.60 g, 14.2 mmol) was added and the mixture was allowed to stir at −78° C. for 20 min. The mixture was allowed to warm to rt and stir overnight. The reaction mixture was poured into 10% sodium thiosulfate (100 mL) and was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated to give methyl 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxylate (3.0 g, 87%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:29][C:30]([O:32]CC)=[O:31])[C:4]([CH3:28])=[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:22])=[O:21])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[N:3]([CH2:29][C:30]([OH:32])=[O:31])[C:4]([CH3:28])=[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:21])=[O:22])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c(C)n1CC(=O)O
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirring solution of ethyl 2-(2,5-dimethyl-3-phenyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (0.029 g, 0.060 mmol) in tetrahydrofuran (1 ml) and water (1 ml) was added 1N sodium hydroxide (0.121 ml, 0.121 mmol). Upon addition, the reaction changed color from pink to yellow. The mixture was stirred overnight, after which LCMS analysis indicated reaction completion. The reaction was quenched with 0.050 ml of 3N HCl and stirred to afford a pink color. The crude mixture was concentrated and taken up in acetonitrile and purified by reverse phase HPLC chromatography. Acetonitrile and water spiked with 0.1% TFA were used as eluents. The desired fractions were collected and quenched with aqueous saturated sodium bicarbonate solution and washed with ether. The aqueous layer was then acidified with 3N HCl to pH=1 and this aqueous layer was extracted 3 times with ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford a purple solid (0.0203 g, 0.045 mmol, 74.3% yield). 1H NMR (CDCl3/400 MHz)ppm) 7.91 (d, 1H), 7.37-7.33 (m, 1H), 7.23-7.17 (m, 1H), 7.15-7.11 (m, 3H), 7.08-7.05 (m, 1H), 6.99-6.97 (m, 2H), 4.63 (s, 2H), 4.07 (s, 2H), 3.08-3.04 (m, 4H), 2.14 (s, 3H), 1.98 (s, 3H), 1.61-1.58 (m, 4H). LCMS (M+1): 453.3.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7]>CO>[CH3:4][C:5]([CH3:9])([CH3:8])[CH2:6][NH:7][CH2:2][CH2:1][OH:3]
Reactant: CC(C)(C)CN
Reactant: C1CO1
Solvent: CO
Product: CC(C)(C)CNCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 975.5 %

Procedure:
Ethylene oxide (2.5 ml, 5.0 mmol) cooled to −20° C. was slowly added to a solution of (2,2-dimethylpropyl)amine (13 g, 150 mmol) in methanol (15 ml) at −30° C. under argon. The mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated, and the residue purified by distillation (b.p. 132° C. @ 9 mmHg) to yield 2-((2,2-dimethylpropyl)amino)ethanol (6.4 g, 97% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[C-]#N.[CH2:16]([NH:20][CH3:21])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([N:20]([CH3:21])[C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)=[O:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Reactant: CNCC(C)C
Agent: [C-]#N
Product: CC(C)CN(C)C(=O)NC(C)(C)c1ccc(Cl)cc1
Yield: 92.2 %

Procedure:
3.9 g of p-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to 1.9 g of N-i-butyl-N-methylamine. The precipitated crystals were separated by filtration and recrystallized from n-hexane to obtain 5.2 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>C(O)C>[CH2:30]([N:32]([CH2:33][CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1)[CH3:31]
Reactant: O=C(c1ccc(OCCCCBr)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
3-[4-(4-Bromobutoxy)benzoyl]-2-phenylbenzofuran (13.0 g., 0.029 mol.) is dissolved in 75 ml. of ethanol containing 8 ml. of diethylamine and refluxed for 24 hours. The solvent is removed under reduced pressure and the residue is dissolved in ether. The ethereal solution is extracted with 5% aqueous sodium hydroxide, water and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:19]=3)=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C=O)C>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([C:17]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([CH:4]=3)[CH2:2][N:37]3[C:33](=[O:43])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:38])[N:14]=[C:15]([C:29]([F:31])([F:32])[F:30])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 70 %

Procedure:
A mixture of 1-[3-chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole from step1 of Example 160 (280 mg, 0.58 mmol) and potassium phthalimide (10 mg, 0.054 mmol) in DMF was heated at 90 ° C. for 1 hour. After cooled to room temperature, the mixture was poured into water (30 mL), and extracted with ether (30 mL×2), washed with water (30 mL) and brine (30 mL), dried over MgSO4, and concentarted in vacuo to give the title compound (240 mg, 70%).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5](=[O:23])[CH2:6][C@:7](O)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+]>[OH:23][C:5]1[CH2:6][C@@:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:24][C:3](=[O:2])[CH:4]=1
Reactant: COC(=O)CC(=O)C[C@@](O)(CCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=C(O)C[C@@](CCc2ccccc2)(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in General Method 7 using 0.46 g (1.41 mmol) of (S)-5-hydroxy-3-oxo-5,7-diphenyl-heptanoic acid methyl ester from Example CC and 0.1N NaOH (450 mL). The reaction was stirred for 2 hours at room temperature then extracted with Et2O. The aqueous layer was decanted and acidified with 1N HCL, extracted with EtOAc, dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CH2Cl2 (2:98) gave the title compound. 1H NMR (CDCl3) δ 2.25 (m, 2 H), 2.45 (m, 1 H), 2.70 (m, 1 H), 2.92 (dd, 2 H), 3.30 (dd, 2 H), 7.04-7.41 (m, 10 H).
Reaction SMILES: S(Cl)(Cl)=O.N.[N:6]([CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[NH2:6][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=NCCc1ccc(C(N)=O)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: NCCc1ccc(C(N)=O)cc1

Procedure:
For the preparation of the starting material of Example 10a, p-(2-bromoethyl)-acetophenone was reacted with sodium azide in dimethylsulfoxide to give p-(2-azidoethyl)acetophenone. Oxidation with sodium hypobromite gave p-(2-azidoethyl)benzoic acid (m.p. 130°-131°, from acetone-hexane), which was converted with thionyl chloride into the corresponding acid chloride and subsequently with ammonia into p-(2-azidoethyl)benzamide. Treatment with triphenylphosphine and hydrolysis gave p-(2-aminoethyl)benzamide, m.p. 132°-133° (from ethanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].CC(C)=[O:23].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:18]([O:17][C:15]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH2:4][CH2:3][C:2]([OH:23])=[O:1])=[O:16])[CH:19]=[CH2:20]
Reactant: CC(C)=O
Reactant: C=CCOC(=O)c1c(CCCO)ccc2ccccc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1c(CCC(=O)O)ccc2ccccc12
Yield: 86 %

Procedure:
A solution of Example 11B (1.4 g, 5.18 mmol) in acetone (20 mL) was treated with Jones reagent (CrO3/H2SO4) until the orange color persisted, quenched with isopropyl alcohol, partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4), filtered, concentrated, and purified on silica gel with a gradient of 30% ethyl acetate/hexanes to 10% MeOH/dichloromethane to provide 1.27 g (86%) of the desired compound as an yellow oil.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].[ClH:21]>CO.O1CCOCC1.CCOCC.O>[ClH:21].[CH2:11]([NH:18][C@H:7]1[CH2:8][CH2:9][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C1CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)[C@H]1CC[C@@H](NCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To a solution of 4-isopropylcyclohexanone (5.0 g, 36 mmol) and benzylamine (3.54 mL, 32 mmol) in MeOH (40 mL) was added 4 Å molecular sieves (2 g). After 16 h at rt NaBH4 (2.45 g, 65 mmol) was added and the mixture stirred for a further 6 h. Water (3 mL) was added and the solvent was removed in vacuo. The residue was partitioned between NaHCO3 (150 mL) and EtOAc (150 mL), the aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (2×50 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, NH4OH:MeOH:DCM 0.25:5:95) to give the product as a free base. 4M HCl in dioxane and Et2O were added to the residue, and the resulting precipitate was filtered to give the title compound: δH (CD3OD) 0.92-0.97 (6H, m), 1.17-1.26 (1H, m), 1.53-1.92 (9H, m), 3.21-3.29 (1H, m), 4.23 (2H, s) 7.44-7.54 (5H, m).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20](/[C:23](=[CH:29]\[CH:30]=[CH:31]\[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][CH:33]=1)/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+]=[N-]>C(OCC)C>[CH2:27]([O:26][C:24]([C:23](=[CH:29][CH:30]=[CH:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=1)[N:20]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)/C(=C/C=C/c1ccc(CC)cc1)N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)C(=CC=Cc1ccc(CC)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure J. A solution of triphenylphosphine (1.2 g, 4.54 mmol) in diethyl ether (10 ml) was added dropwise to a solution of ethyl (2Z,4E)-2-azido-5-(4-ethylphenyl)penta-2,4-dienoate (Compound 44, 1.2 g, 4.54 mmol) in diethyl ether (20 ml) at 0° C. The solution was stirred for 12 hours at room temperature. Evaporation of solvent afforded a crude yellow solid, which was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to give the title compound.