Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:9][C:10]([O:12]C)=O)=[N:6][CH:7]=1.[NH3:32]>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][S@@:15]([C:17]([CH3:18])([CH3:19])[CH3:20])=[O:16])[CH2:9][C:10]([NH2:32])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)C[C@](N[S@](=O)C(C)(C)C)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: N
Solvent: OCCO
Product: CC(C)(C)[S@@](=O)N[C@@](CC(N)=O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 180 °C

Procedure:
(S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-((R)-2-methylpropan-2-ylsulfinamido)propanoate (0.10 g, 0.20 mmol) was dissolved in 8N NH3 solution in ethylene glycol (1 mL) in a microwave vial. The reaction mixture was heated to 180° C. for 300 sec, the pressure was cautiously vented and the reaction mixture purified directly by prep HPLC (YMC ODSA30×100 mm, 0-100% over 10 min, MeOH/H2O/0.1% TFA). (S)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-((R)-2-methylpropan-2-ylsulfinamido)propanamide was isolated as a white solid (0.041 g, 41% yield) LCMS: 1.85 min [M+1] 466.1 (2 min gradient, MeOH/H2O 0.1% TFA). Starting material was also recovered (0.055 g, 55% recovered yield).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([S:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[N:11]=1)[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH3:29][C:4]([S:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[N:11]=1)([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)Sc1nc(CCOc2ccc(C#Cc3ccccc3)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Sc1nc(CCOc2ccc(C#Cc3ccccc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
2-Methyl-2-[(4-{2-[4-(phenylethynyl)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid methyl ester (400 mg) obtained in Example 144-3 was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL), aqueous sodium hydroxide solution (1 mol/L, 2 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (290 mg) as a slightly yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(C(C)C)CC)(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:33]1([S:39]([N:21]2[CH2:22][CH2:23][CH:18]([C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]3[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:19][CH2:20]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ncccc1-c1[nH]c2ccccc2c1C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1[nH]c2ccccc2c1C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 2-(2-methoxy-pyridin-3-yl)-3-piperidin-4-yl-1H-indole (0.12 g, 0.39 mmol) in dichloromethane (10 ml) and diisopropylethylamine (0.20 ml, 1.17 mmol) was added phenylsulfonyl chloride (52 μl, 0.41 mmol). The reaction was stirred at room temperature for 4 h and quenched by adding water. The organic layer was separated, washed with aqueous sodium hydroxide, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by a flash chromatography (SiO2, 30% EtOAc in hexane) to give the desired product as a white solid (0.042 g, 24%); M.p.=231-234° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.00 (s, 1H), 8.20 (dd, J1=0.8 Hz, J2=4.8 Hz, 1H), 7.77 (m, 3H), 7.66 (m, 3H), 7.29 (m, 2H), 7.07 (m, 2H), 6.92 (m, 1H), 3.84 (m, 5H), 2.56 (m, 1H), 2.42 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H); LCMS: 448.69 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.CC(C)N=C=NC(C)C.O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:12][C:7]2[CH:6]=[C:5]([C:4]([OH:3])=[O:13])[CH:10]=[CH:9][C:8]=2[N:11]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 3,4-diamino-benzoic acid ethyl ester (5.0 g, 27.8 mmol) and 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h. DIC (4.40 mL, 28.2 mmol) was added and the mixture stirred overnight. After 30 min stirring at 80° C. water was added and the mixture was concentrated i.vac. The residue was taken up in ethanol and 1 M aq. NaOH. The mixture stirred overnight at reflux. Ethanol was evaporated and the aq. phase diluted with water. The precipitate was filtered and washed with water. The filtrate was acidified with formic acid and cooled. The mixture was filtered and washed with water.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.[CH2:32](OC[C@H]1[C@@H](C=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)C>>[CH2:1]([O:2][CH2:3][C@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH3:32]
Reactant: CCOC[C@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 92 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 13b as the starting material afforded the title compound (44 mg, 92% yield) as a white solid:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[CH2:26]([N:33]1[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][C:34]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:39]([C:36]1[CH:37]=[CH:38][N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:34](=[O:42])[CH:35]=1)=[O:40])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccn(Cc3ccccc3)c(=O)c2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
3-{[(1-Benzyl-2-oxo-1,2-dihydro-pyridine-4-carbonyl)-amino]-methyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 1-benzyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C32H28ClN4O4 [(M+H)+] 567.2, obsd. 567.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:4]2[N:3]=1.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=2)[N:5]2[N:16]=[C:17]([CH3:19])[C:18]([I:20])=[C:4]2[N:3]=1
Reactant: Cc1cc2nc(Cl)cc(-c3cc(F)cc(F)c3)n2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(Cl)nc2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
5-Chloro-7-(3,5-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (327 mg) is dissolved in CH2Cl2 (50 mL). N-Iodosuccinimide (NIS, 304 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for about 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (301 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.[CH2:22]([N:25]1[CH2:30][C@@H:29]([CH3:31])[NH:28][CH2:27][C@@H:26]1[CH3:32])[CH:23]=[CH2:24].C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C@@H:1]([N:28]2[CH2:27][C@@H:26]([CH3:32])[N:25]([CH2:22][CH:23]=[CH2:24])[CH2:30][C@@H:29]2[CH3:31])[N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[N:14]2)[CH:4]=1
Reactant: C=CCN1C[C@@H](C)NC[C@@H]1C
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCN1C[C@H](C)N([C@H](c2cccc(C(=O)OC)c2)n2nnc3ccccc32)C[C@H]1C
Yield: 109.6 %

Procedure:
Methyl 3-formylbenzoate (10 g, 60.91 mmol, 1 eq), benzotriazole (7.25 g, 60.91 mmol, 1 eq) and (2S,5R)-1-allyl-2,5-dimethylpiperazine (Chirotech Division of Dow Pharmaceutical Services, Cambridge, UK, 9.39 g, 60.91 mmol, 1 eq) were placed in a flask with dry toluene (300 mL) and triethylamine (1 mL). The flask was fitted with a Dean-Stark trap and condenser and heated to a gentle reflux in an oil bath (temperature ≦135° C.) for several hours with azeotropic removal of water. Most of the toluene was removed under reduced pressure to give 28 g of crude 3-[(S)-((2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl)benzotriazol-1-yl-methyl]benzoic acid methyl ester as a dark amber viscous liquid.
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([O:14][CH3:15])[CH:6]=1.Cl>CN(C=O)C>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: C[S-]
Reactant: COc1cc(F)ccc1C(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.5 %

Procedure:
Sodium thiomethoxide (1.3 g, 18.5 mmol) in DMF (15 ml) was added to 1-(4-fluoro-2-methoxyphenyl)ethanone (2.85 g, 16.9 mmol) in DMF (5 ml). The mixture was stirred for overnight at room temperature. HCl (1%) was added, the water phase was extracted with EtOAc, the combined organic phases were washed with LiCl (5%), brine and were concentrated to give the title compound (3.6 g) MS m/z (rel. intensity, 70 eV) 196 (M+, 35), 182 (11), 181 (bp), 166 (8), 136 (10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]([OH:37])[C:27]2([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[Cl:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH:26]([OH:37])[C:27]2([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:29][CH2:28]2)=[CH:20][C:19]=1[NH:18][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(N)c2)CC1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(C(O)C2(C(=O)OC(C)(C)C)CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 2.65 g (9.92 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 1.97 g (6.62 mmol) of tert-butyl 1-[(3-amino-4-chlorophenyl)(hydroxy)methyl]cyclopropane-carboxylate and 3.27 g (8.60 mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) in 5 ml of pyridine and 10 ml of DMF was stirred at room temperature for three days. 100 ml of ethyl acetate were then added to the mixture, and the solution obtained was washed with 1 M hydrochloric acid and saturated sodium chloride solution. The solution was dried over magnesium sulphate and then filtered, and the filtrate was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→40:1→30:1). The product obtained in this manner was taken up in 100 ml of ethyl acetate, and the solution was extracted three times with saturated sodium bicarbonate solution. The organic phase was washed once more with saturated sodium chloride solution, then dried over magnesium sulphate and finally concentrated to dryness under reduced pressure. This gave 2.75 g of the target compound (76% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:21]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)c1ccccc1N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1NC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A solution of ethyl 2-aminobenzoate (3.0 g, 18 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (3.68 g, 1.6 mL, 18 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 3.32 g (65%) of the title compound as a white solid, mp 65°-66° C.: 1H NMR (DMSO-d6) δ11.08 (s, 1H), 8.25 (dd, J=7.6, J=0.8, 1H), 7.95 (dd, J=8.0, J=1.2, 1H), 7.63 (t, J=8.4, 1H), 7.25 (dt, J=7.6, J=1.2, 1H), 4.33 (q, J=7.2, 2H), 4.23 (s, 2H), 1.33 (t, J=7.2, 3H); 13C NMR (DMSO-d6) δ166.82, 165.02, 138.86, 133.95, 130.62, 123.93, 121.11, 118.23, 61.30, 30.40, 13.99; MS (EI, m/z) 287 (M+).
Reaction SMILES: [C:1]1([N: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.CN(C)[CH:22]=[O:23]>>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][C:4]([CH:22]=[O:23])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C

Procedure:
46 g of phosphoryl trichloride (POCl3) was added dropwise to 22 g of N,N-dimethylformamide while stirring on a ice bath, and the stirring was continued for about 1 hour to produce a sirupy Vilsmeier reagent. To this reagent, a solution containing 50 g of N,N,N-triphenylamine in 200 ml of N,N-dimethylformamide was added while maintaining on the ice bath. After continued the stirring for about 1 hour, the temperature of the bath was raised to about 90° C., and the mixture was stirred for 2 additional hours. After the reaction, the mixture was cooled to room temperature and poured into ice. The resulted aqueous solution was neutralized with alkali to form a yellow precipitate. After it was separated by filtration and dried, it was recrystallized with ethyl alcohol to obtain 43 g of p-(N,N-diphenylamino)benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:29](OC4C=CC([N+]([O-])=O)=CC=4)=[O:30])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:41]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)[CH2:16][N:15]([C:29]([N:41]4[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]4)=[O:30])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Reactant: OC1CCNC1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.18 mmol) of the compound from Example 187A and 47 mg (0.54 mmol) of 3-pyrrolidinol were reacted according to the General Method 6. Yield: 25 mg (26% of theory)
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl.[CH3:17][NH:18][O:19][CH3:20].O>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7]
Reactant: CNOC
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
Cyclopentane carbonyl chloride (65 g, 0.49 mol) was added dropwise into a mixture of Et3N (180 mL, 1.3 mol) and N,O-dimethyl hydroxylamine hydrochloride (50 g, 0.52 mol) in anhydrous CH2Cl2 at 0° C. After the addition, the reaction mixture was allowed to stir at ambient temperature overnight. To the reaction mixture was added about 100 g of crushed ice followed 100 g of water. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (100 mL×2). The combined organic layers were washed with 1N HCl, water, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford 61 g of desired product as oil in 78.8% of yield.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:13][CH:12]=2)[C:3]([OH:26])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.8 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid methyl ester (753 mg, 2.0 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (1.02 g, 24.3 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid (727 mg, quant.) as an amber foam: EI-HRMS m/e calcd for C22H28O3 (M+) 340.2038, found 340.2037.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:19][OH:20])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C=NO)cc1
Yield: 90 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (which may be prepared as described in Preparation of Intermediate 16; 15.21 g, 61.5 mmol) in toluene (100 mL) at 0° C. under argon was added dropwise di-isobutylaluminum hydride (1.0 M in toluene, 15 mL, 15 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, after which it was cooled to 0° C. and charged with 100 mL of saturated aqueous Rochelle salt solution. The mixture was allowed to stir for 14 hours after which the mixture was extracted three times with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde which was used without further purification. To a solution of the aldehyde in ethanol was added hydroxylamine hydrochloride (4.66 g, 67 mmol) and pyridine (5.4 mL, 67 mmol). The reaction mixture was stirred until no starting material was observed by TLC and then all volatiles were removed under reduced pressure. The resulting product was suspended in water and the aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde oxime (14.60 g, 90%) as a white solid. LRMS (ESI+): m/z [M+H]+ 266.1; 1H NMR (300 MHz, CDCl3) δ ppm 11.12 (s, 1H), 8.05 (s, 1H), 7.50 (d, 2H), 7.24 (d, 1H), 4.64 (s, 2H), 0.82 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[ClH:22].[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH:10]=1)=[O:26]
Reactant: CN1CCC(Oc2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCC(Oc2cccc(NC(=O)c3ccccc3Cl)c2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Combine 3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 28, 185 mg, 0.90 mmol) in dichloromethane (9 mL), add pyridine (0.145 mL, 1.79 mmol) and stir at 0° C. for 5 min. Add 2-chloro-benzoyl chloride (0.142 mL, 1.12 mmol) and allow to warm to ambient temperature and stir. After 18 hr., dilute with dichloromethane (10 mL) and wash with sodium hydroxide (1N, 3×10 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purify by flash chromatography, eluting with dichloromethane/ammonia (2.0 N in methanol) [20/1] to give the title compound as free base (112 mg, 36%). Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride (1.0 M). Triturate the resulting gum with ether to give the title compound as a white solid (115 mg). Mass spectrum (ion spray): m/z=345.1 (M+1); 1H NMR (free base, CDCl3): 7.88 (bs, N—H), 7.76 (dd, J=1.5 Hz, 7.3 Hz, 1H), 7.52 (bs, 1H), 7.47-7.36 (m, 3H), 7.28-7.24 (m, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.72 (dd, J=8.2 Hz, 2.4 Hz, 1H), 4.48 (bs, 1H), 2.88-2.80 (bm, 2H), 2.66-2.56 (bm, 2H), 2.45 (s, 3H), 2.22-2.13 (bm, 2H), 2.01-1.92 (bm, 2H).