Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([C:24]2[C:29]([O:30][CH3:31])=[N:28][C:27]([P:32]([CH3:35])([CH3:34])=[O:33])=[CH:26][N:25]=2)[N:15]=1>>[CH3:35][P:32]([C:27]1[N:28]=[C:29]([O:30][CH3:31])[C:24]([C:16]2[N:17]=[C:18]([NH:1][CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:14][N:15]=2)=[N:25][CH:26]=1)([CH3:34])=[O:33]
Reactant: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(Cl)n1
Reactant: NCCc1c[nH]c2ccccc12
Product: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(NCCc2c[nH]c3ccccc23)n1

Procedure:
This compound can be prepared by reacting tryptamine with 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine as described in Example 36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH2:30][C@H:31]([CH2:33][OH:34])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:30][C@@H:31]([CH3:32])[CH2:33][OH:34])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: C[C@@H](CO)NC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and L-alaninol gave 178. MS: (ESI+) 471.1
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21])[N:12]=[CH:11]2.Br[CH2:27][CH:28]([CH3:30])[CH3:29]>CN1C(=O)CCC1>[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([O:22][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:21])[N:12]=[CH:11]2
Reactant: CC(C)CBr
Reactant: O=C(O)c1cccc(-n2ncc3cc(I)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(I)ccc32)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A 50 mL.s flask was charged with sodium carbonate (0.700 g, 6.60 mmol), 3-(5-iodo-1H-indazol-1-yl)benzoic acid (I1a) (2.185 g, 6 mmol) and NMP (15 mL) at 40° C. with magnetic stirring. After a couple of minutes 1-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added in one portion. After one hour at 40° C., the temperature was raised to 55° C. and another portion of 1-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added. The stirring was continued overnight. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a syrup (2.5 g, 99%). The product solidified to a beige material upon standing.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C([NH:50][CH2:51][C:52]([OH:54])=[O:53])(C)(C)C>C(O)(C)C>[Cl:23][C:19]1[C:18]([F:24])=[C:17]([C@@H:16]2[C@:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13][C@H:12]2[C:10]([NH:9][C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C:2]([CH3:1])([CH3:40])[O:41][CH2:42][C@@H:43]([OH:44])[CH2:45][NH:50][CH2:51][C:52]([OH:54])=[O:53])[N:5]=2)=[O:11])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)NCC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC(C)(C)OC[C@@H](O)CNCC(=O)O)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (85.8 mg, 0.133 mmol), isopropyl alcohol (2 mL), and t-butyl glycine (35 mg, 0.266 mmol) was microwaved at 130° C. for 15 min. The solvent evaporated under reduced pressure. The resulting oil was dissolved in dichloromethane (2 mL) and cooled to 0° C.; then TFA (1 mL) was slowly added and stirred for 4 h. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-{(S)-3-[2-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-2-hydroxy-propylamino}-acetic acid (18.1 mg, 19%) as an off-white powder. HRMS (ES+) m/z Calcd for C35H42Cl2F2N6O5S+H [(M+H)+]: 735.2635. found: 735.2631
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 44.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (1.4 g, 9.72 mmol), 4-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 448) (2.97 g, 12.6 mmol), pyridine (7 ml) DMAP (cat.) and DCM (30 ml) gave the title compound (1.5 g, 45%), after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[C:8]2[C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:42]1([CH3:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:46]1[C:47]2[NH:7][C:1]3[C:48](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:42]=2[CH:43]=[C:44]([C:24]2[CH:23]=[CH:22][C:21]([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]4[S:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:26][CH:25]=2)[CH:45]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3cccc4c3sc3ccccc34)cc2)OC1(C)C
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: c1ccc(N(c2ccc(-c3ccc4[nH]c5ccccc5c4c3)cc2)c2cccc3c2sc2ccccc23)cc1
Yield: 91 %

Procedure:
To a solution of N-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dibenzo[b,d]thiophen-4-amine (5.9 g, 12.4 mmol), 3-bromocabazole (3.5 g, 14.2 mmol), K2CO3 (16.6 g, 120.0 mmol) in toluene (150 mL), water (50 mL) and EtOH (50 mL) was bubbled for 30 min. Pd(PPh3)4 (0.4 g, 0.4 mmol) was added. The mixture was bubbled for 15 min. The resultant mixture was refluxed for 12 h. After cooling, the reaction mixture was extracted by CH2Cl2 and dried by MgSO4. The solvent was removed in vacuo and the residue was purified by flash chromatography using 25-50% CH2Cl2/hexane to afford N-(4-(9H-carbazol-3-yl)phenyl)-N-phenyldibenzo[b,d]thiophen-4-amine (5.8 g, 91% yield) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:21][S:22][C:23]2[S:24][C:25]([CH2:28][CH3:29])=[N:26][N:27]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.[CH3:38][O:39]C1C=C(C=CC=1)CBr>>[CH2:28]([C:25]1[S:24][C:23]([S:22][CH2:21][C:11]2[N:10]=[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([O:39][CH3:38])[CH:7]=3)[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=2)=[N:27][N:26]=1)[CH3:29]
Reactant: COc1cccc(CBr)c1
Reactant: CCc1nnc(SCc2cc(N3CCOCC3)cc(NCc3ccccc3)n2)s1
Agent: BrCc1ccccc1
Product: CCc1nnc(SCc2cc(N3CCOCC3)cc(NCc3cccc(OC)c3)n2)s1

Procedure:
The above identified compound was obtained as a vermilion oily substance in the same manner as in Example 1-(6) and (7) except that benzyl bromide was changed to 3-methoxybenzyl bromide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)C(C)N
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Product: Cc1ccc(CC(=O)NC(C)C(=O)OCC(C)C)cc1

Procedure:
Following General Procedure B′ and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 102°-104° C. The reaction was monitored by tlc on silica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=3[F:23])[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10]2)=[N:6][C:7]=1[NH2:8].O=[C:33]([CH3:36])[CH:34]=O.C(=O)(O)[O-]>CO.C(Cl)Cl>[CH3:36][C:33]1[N:8]=[C:7]2[N:6]=[C:5]([N:9]3[CH2:14][CH2:13][C@H:12]([C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=4[F:23])[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:10]3)[CH:4]=[CH:3][C:2]2=[N:1][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccc(N)c(N)n2)CC[C@@H]1c1cc(F)c(F)cc1F
Reactant: CC(=O)C=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc2ccc(N3CC[C@H](c4cc(F)c(F)cc4F)[C@@H](NC(=O)OC(C)(C)C)C3)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 40 mg (0.09 mmol) of the product of Step B in 2 mL of methanol was added 0.07 mL (0.46 mmol) of 2-oxopropanal solution (40 wt. % in water) and stirred at ambient temperature for 1 h. The reaction mixture was then, diluted with 10 mL of methylene chloride and poured into 10 mL of a saturated aqueous bicarbonate solution. The layers were separated and the aqueous layer extracted with three 10 mL portions of methylene chloride and the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield a tan solid which was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (1:3 hexane/ethyl acetate solvent) to give the title compound as a tan crystalline solid. LC/MS 474.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[OH:23][CH2:24][CH2:25][CH:26]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:26][CH2:25][CH2:24][OH:23]
Reactant: O=CCCO
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: CC1=C(CCON=CCCO)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-hydroxypropanal by the method of Example 1.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH:34]1[S:38][CH:37]=[CH:36][C:35]=1[C:39]([CH:41]([CH3:43])[CH3:42])=[O:40]>O1CCCC1>[Br:1][C:41]([C:39](=[O:40])[C:35]1[CH:36]=[CH:37][S:38][CH:34]=1)([CH3:43])[CH3:42]
Reactant: [Br-]
Reactant: CC(C)C(=O)c1ccsc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)c1ccsc1

Procedure:
2.88 g of phenyltrimethylammonium tribromide was added to a mixed solution comprising 1.54 g of 2-(3-thenoyl)propane and 30 ml of tetrahydrofuran, followed by a reaction at room temperature for 15 hours. After completion of the reaction, the precipitate was separated by filtration and concentrated, and then purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/8-4/6) to obtain 0.87 of 2-bromo-2-(3-thenoyl)propane. The NMR spectrum data of this product were as follows.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10]OS(C)(=O)=O.CC(C)([O-])C.[K+]>CCOCC>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10]
Reactant: CS(=O)(=O)OCCc1ccccc1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccccc1CCl
Temperature: -35 °C
Yield: 82 %

Procedure:
Dissolve methanesulfonic acid 2-(2-chloromethyl-phenyl)-ethyl ester (8.8 g, 35.4 mmol) in ether (80 mL) and cool to −35° C. Add potassium t-butoxide (10 g, 89 mmol) and stir for 30 minutes. Add water (50 mL) and ether (150 mL), extract, dry (Na2SO4) and purify by silica gel chromatography (2:3 methylene chloride/pentane) to give 1-chloromethyl-2-vinyl-benzene as a colorless oil (4.43 g, 82%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[CH3:22][S:19]([C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:10][C:14]2=[N:15][CH:16]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccccn1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ccccn3)cc2c1
Yield: 95.5 %

Procedure:
To a solution of the compound obtained in Example 5 (3) (3.8 mg) in methanol (0.5 ml), a 1N aqueous potassium hydroxide solution (2 ml) was added and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction solution was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was poured into a phosphorate buffer (pH 7.0), extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol 50:1) to obtain 2.4 mg of the desired product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[NH:6]2.Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[O:23][N:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:6]2[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[O:23][N:22]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1Cl
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1Cl

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1 H), 8.23 (d, J=7.8 Hz, 1 H), 7.86 (d, J=7.9 Hz, 1H), 7.67 (dd, J=7.8 Hz, 1 H), 7.45 (s, 2 H), 6.56 (s, 1 H), 5.45 (s, 2 H), 3.27 (t, 2 H), 2.89-2.61 (m, 2 H); MS (ES) m/z 499 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:34][O+](C)C>C(Cl)Cl>[CH3:34][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=1
Reactant: CCOC(=O)C(CCCC1CCCCC(=O)N1)NC(=O)OCc1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CCCC1CCCCC(OC)=N1)NC(=O)OCc1ccccc1

Procedure:
The product of EXAMPLE 247 is treated with trimethyloxonium tetraflouroborate in CH2Cl2 by the method of EXAMPLE 26 to yield title material.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:23]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: C=CCCCCCCCCCCCCCC
Reactant: Oc1ccccc1
Product: CCCCCCCCCCCCCCCCc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Phenol (376 g, 4 mol), hexadecene (α-olefin) (449 g, 2 mol) and ion exchange resin (trade-mark: Dia-ion RCP-145HD) (34 g) were charged in a reactor and stirred at 110° C. for 2 hours. The ion exchange resin was filtered off and the excessive phenol and hexadecene were distilled off under reduced pressure. After distillation under reduced pressure, mono-hexadecylphenol was obtained. The yield was 510 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[Cl:13]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[Cl:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1Cl
Reaction time: 3 h

Procedure:
A solution of 4-nitro-2-chlorobenzoic acid methyl ester (Aldrich, 700 mg, 3.24 mmol) in ethyl acetate (50 mL) was added 10% Pd/C (50 mg). The mixture was vigorously shaken in a Parr under an atmosphere of hydrogen (50 psi) for 3 h. The mixture was filtered through a short pad of celite and the filtrate was concentrated to give 4-amino-2-chlorobenzoic acid methyl ester as a light yellow solid which was directly used for the next step.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:33][CH2:34][CH3:35])[C:5]=1[OH:36])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:33][CH2:34][CH3:35])[C:5]=1[OH:36])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCCC(=O)O)cc2)ccc(C(C)=O)c1O

Procedure:
The compound of Step C above, (800 mg, 1.54 mmoles, 1N NaOH (3.2 ml), water (3.2 ml) and THF (10 ml) were stirred at room temperature for three hours. The THF layer was removed and the aqueous portion diluted with water and extracted with ether. The aqueous portion was acidified with concentrated HCl. A solid precipitate formed which was extracted into ether, dried and concentrated. Trituration of the residue with ether-methanol afforded the title compound; mp 138°-140°.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C@@H:3]([CH3:9])[C@H:4]([NH:5][C:11]([O:13][CH3:14])=[O:12])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)Cl
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
A solution of allo-O-methyl-L-threonine (519 mg, 3.90 mmol) in saturated sodium bicarbonate solution (47.6 mL) was treated dropwise with methyl chloroformate (453 μL, 553 mg, 5.85 mmol) followed by stirring at RT for 18 h. The mixture was extracted with ether and the aqueous phase was cooled to 0° C. and acidified to pH 2-3 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×). The combined organic layers were extracted with saturated sodium chloride solution and dried (Na2SO4). Concentration in vacuo afforded the title compound (640 mg, 86%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.48 (d, J=7.8 Hz, 1 H), 4.52 (d, J=4.7 Hz, 1 H), 3.71 (s, 3 H), 3.39 (s, 3 H), 1.25 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2>>[ClH:1].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:20][CH:19]=1)[C:26]([CH3:31])=[CH:25]2
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Agent: Cl
Product: Cc1cc2cc(F)ccc2n1C(=O)c1ccc(OCCCN2CCCCC2)cc1

Procedure:
The title compound (E6) was prepared from 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) and 5-fluoro-2-methyl-indole using the method described in Example 5 (E5).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7](I)[CH:6]=[N:5]1.[C:10]([C:12]1[CH:13]=[C:14]([C:18]2[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)#[CH:11]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:24][C:19]1[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]#[C:11][C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][F:1])[CH:8]=3)[CH:13]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: C#Cc1cccc(-c2cccnc2F)c1
Reactant: FCCn1cc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: FCCn1cc(C#Cc2cccc(-c3cccnc3F)c2)cn1
Temperature: 65 °C
Yield: 75.6 %

Procedure:
To a solution of 1-(2-fluoroethyl)-4-iodo-1H-pyrazole (148 mg, 0.62 mmol) in DMF (5.0 mL) is added dichlorobis(triphenylphosphine)palladium (16 mg, 0.022 mmol), copper iodide (3 mg, 0.015 mmol), TEA (0.53 mL, 3.8 mmol) and 3-(3-ethynylphenyl)-2-fluoropyridine (150 mg, 0.76 mmol). The reaction mixture is heated at 65° C. for 3 h, cooled and quenched with H2O. The aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:30/70) to afford the title compound (145 mg, 76%) as an oil. MS (+) ES: 310 (M+H)+.