Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][C:18](Cl)=[O:19].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:16][CH2:17][C:18]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:19]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.1 g of 3-phenylindoline in 60 ml of acetone was cooled to 0° C, 5.1 ml of chloroacetylchloride was added and the mixture poured into an ice cold solution of 10 g of sodium acetate in 50 ml of water. The mixture was then stirred for one hour at room temperature and the residual solid removed by filtration. Recrystallization from ethanol gave a yield of 13.0 g of the desired N-chloroacetyl-3-phenylindoline having a melting point of 76°-78° C.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:1]2[CH2:5][C:4](=[O:6])[NH:3][CH2:2]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C1CNCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)CN1
Temperature: 25 °C

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 4-nitrobenzene (1 eq) and diisopropyl ethylamine (28.6 mL, 165 mmol) in dry DMF (80 mL) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was air dried to yield the nitro compound as yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][O:23]C(=O)C)[CH2:17][CH2:16]1)=[O:2].C(=O)([O-])[O-].[K+].[K+].CO.O>ClCCl.CO>[OH:23][CH2:22][C:21]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[NH:4][C:3]=2[CH:1]=[O:2])[CH2:20][CH2:19]1)=[O:27]
Reactant: CC(=O)OCC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=Cc1[nH]c2c(c1CCCN1CCN(C(=O)CO)CC1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Each fraction of acetic acid 2-{4-[3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-2-oxo-ethyl ester was treated separately with potassium carbonate (3.0 eq.) in 6 ml of (methanol/ water 4/1). The two reactions were stirred at room temperature for overnight. Thin layer chromatography (dichloromethane: methanol 15:1) for both reactions showed the same spot and also LCMS showed that they have the same molecular weight. The two reactions were combined and the solvent was evaporated. The formed solid was washed with 30 ml of (dichloromethane/methanol 10/1) three times and sonicated. The liquid was collected and concentrated to give 268 mg of 3-{3-[4-(2-hydroxyacetyl)piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde.
Reaction SMILES: Cl[C:2]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)=[O:3].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].II>C(Cl)(Cl)Cl>[CH3:22][C@@H:15]([C@@H:14]1[C@@:23]2([CH3:31])[CH2:24][CH2:25][C@@H:26]3[C@@:27]4([CH3:30])[CH2:28][CH2:29][C@H:5]([O:4][C:2]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:3])[CH2:6][C:7]4=[CH:8][CH2:9][C@H:10]3[C@@H:11]2[CH2:12][CH2:13]1)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CN(C)CCN
Agent: II
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Compound XIV was synthesized by mixing a-solution of cholesterol chloroformate (0.5 mmol) in chloroform with a solution of N,N-dimethylethylenediamine (9.1 mmol) in chloroform in a dry ice-ethanol bath. The solvent and the unreacted amine were removed in vacuo. Compound XIV was purified by two successive recrystallizations in ethanol. (Yield, 65%) TLC (chloroform:methanol=65:35) showed a single spot (Rf=0.37) when developed with iodine. The product was characterized by proton NMR.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.P(Cl)(Cl)([Cl:8])=O.C[O:12][CH:13](OC)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1.[OH-].[Na+].CNC>O.C(Cl)(Cl)Cl>[Cl:8][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:14](=[CH:3][N:2]([CH3:5])[CH3:1])[CH:13]=[O:12]
Reactant: COC(COc1ccc(Cl)cc1)OC
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C=O)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dimethylformamide (109.5 g., 1.5 moles) was cooled in an ice-water bath. Phosphorus oxychloride (229.5 g., 1.5 moles) was added dropwise over 1.5 hours and the reaction mixture then allowed to stir for 45 minutes at room temperature. Chloroform (300 ml.) was added and then 4-chlorophenoxyacetaldehyde dimethylacetal (122 g., 0.5 moles) and the mixture refluxed for approximately 16 hours. The reaction was cooled to room temperature and added slowly to approximately 300 ml. of chloroform mixed with ice and water while maintaining the pH approximately 10 with sodium hydroxide. Aqueous 40% dimethylamine (400 ml.) was added, the organic layer separated and the aqueous extracted with additional chloroform. The chloroform extracts were combined, dried over anhydrous sodium sulfate, concentrated to a semisolid, and crystalline product recovered by trituration with isopropyl ether (95 g., Rf 0.25 on thin layer chromatography on silica gel with ethyl acetate as eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCC(CNS(=O)(=O)c1ccc(Cl)cc1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)CCCCC(CNS(=O)(=O)c1ccc(Cl)cc1)c1cccnc1

Procedure:
A solution of 8 g of methyl 7-(p-chlorophenylsulfonamido)-6-(3-pyridyl)heptanoate in 100 ml of methanol and 100 ml of 1N aqueous sodium hydroxide is stirred at room temperature for 24 h, then evaporated to remove the methanol and acidified with 1N hydrochloric acid. The mixture is then extracted with ethyl acetate, the extract is dried over magnesium sulfate, filtered and evaporated, and the residue is treated with a saturated solution of HCl gas in ethyl acetate to yield 7-(p-chlorophenylsulfonamido)-6-(3-pyridyl)-heptanoic acid hydrochloride, m.p. 169°-172°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:22])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1Br
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 4-bromo-3-fluorotoluene (11.34 g, 60 mmol), azobisisobutyronitrile (0.99 g, 6 mmol), and N-bromosuccinimide (11.75 g, 66 mmol) in carbon tetrachloride (60 ml) was heated to reflux for 3.5 h. The reaction mixture was cooled to room temperature and then filtered through Celite, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, ethyl acetate:hexane=0:100 to 100:0, gradient) to obtain the title compound (12.8 g, 80%) as a light yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.Cl[C:17]1[C:18]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1>CN(C)C=O>[CH3:27][N:26]1[C:18]2[C:17]([NH:6][C@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])=[N:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24]([CH3:28])=[N:25]1
Reactant: COC(=O)[C@@H](C)N
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Nc1nc(C)nc2c(C)nn(C)c12
Reaction time: 0.25 h

Procedure:
D-alanine methyl ester hydrochloride (6 g, 0.043 mol) is dissolved in 30 ml of cold (5° C.) dimethylformamide and 7 ml (0.05 mol) of triethylamine is added dropwise. After stirring 15 minutes, 6 g of triethylamine hydrochloride is removed by filtering. To the filtrate is added 7 g (0.035 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo-[4,3-d]pyrimidine and another 6 ml of triethylamine. The mixture is stirred at 50°-55° C. for 60 hours and evaporated in vacuo. The residue is dissolved in 100 ml of methylene dichloride, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to give 7.6 g of slightly impure (R)-2-[1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]aminopropionic acid, methyl ester, mp 68°-70° C. from ether as a dihydrate.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]2[CH:14]=1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:13][C:12]1[C:7]2[N:8]([CH:14]=[C:5]([CH2:1][CH2:2][C:3]#[C:4][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCCc1cn2cccc(Cl)c2n1
Reactant: Brc1ccccn1
Product: Clc1cccn2cc(CCC#Cc3ccccn3)nc12

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol) and 2-bromopyridine (405 mg, 2.57 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 293 mg (1.04 mmol, 43%) of 8-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine as a white solid (M.P.=106-107° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCOCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-morpholin-4-yl-ethylamine according to conditions described in general procedure C. Mp: 112-114° C.; 1H NMR (400 MHz, CDCl3) δ 2.33-2.43(m, 6 H), 3.25-3.31(m, 6 H), 3.65-3.71(m, 4H), 3.84-3.89(m, 4 H), 5.54(s, 1 H), 6.08-6.10(m, 1 H), 6.77-6.80(m, 1 H), 7.09(d, J=8.0 Hz, 1 H), 7.27-7.33(m, 2 H), 7.50-7.57(m, 2 H), 7.92-7.97(m, 2 H), 8.13-8.17(m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][CH:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=447.
Reaction SMILES: [CH:1]1[C:6]2[CH:7]([CH2:10][C:11]#[N:12])[CH2:8][CH2:9][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2:13]OC1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.[C:27]([O:33][CH2:34][CH3:35])(=[O:32])[C:28]#[C:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:11]([CH2:10][CH:7]1[C:6]2[C:1]3[N:2]([N:13]=[C:29]([CH2:30][CH3:31])[C:28]=3[C:27]([O:33][CH2:34][CH3:35])=[O:32])[CH:3]=[CH:4][C:5]=2[CH2:9][CH2:8]1)#[N:12]
Reactant: CCC#CC(=O)OCC
Reactant: N#CCC1CCc2ccncc21
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(CC)nn2ccc3c(c12)C(CC#N)CC3
Temperature: 40 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
To a solution of 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ylacetonitrile (1.77 g, 11.2 mmol) in acetonitrile (22 mL) was added 1-(aminooxy)-2,4-dinitrobenzene (5.00 g, 25.1 mmol), and the mixture was stirred at 40° C. for 16 hr. The solvent was evaporated under reduced pressure. Half of the residue was dissolved in dimethylformamide (22 mL), ethyl 2-pentynoate (886 μL, 6.72 mmol) and potassium carbonate (1.55 g, 11.2 mmol) were added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was diluted with water, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (644 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:49])[CH:38](Br)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=1.CO.N(CC)CC>CC#N>[CH3:35][O:36][C:37](=[O:49])[CH:38]([N:12]1[C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][N:14]=[CH:13]1)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=1
Reactant: COC(=O)C(Br)c1ccc(OC)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: CCNCC
Solvent: CO
Product: COC(=O)C(c1ccc(OC)c(F)c1)n1cncc1CCO[Si](C)(C)C(C)(C)C
Temperature: 75 °C

Procedure:
4-[2-(tert-Butyl-dimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (6.5 g, 14.0 mmol) and bromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester (5.8 g, 21.0 mmol) are stirred in 60 mL MeCN at room temperature for 2 days. At that point MeOH (50 mL) and Et2NH (50 mL) are then added and the resulting solution heated at 75° C. for 0.5 h. The solution is evaporated and the residue purified via flash column chromatography (EtOAc/DCM 1:9→EtOAc/DCM 1:1) to give {5-[2-(tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester as an oil. MS (ESI) m/z 423.3 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:28]1([C:38](=[NH:40])[NH2:39])[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH2:29]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:40]=[C:38]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=4)[N:39]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: N=C(N)C1(O)C=CC=C(C(F)(F)F)C1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C(F)(F)F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 68 mg (0.33 mmol) of 1-hydroxy-3-(trifluoromethyl)benzenecarboximidamide were reacted according to the General Method 2. Yield: 75 mg (64% of theory)
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.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.[NH2:48][CH2:49][C:50]1[C:51](=[O:58])[NH:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[CH3:56][C:55]1[CH:54]=[C:53]([CH3:57])[NH:52][C:51](=[O:58])[C:50]=1[CH2:49][NH:48][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1cccc(F)c1C(F)(F)F
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
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: Cc1cc(C)c(CNC(=O)c2cccc(F)c2C(F)(F)F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 3-fluoro-2-(trifluoromethyl)benzoic acid (1.00 g, 4.81 mmol) in DMF (25 ml) cooled in an ice bath was added HATU (2.19 g, 5.77 mmol) and DIPEA (1.67 ml, 9.61 mmol). The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 904 mg, 5.29 mmol) was added and the reaction was warmed room temperature for 4 h. The reaction mixture was then poured onto distilled water (300 ml) and stirred for 1 h after which time the precipitate was collected via vacuum filtration using microfibre paper. The resulting solid was triturated using diethyl ether and filtered to afford the title compound as a pale brown solid (1.19 g, 72%). LC-MS 100%, m/z=343.0, 1H NMR (500 MHz, DMSO) δ 11.48 (s, 1H), 8.54 (t, J=4.8 Hz, 1H), 7.71 (dd, J=13.3, 8.0 Hz, 1H), 7.56-7.45 (m, 1H), 7.20 (d, J=7.6 Hz, 1H), 5.86 (s, 1H), 4.25 (d, J=4.9 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: O[CH:2]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25].[K+].[Br-]>ClCCl.C(OCC)(=O)C>[F:22][C:23]([F:34])([F:33])[C:24]([O:26][CH2:5][CH2:4][CH2:3][CH2:2][C:6]1[CH:7]=[CH:8][C:9]2[O:10][CH2:11][C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:17](=[O:19])[C:20]=2[CH:21]=1)=[O:25]
Reactant: CCCC(O)c1ccc(OCc2ccsc2C(=O)O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1c2cc(CCCCOC(=O)C(F)(F)F)ccc2OCc2ccsc21
Reaction time: 48 h

Procedure:
A stirred suspension of 14.33 g (0.468 mol) of 3-[4-(1-hydroxybutyl)phenoxy]methyl-2-thiophenecarboxylic acid and 150 ml of anhydrous CH2Cl2 was treated with one portion of trifluoroacetic anhydride (22.60 g, 0.107 mol). The suspended material rapidly dissolved and the stirred solution was heated under reflux for four hours. After standing two days at ambient temperature, the reaction was quenched with water (70 ml) and washed with 50 ml of 5% NaHCO3 solution. The dried (Na2SO4) organic phase was concentrated to an oil, which was further dried by azeotropic distillation of toluene. The oil was dissolved in approximately 15 ml of isopropanol, seeded with product previously prepared on a smaller scale, and stirred until a thick crystalline mass formed. The mass was triturated with isopropanol, followed by vacuum filtration. The filter cake was dried in vacuo at 40° C. to afford 15.08 g (83.8%) of almost colorless crystals, m.p. 65.5°-67° C. The material appeared pure by TLC (siica gel, ethyl acetate, Rf =0.70; dichloromethane, Rf =0.51) and the IR (KBr), 1H-NMR (CDCl3) and MS (M+, 384) were consistent with structure.
Reaction SMILES: ClC(Cl)(Cl)C(=N)[O:4][CH:5]([C:7]1[CH:8]=[C:9]([C:24]([F:27])([F:26])[F:25])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:12]2)[CH3:6].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([CH2:51]O)[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C1CCCCC1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([CH2:51][O:4][CH:5]([C:7]3[CH:8]=[C:9]([C:24]([F:26])([F:27])[F:25])[CH:10]=[C:11]4[C:15]=3[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[CH:13]=[CH:12]4)[CH3:6])[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (361 mg, 0.716 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (244 mg, 0.788 mmol) at 0° C. was added cyclohexane (2 ml, 18.49 mmol) and fluoroboric acid diethyl ether complex (0.019 ml, 0.143 mmol). The reaction was stirred at 0° C. for 45 min and was judged complete by TLC. The reaction was quenched with aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of ethyl acetate/hexanes from 12% to 100%. The product (245 mg, 0.376 mmol, 52.5% yield) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.77 (m, 1H), 7.34 (s, 1H), 7.18 (m, 2H), 7.08 (d, J=3.7 Hz, 1H), 6.94 (m, 2H), 6.54 (m, 1H), 5.29 (m, 2H), 5.18 (m, 1H), 3.65 (m, 2H), 3.33 (m, 2H), 3.24 (m, 1H), 3.14 (m, 1H), 3.00 (m, 2H), 2.03 (m, 2H), 1.86 (m, 2H), 1.44 (d, J=6.4 Hz, 3H), 1.419 (s, 9H), 0.74 (m, 2H), −0.09 (s, 9H); LC/MS (HPLC method 4): tR=4.871 min, 651.28(MH)+.
Reaction SMILES: [CH2:1]([N:4](CC=C)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]>CN1CCCC1=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)CC=C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=CCN
Product: C=CCNCC=C
Reaction time: 0.5 h

Procedure:
A 300 ml autoclave was charged with 5.8g (5 millimoles) of tetrakis (triphenylphosphine) palladium, 1.8g (13.3 millimoles) of triallylamine and 80ml of N-methyl pyrrolidone as a solvent. Oxygen was removed from the autoclave by a nitrogen purge and then ammonia was added with stirring until the internal pressure reached 3.87 Kg/cm. The reactor was then heated with stirring to 100° C (pressure - 10.19 kg/cm) and subsequently to 130° C (pressure - 13.34 kg/cm). At 100° C the reaction was very slow but after 30 minutes at 130° C the triallylamine had reacted to form 5.2 millimoles of monoallylamine and 6.6 millimoles of diallylamine.