Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CN1CCCC1=O.[CH:21]1([Mg]Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C1COCC1.C(OCC)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCCC1
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#Cc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1.5 g), iron (III) acetylacetonate (130 mg), and 1-methylpyrrolidin-2-one (4 mL) in THF (45 mL) was added a 1 M solution of cyclopentyl magnesium bromide in THF (8.8 mL) at 5° C., followed by stirring at room temperature for 0.5 hours and diluting with diethylether. 1 M hydrochloric acid was slowly added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 95:5) to obtain 4-cyclopentyl-3-(trifluoromethyl)benzonitrile (367 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:11])=[O:10]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of 3-(2,5-dimethylphenylsulfonyloxy)-5-methylphenol (585 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a pale yellow oil (650 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 6.60 (s, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.81 (m, 2), 2.70 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 1.98 (m, 2H), 1.63 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[C:17]1([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[ClH:15].[CH2:3]([C:2]1([CH3:1])[N:23]([C:17]2[CH:18]=[CH:19][C:20]([Cl:15])=[CH:21][CH:22]=2)[C:24]([NH2:25])=[N:26][C:27]([NH2:29])=[N:28]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: N=C(N)NC(=N)Nc1ccccc1
Reactant: CCCCCCCCCCCC(C)=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1(C)N=C(N)N=C(N)N1c1ccc(Cl)cc1

Procedure:
200 ml of ethanol, 10.1 g (50.9 mmol) of 2-tridecanone and 2.0 ml of concentrated hydrochloric acid were added to 12.0 g (48.4 mmol) of N1-phenyl-biguanide hydrochloride, and the mixture was refluxed for 40 hours. The solvent was distilled off under reduced pressure, and the residue was purified two times by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:1.5) and subsequently with a mixture of chloroform/methanol/acetic acid (8:0.5:0.5→8:1:1)). The eluate was dissolved in 80% aqueous ethanol, and the solvent was distilled off under reduced pressure. The residue was dried well under reduced pressure to obtain 6.6 g of a pale yellow resinous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:49]=[C:50]([N+:52]([O-:54])=[O:53])[CH:51]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:48])[C:18]1[CH:23]=[C:22]([O:24][C:25]([C:27]2([CH3:35])[CH2:32][O:31]C(C)(C)[O:29][CH2:28]2)=[O:26])[CH:21]=[C:20]([O:36][C:37]([C:39]2([CH3:47])[CH2:44][O:43]C(C)(C)[O:41][CH2:40]2)=[O:38])[CH:19]=1)=[O:8])([O-:3])=[O:2]>CO>[OH:31][CH2:32][C:27]([CH2:28][OH:29])([CH3:35])[C:25]([O:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([O:36][C:37](=[O:38])[C:39]([CH2:40][OH:41])([CH2:44][OH:43])[CH3:47])[CH:21]=1)[C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:7](=[O:8])[C:6]1[CH:49]=[C:50]([N+:52]([O-:54])=[O:53])[CH:51]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:48])=[O:26]
Reactant: CC1(C)OCC(C)(C(=O)Oc2cc(OC(=O)C3(C)COC(C)(C)OC3)cc(C(=O)OCCCCCCOC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)CO1
Solvent: CO
Product: CC(CO)(CO)C(=O)Oc1cc(OC(=O)C(C)(CO)CO)cc(C(=O)OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
1.38 g (1.81 mmol) 6-({3,5-bis{[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]oxy}benzoyl}oxy)hexyl 3,5-dinitrobenzoate was dissolved in 20 ml methanol. 0.50 g of Dowex 50Wx2 resin and the reaction mixture was stirred for 4 hours at room temperature. The Dowex resin was filtered off and washed with methanol. The filtrate was concentrated by rotary evaporation yielded 1.14 g (92%) 6-[(3,5-dinitrobenzoyl)oxy]hexyl 3,5-bis{[2,2-bis(hydroxymethyl)propanoyl]oxy}benzoate as a colorless viscous oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([NH:5][C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)CC(N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (0.200 g, 0.651 mmol), methyl 5-chloropyrazine-2-carboxylate (124 mg, 0.716 mmol), and diisopropylethylamine (168 mg, 1.30 mmol) in 2-propanol (5 mL) was heated in a microwave reactor at 100° C. for 2 h. The mixture was cooled to room temperature and concentrated. The mixture was concentrated and purified by column chromatography to give methyl 5-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrazine-2-carboxylate (150 mg, 52%). 1H NMR (400 MHz, CDCl3, δ): 8.75 (s, 1H), 7.87 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 5.46 (s, 1H), 5.04 (t, 1H), 4.12 (s, 3H), 1.87-1.80 (m, 1H), 1.80-1.60 (m, 2H), 1.02 (d, J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:32]([C@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][N:35]1C(OC(C)(C)C)=O)[CH3:33]>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:32][CH3:33])[CH2:39]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: CC[C@H]1CN(Cc2cn(CC3CC3)c(=O)c3ccc(-c4cc(C(=O)NC5CC5)cc(F)c4C)cc23)CCN1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-ethyl-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: ClCl.[Cl:3][C:4]1[C:9]([OH:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([OH:13])[C:5]=1[Cl:14]>>[C:4]1([Cl:3])[C:9](=[O:10])[C:8]([Cl:11])=[C:7]([Cl:12])[C:6](=[O:13])[C:5]=1[Cl:14]
Reactant: Oc1c(Cl)c(Cl)c(O)c(Cl)c1Cl
Agent: ClCl
Product: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl

Procedure:
After 146 parts (2.1 mol) of chlorine gas have been introduced over a period of 7.5 hours, a thick, light beige-colored suspension composed predominantly of tetrachlorohydroquinone, is obtained at the temperature level of 95° C. 21 parts of chlorine were found in the off-gas. After a further 84 parts (1.2 mol) of chlorine gas have been introduced over a period of a further 8 hours, a thin, light yellow suspension is obtained at the temperature level of 105° C., from which 106.4 parts of chloranil having a melting point of 255° to 260° C. are isolated under the working-up conditions according to the example. The chloranil still contains significant amounts of mono-, di- and tetra-chlorohydroquinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:31]([C:30]1[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 44.3 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (128 mg, 0.373 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (77.2 mg, 0.485 mmol), triethylamine (113 mg, 1.12 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (77 mg, 44%) was obtained as a white powder. melting point 255° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[C:21]2[CH:22]=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[NH:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[N:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: N=C(NO)c1cccc2[nH]ccc12
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Temperature: 25 °C
Yield: 33.7 %

Procedure:
To a solution of 3,4-diethoxybenzoic acid (0.11 g; 0.52 mmol), and the product of Step A (0.09 g; 0.51 mmol) in anhydrous THF (2 ml), PyBroP (0.25 g; 0.54 mmol) was added followed by DIPEA (0.21 ml; 1.22 mmol), with stirring, at room temperature under N2. After 2 h of stirring, the mixture was diluted to 15 ml with EtOAc, washed with saturated NH4Cl (2×5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was suspended in anhydrous toluene (10 ml). To it 1M TBAF in THF (0.5 ml) was added and the reaction mixture was refluxed for 3 h under N2, cooled to room temperature and solvents were removed under reduced pressure. The residue was washed with H2O (5 ml) and the solid was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.06 g; 34%) as colourless solid. 1H-NMR (CDCl3) 1.5 (m, 6H); 4.16-4.26 (m, 4H); 6.98 (d, 1H, J=8.5 Hz), 7.31-7.37 (m, 3H); 7.54 (d, 1H, J=8.1 Hz); 7.74 (d, 1H, J=2 Hz); 7.83 (d, 1H, J=8.4 Hz); 8.06 (dd, 1H, J=2, 8.4 Hz); 8.42 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[C:4]([F:30])[CH:3]=1.[CH3:31][S:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:32][CH3:31])[CH:38]=3)=[CH:3][C:4]=2[F:30])[CH2:9][C:10]([C:20]([C:26]([F:27])([F:28])[F:29])([C:22]([F:23])([F:24])[F:25])[OH:21])=[N:11]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1)(C(F)(F)F)C(F)(F)F
Reactant: CSc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
5-(4-Bromo-2-fluoro-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 5 of Preparation 19, 3-methylthiophenylboronic acid (17.8 mg, 0.11 mmol), potassium carbonate (40.0 mg, 0.29 mmol), and Pd(dppf)Cl2 (7.0 mg, cat.) were added to a mixed solvent of 1,4-dioxane (750.0 uL) and distilled water (150.0 uL). The reaction mixture was stirred for 15 minutes, additionally at 90° C. for 2 hours, and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to give 20.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][N:13]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2C(F)(F)F)n[nH]1
Temperature: 180 °C
Yield: 20.8 %

Procedure:
A microwave reaction vessel was charged with (S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63 mmol), 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (Method 23, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol). Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours.) The solvent was removed under reduced pressure and the residue was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (50 mg) 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 2H) 8.16 (s, 1H) 8.08 (s, 1H) 5.77 (s, 1H) 5.13 (m, 1H) 2.12 (s, 3H) 1.43 (d, 3H); m/z 383.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][C:11]2[CH2:12][O:13][CH2:14][C:15]([F:41])([F:40])[C@:16]([C:19]3[CH:24]=[C:23]([N:25]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[CH:21][C:20]=3[F:39])([CH3:18])[N:17]=2)=CC=1>ClCCl.O1CCOCC1.Cl>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([F:39])=[C:19]([C@:16]2([CH3:18])[C:15]([F:40])([F:41])[CH2:14][O:13][CH2:12][C:11]([NH2:10])=[N:17]2)[CH:24]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reaction time: 1 h

Procedure:
To a solution of crude (R)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-(diphenylmethyleneamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.2 mmol) in dichloromethane (20 ml) was added at 22° C. trifuoroacetic acid (2.6 ml) and stirring was continued for 1 h. The mixture was diluted with 1,4-dioxane (40 ml) and aqueous hydrochloric acid (1 M, 33 ml) and vigorous stirring of the emulsion at 22° C. was continued for 16 h. The mixture was evaporated and the residue partitioned between saturated aqueous NaCl and ethyl acetate, the aqueous layer was separated, the pH was adjusted to 14 using saturated aqueous Na2CO3 solution and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silica-NH2 using dichloromethane to give (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine as a colorless oil. MS (ISP): m/z=274.3 [M+H]+.
Reaction SMILES: ClC1C=C(F)C=CC=1CN[C:11](=[O:27])[C@@H:12]1[CH2:16][CH:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[N:13]1[CH2:25][CH3:26].[Cl:28][C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:39][NH2:40].C(N1C(=O)C(CC2C=CC=CC=2)C[C@H]1C(O)=O)C>>[Cl:28][C:29]1[C:34]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:39][NH:40][C:11](=[O:27])[C@@H:12]1[CH2:16][CH:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[N:13]1[CH2:25][CH3:26]
Reactant: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)O
Product: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl

Procedure:
N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-ethyl-5-oxo-4-(phenylmethyl)prolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-4-(phenylmethyl)-prolinamide (E37), but using {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine in the place of [(2-chloro-4-fluorophenyl)methyl]amine. Method B, as described in Example 37, was used to prepare the 1-ethyl-5-oxo-4-(phenylmethyl)-proline.
Reaction SMILES: [F:1][C:2]([F:21])([C:12]([F:20])([F:19])[C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH2:3]OS(C(F)(F)F)(=O)=O.[C:22](#[N:26])[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:21][C:2]([F:1])([C:12]([F:19])([F:20])[C:13]([F:17])([F:18])[CH:14]([F:15])[F:16])[CH2:3][CH:23]([C:22]#[N:26])[C:24]#[N:25]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)C(F)(F)F
Reactant: N#CCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reaction time: 3 h
Yield: 18.1 %

Procedure:
15 g of (2,2,3,3,4,4,5,5-octafluoropentyl)trifluoromethanesulfonic acid and 2.6 g of malononitrile were dissolved in 20 ml of dimethyl sulfoxide, 5.5 g of potassium carbonate was added, and the mixture was stirred in a water bath for 3 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile.
Reaction SMILES: C1(C[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]([C:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=2)=[CH:9][NH:10]3)CC1.C[Si](I)(C)C>>[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=1)=[CH:9][NH:10]2
Reactant: CN1CC=C(c2c[nH]c3cccc(OCC4CC4)c23)CC1
Agent: C[Si](C)(C)I
Product: CN1CC=C(c2c[nH]c3cccc(O)c23)CC1
Yield: 43.8 %

Procedure:
Following the procedure described in detail in Example 58, 0.300 gm (1.1 mMol) 4-cyclopropylmethoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole were reacted with trimethylsilyl iodide to provide 0.11 gm (44%) of the title compound as a tan solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>CO>[CH2:13]([O:12][C:10]([NH:9][C@H:4]([CH2:3][NH:2][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][Cl:27])[C:5]([O:7][CH3:8])=[O:6])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)[C@@H](CN)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CNC(=O)CCCCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A solution of (R)-methyl 3-amino-2-(benzyloxycarbonylamino)propanoate hydrochloride (4.0 g, 0.014 mol) in methanol (80 mL) was cooled to 0° C. To this mixture was added Et3N (3.3 g, 31 mmol), followed by 4-chlorobutanoyl chloride (2.3 g, 15.0 mmol). The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction was quenched with saturated brine (200 mL), the organic layer extracted with CH2Cl2, washed with 1N HCl, saturated brine, dried over MgSO4 and concentrated to give crude (R)-methyl 2-(benzyloxycarbonylamino)-3-(4-chlorobutanamido)propanoate (5.0 g) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.45-7.35 (m, 5H) 6.01 (s, 1H), 5.84 (d, 1H), 5.11 (d, 2H), 4.42 (t, 5H), 3.68-3.50 (m, 6H), 2.32 (t, 2H), 2.08 (t, 2H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[CH:16]([OH:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:9]=1.[OH-].[Na+]>CO>[OH:25][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:15]=[CH:14]/[C:10]1[N:9]=[C:8]([C:7]#[C:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C#CCCC(=O)OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C#CCCC(=O)O)n1
Yield: 57.2 %

Procedure:
Under the conditions of example 2, 20 mg of 5-{6-[(1E)(3RS)-3-hydroxy-1-undecenyl]-2-pyridyl}-4-pentynoic acid methyl ester in 1 ml of methanol is saponified with 2 ml of 1 n sodium hydroxide solution and worked up. 11 mg of the title compound is obtained as yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:3].[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[N:26]=[C:25]([CH:27]4[CH2:32][CH2:31][N:30](S(CC5C=CC=CC=5)(=O)=O)[CH2:29][CH2:28]4)[NH:24][C:23]=3[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:21][C:16]=2[O:15][CH2:14]1>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:2]([N:30]1[CH2:29][CH2:28][CH:27]([C:25]2[NH:24][C:23]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[C:22]([C:20]3[CH:19]=[CH:18][C:17]4[O:13][CH2:14][O:15][C:16]=4[CH:21]=3)[N:26]=2)[CH2:32][CH2:31]1)=[O:3]
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1Cl)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
2-Chlorobenzyl chloroformate (0.011 mL, 0.070 mmol) was added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.021 g, 0.059 mmol; prepared as described in Example 11) in a mixture of THF (3 mL) and 2 M sodium bicarbonate aqueous solution (0.3 mL). The mixture was stirred at room temperature for 2 hours. Mixture was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated. HPLC purification eluting with acetonitrile:water gave 0.026 g (70%) of the title compound as a yellow solid. MS (ESP+) m/z 517.03 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.81 (m, 1H), 7.60 (d, 1H, J=8.2 Hz), 7.39 (m, 3H), 7.27 (m, 2H), 7.07 (dd, 1H, J=8.1, 1.8 Hz), 6.99 (d, 1H, J=1.8 Hz), 6.90 (d, 1H, J=8.1 Hz), 6.05 (s, 2H), 5.24 (s, 2H), 4.36 (m, 2H), 3.48 (m, 1H), 2.98 (m, 2H), 2.17 (m, 2H), 1.86 (m, 2H).