Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Si:23]([O:4][CH2:3][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[NH2:1])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(CO)c1ccc(I)cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(N)c1ccc(I)cc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a mixture of the compound (4.70 g) obtained in step (3) above, 4-dimethylaminopyridine (48.2 mg), triethylamine (4.40 mL) and chloroform (63.2 mL), a solution of tert-butyldimethylchlorosilane (2.38 g) in chloroform (31.6 mL) was added dropwise under cooling with ice and the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for three days. The reaction mixture was concentrated under reduced pressure and water and ethyl acetate were then added. Extraction was conducted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-98:2) to give the titled compound as a pale yellow oil (4.68 g).
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:10]=1[F:24])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[C:10]([F:24])[C:9]=1[OH:8]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (E)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylacrylate (8) (1.4 g, 4.21 mmol) in ethanol (25 mL) was added Pd/C (140 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (9).
Reaction SMILES: [H-].[K+].[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=2)(=[O:5])[CH3:4].[CH3:32]OS(OC)(=O)=O.O>CS(C)=O>[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]1[N:20]([CH3:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=2)(=[O:5])[CH3:4]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3[nH]2)cc1OC
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3n2C)cc1OC
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
In dimethyl sulfoxide was slowly suspended 480 mg of 35% potassium hydride, and 1.37 g of 2-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-5,6-dimethoxyindole was added to the suspension, followed by stirring for 10 minutes. To the mixture was further added 700 mg of dimethylsulfate, followed by stirring for 30 minutes. The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed successively with water and a saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Recrystallization of the residue from ethanol yielded 1.20 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1c(OC)cccc1OC
Reactant: Nc1ccncc1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)Nc2ccncc2)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 74E) and 4-aminopyridine, the title compound was obtained as colorless crystals, melting at 169-172° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:9][C:10]([CH3:17])=[CH:11][C:12](OCC)=[O:13].[F-]>>[CH3:9][C:10]1([CH3:17])[C:4]2[C:3](=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[CH3:8])[C:12](=[O:13])[CH2:11]1
Reactant: Cc1ccc(C)cc1
Reactant: CCOC(=O)C=C(C)C
Agent: [F-]
Product: Cc1ccc(C)c2c1C(=O)CC2(C)C
Yield: 95.6 %

Procedure:
10.6 g (100 mmol) of p-xylene (99% purity) and 14.4 g (112 mmol) of ethyl 3,3-dimethylacrylate were reacted with liquid fluoride and worked up analogously to Example A, giving 18 g of the compound (2) in a purity of 96% (GC). (Yield: 92% of theory).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23]O)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:32][N:2]([CH3:1])[C:3]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: C1COCCN1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CN4CCOCC4)no3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (53 mg, 0.12 mmol) by treatment with SOCl2 (3 eq.) and morpholine (10 eq.) as described in Example 45. Obtained as a yellow solid (33 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])=[CH:4][CH:3]=1.[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>N1C=CC=CC=1>[CH:19]([NH:22][C:23](=[S:24])[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:11]([NH:10][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:18])[CH:12]=1)([CH3:21])[CH3:20]
Reactant: Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reactant: CC(C)N=C=S
Solvent: c1ccncc1
Product: CC(C)NC(=S)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-(3-p-chlorophenylureido)aniline (2.0 g.) in pyridine (40 ml.) is stirred at 0° C. with isopropyl isothiocyanate (0.77 ml.). The solution is allowed to warm slowly to room temperature and is stirred for 48 hours. The solution is filtered, the pyridine is removed by distillation under reduced pressure and the residue is crystallized from methanol (300 ml.) to give 1-(3-isopropylthioureido)-3-(3-p-chlorophenylureido)benzene, m.p. 197°-198° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:4]([O:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 16 h
Yield: 65.8 %

Procedure:
tert-Butyl 4-((3-methyl-4-nitrophenoxy)methyl)piperidine-1-carboxylate (5.68 g, 16.22 mmoles) was dissolved in ethyl acetate (60 ml) and methanol (40 ml). The solution was treated with 600 mg of 10% palladium on carbon (50% water w/w). The slurry was then shaken on a Parr hydrogenator and treated with a 40 psi of hydrogen gas, at room temperature. After 16 hours, the slurry was filtered through a plug of Celite, which was subsequently washed with ethyl acetate (50 ml) and methanol (50 ml). The resulting filtrate was then evaporated at reduced pressure to give 3.42 g of tert-butyl 4-((4-amino-3-methylphenoxy)methyl)piperidine-1-carboxylate as a pink solid (100% yield). The material was used in the next step without any further purification. 1H-NMR (400 MHz, DMSO-d6) d 6.34 (d, 1H), 6.32 (s, 1H), 6.23 (d, 1H), 5.84 (br s, 2H), 3.90 (s, 2H), 3.34 (m, 4H), 2.00 (m, 1H), 1.46 (m, 4H), 1.42 (s, 9H). MS (EI): 321 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH3:31].O>CN(C)C=O>[CH2:30]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:31]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (32 mg, 0.098 mmol) in 1 mL of dimethylformamide was added cesium carbonate (95 mg, 0.29 mmol) and iodoethane (0.0094 mL, 0.12 mmol). After one hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C15H20N3O5S (M+H+): 354.1118. Found 354.1094.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[Cl:14].[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][O:13][C:9]1[CH:10]=[C:11]([Cl:12])[C:6]([O:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])=[C:7]([Cl:14])[CH:8]=1)[CH3:20]
Reactant: CCOC(CBr)OCC
Reactant: Oc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1)OCC
Temperature: 90 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A mixture of 0.85 g of 4-(2-chlorobenzyloxy)-3,5-dichlorophenol, 0.47 ml of bromoacetaldehyde diethyl acetal, 0.46 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 90° C. for 6 hours. After cooling to room temperature, the reaction mixture was poured into ice water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, and dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 0.85 g of 4-(2-chlorobenzyloxy)-3,5-dichlorophenoxyacetaldehyde diethyl acetal (72% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:15]1[N:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:22])[C:18]([OH:32])=[C:17]([OH:33])[N:16]=1)[NH:11][CH2:12][CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].FC(F)(F)C(O)=O>O1CCOCC1>[CH2:1]([O:8][CH2:9][CH:10]1[C:15]2=[N:20][C:19]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:22])=[C:18]([OH:32])[C:17](=[O:33])[N:16]2[CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(C(COCc2ccccc2)NCCCl)nc(O)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCNC2COCc1ccccc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2-{2-(benzyloxy)-1-[(2-chloroethyl)amino]ethyl}-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide in dry 1,4-dioxane under nitrogen atmosphere potassium tert-butoxide (3 eq.) was added in one portion. The resulting suspension was aged at 120° C. for 2 hours. The reaction mixture was cooled to about 15° C. then acidified with trifluoroacetic acid to pH=3-4. The solvent was removed under reduced pressure and the residue, dissolved in the minimum amount of MeOH, was applied on cation-exchange resin cartridges (Varian MEGA BOND ELUTE SCX), the cartridges washed with MeOH and the crude product was eluted with 1M ammonia in methanol. The pooled eluants were concentrated to dryness under reduced pressure to get 9-[(benzyloxy)methyl]-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide as a brown oil (85% yield). The crude product was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) and product was obtained after freeze drying of appropriate fractions.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl-].[NH4+].CO>[Fe].O>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1ccc(Nc2ccccc2N)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
200 mg ethyl 2-fluoro-4-(2-nitrophenylamino)benzoate (compound in Production Example 331), 180 mg iron powder, 350 mg ammonium chloride and 8 mL solution mixture of methanol and water (5:3) were stirred at 100° C. for 1 hour. Insolubles were filtered off with Celite, and water was added to the filtrate which was then extracted with dichloromethane. The extract was purified by NH silica gel chromatography (ethyl acetate), to give 179 mg of the title compound as pale brown crystals.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[CH3:8][N:9]([CH3:13])[C:10]([NH2:12])=[S:11]>C1COCC1>[CH3:8][N:9]([CH3:13])[C:10]1[S:11][CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:12]=1
Reactant: CN(C)C(N)=S
Reactant: O=C(O)C(=O)CBr
Solvent: C1CCOC1
Product: CN(C)c1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
3-Bromopyruvic acid (2.94 g, 17.6 mmol) was added to a stirred solution of 1,1-dimethyl-thiourea (1.87 g, 17.6 mmol) in dry THF (60 mL). The reaction mixture was stirred at rt for 4 hrs. The precipitate that had formed was filtered off, washed with cold THF and dried on high vacuum. LC-MS showed the product peak. The product was obtained as a white solid (2.64 g, 59%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:27]O)[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:27][NH:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:14][CH:13]=3)[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 48.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (500 mg, 48%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:17]([C:22](=O)[CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19]>C(O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:22]([CH2:23][CH3:24])[N:15]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Nc1ncccc1OCC1CCCCC1
Solvent: CCO
Product: CCc1nc2c(OCC3CCCCC3)cccn2c1C(=O)OC

Procedure:
A solution of 100 mg (0.485 mmol) of 3-(cyclohexylmethoxy)pyridine-2-amine and 399 mg (2.42 mmol) of methyl 2-chloro-3-oxopentanoate in 4 ml of ethanol was heated at reflux overnight. The mixture was then cooled and concentrated and the residue obtained was purified by preparative HPLC (Method 6). This gave 26 mg (17% of theory) of methyl 8-(cyclohexylmethoxy)-2-ethylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N+:16]([O-])=O)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc([N+](=O)[O-])c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)c2ccccc12
Yield: 90.4 %

Procedure:
(4-Nitro-naphthalen-1-yloxy)-acetic acid methyl ester (0.90 g) and 10% Pd/C (90 mg) in MeOH (150 ml) is stirred at room temperature under 1 atmosphere of hydrogen for 4 h. The mixture is then filtered through Celite® and evaporated to dryness to provide (4-amino-naphthalen-1-yloxy)-acetic acid methyl ester (0.72 g). MS 232 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33].CCN(CC)CC.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33])[C:46]([CH:43]1[CH2:45][CH2:44]1)=[O:47]
Reactant: FC(F)(F)c1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1CNCc1ccccn1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N(Cc1ccccn1)Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 482.4 %

Procedure:
(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Cl2 (3 mL). To this was added Et3N (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min After 10 min, the reaction mixture was cooled to 0° C., and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with H2O and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]−); IR (thin film) 1645, 1115, 808 cm−1.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[N:10]=1.[OH-].[Na+]>CO>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])=[N:10]2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: COC(=O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCC2

Procedure:
A solution of 6-[1-(4-nitrophenyl)-1,4,5,6-tetrahydro-3-cyclopentapyrazolyl]hexanoic acid methyl ester (see Example 18) (0.07 g) in methanol (10 ml) was treated with 2N sodium hydroxide (2 ml) and heated at reflux temperature for 45 minutes. The solution was cooled, evaporated, diluted with water and acidified. The precipitate was extracted into ethyl acetate, washed with 5% saline, dried, and evaporated. The residue was filtered through CC-4 silica gel to remove polar impurities, and the 25% ethyl acetate in hexane effluent gave pure title compound, m.p. 131°-132° C., after ethanol-water recrystallization.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
The title acid of Step 9 (5.2 g, 30 mmol) was dissolved in dimethylformamide (25 mL) and cooled to 0° C. To this solution potassium carbonate (5.7 g, 41.48 mmol) was added followed by benzyl bromide (5.7 g, 29.7 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 3 times of water, brine. The solution was dried (Na2SO4) and evaporated. The residue was purified by flash chromotography on silica gel, eluting with 90:10 heptane:ethyl acetate to give the pure title compound as colorless oil (4.5 g, 60% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C17H16O2 : C, 80.93; H, 6.39. Found: C, 80.69; H, 6.47.
Reaction SMILES: [CH:1]1([CH:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:19]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=4)[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,2-Dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (154 mg, 0.463 mmol) from Example 53 and 3-(trifluoromethyl)benzaldehyde (0.062 mL, 0.463 mmol) were combined in dichloromethane (5 mL), and then 2 mL of acetic acid was added. The reaction was stirred at room temperature for 20 minutes, and then PS-cyanoborohydride (396 mg, 0.926 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-25) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.73 (s, 1H), 7.66 (d, J=7.7, 1H), 7.56 (s, 1H), 7.50 (t, J=7.7, 1H), 4.51-4.43 (m, 1H), 3.55 (d, J=12.9, 1H), 3.46 (d, J=12.9, 1H), 2.75 (d, J=8.6, 2H), 2.52-2.41 (m, J=8.5, 19.1, 2H), 2.34-2.29 (m, 1H), 2.20 (dd, J=7.7, 9.8, 1H), 2.14 (s, 3H, OAc), 1.96-1.54 (m, 15H), 1.49-1.05 (m, 12H), 1.03-0.93 (m, J=11.7, 21.1, 1H); MS (ESI+) m/z 491 (M+H)+.