Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[CH2:8][CH2:7]1)(OCC)=O.[BrH:23]>>[BrH:23].[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[C:13]([CH:18]=1)[NH:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Agent: Br
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCNCC1
Reaction time: 4 h

Procedure:
30 g of 1-carbethoxy-4-(5-chloro-2-nitroanilino)-piperidine in 400 ml of 48% strength hydrobromic acid were boiled under reflux, with stirring, for 4 hours. After the mixture had been cooled, the precipitate which had formed was filtered off with suction and washed with water and petroleum ether. The product was obtained as a light beige powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](OC2N(C3C=CC=CC=3)N=NN=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:28][CH3:29])[C:7]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:5])[CH3:2].[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:28][CH3:29])[C:7]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:5])[CH3:2]
Reactant: CCCCc1c(C(=O)OCC)cc(Oc2nnnn2-c2ccccc2)c2c(OC)cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCc1c(C(=O)OCC)ccc2c(OC)cccc12

Procedure:
A solution of 1-butyl-5-methoxy-4-[(1-phenyl-1H-tetrazole-5-yl)oxy]-2-naphthalenecarboxylic acid ethyl ester in a mixture of tetrahydrofuran (25 mL) and ethanol (75 mL) was hydrogenated over 10% palladium on carbon (1.3 g) at 50° C. and three atmospheres. After the uptake of hydrogen had stopped, the catalyst was removed by filtration and the filtrate was concentrated to dryness. The resulting material was dissolved in diethyl ether (150 mL) and the solution extracted with 1N sodium hydroxide (2×50 mL). After the base extracts were backwashed with diethyl ether, the combined organic layers were dried (MgSO4) and evaporated to yield 3.6 g of 1-butyl-5-methoxy-2-naphthalenecarboxylic acid ethyl ester as an oil. A portion was distilled on a Kugelrohr apparatus (140° C.; 0.1 mm) to furnish the analytical sample. Anal. Calcd for C18H22O3 : C, 75.50; H, 7.74 Found: C, 75.02; H, 7.97
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[C:25]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:26][O:27][C:28]=2[C:29]([F:32])([F:31])[F:30])=[N:18][CH:17]=1.O>O1CCOCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][N:5]([C:15]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[C:25]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)=[N:26][O:27][C:28]=3[C:29]([F:30])([F:32])[F:31])=[CH:20][CH:21]=2)=[O:14])[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCNCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 504 μL, 1.0 mmol) was added dropwise (exothermic) to a solution of thiomorpholine-S,S-dioxide (136 mg, 1.0 mmol) in dioxane (7 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 days and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (32 mg, 25%) which was obtained as an off white solid. MS: m/e=500.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[CH:7]1([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)[N:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:7]1([C:13]2[N:14]([CH2:2][C:3]([OH:5])=[O:4])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)[N:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)CBr
Reactant: Cc1cc(-c2c[nH]c(C3CCCCC3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cn(CC(=O)O)c(C3CCCCC3)n2)ccc1F
Temperature: 25 °C

Procedure:
0.38 mL methyl bromoacetate was added to 940 mg 2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazole and 1.52 g potassium carbonate in 10 mL DMF. The reaction was stirred over night at RT and evaporated. Methanol and 1 mol/L sodiumhydroxide solution was added and the mixture was stirred 2 h at RT. The solvent was removed. The residue was dissolved in water and acidified with 1 mol/L HCL solution. The precipitate was filtered and dried to give 700 mg desired product. Rt: 0.92 min (method B), (M+H)+: 317
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([CH2:14][NH2:15])[OH:13].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:15][CH2:14][CH2:12][OH:13])[CH:7]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(F)cc1NCCO
Temperature: 80 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 2,4-difluoronitrobenzene (6.36 g., 40 mmole), ethanolamine (3.04 g., 50 mmole) and calcium carbonate (4 g., 40 mmole) in dioxane (40 ml) was stirred at 80° C. for 1 hour and filtered while hot. The filtrate was diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over sodium sulfate and evaporated to give a reddish orange solid. Recrystallization from ethyl acetate gave the compound (11) as reddish orange crystals (5.3 g, 66%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[CH:20]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[O:9][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Reactant: BrC1CCCCC1
Product: CCOC(=O)c1cnn(-c2ccc(OC3CCCCC3)c(C#N)c2)c1

Procedure:
The same reaction and treatment as in Example 5 using ethyl 1-(3-cyano-4-hydroxyphenyl)pyrazole-4-carboxylate and cyclohexyl bromide gives ethyl 1-(3-cyano-4-cyclohexyloxyphenyl)pyrazole-4-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[S:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[BH:15]([OH:17])[OH:16]>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:9](=[CH:10][C:11]([CH3:12])=[CH:2][CH:3]=2)[S:8][CH:7]([B:15]([OH:17])[OH:16])[CH2:6]1
Reactant: OBO
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCS2
Product: Cc1ccc2c(c1)SC(B(O)O)CC2(C)C

Procedure:
In a similar manner to Example 3(a), starting with 5.8 g (21.4 mmol) of 6-bromo-4,4,7-trimethylthiochroman, 3.88 g (76%) of the expected boronic acid are obtained, with a melting point of 252-3° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.CC1(C)CCCC(C)(C)N1>CN(C=O)C.CCOC(C)=O>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([N:7]2[CH2:8][CH2:9][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)=[N:12][CH:13]=1)#[N:16]
Reactant: N#Cc1ccc(Br)nc1
Reactant: COC(=O)C1CCNC1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C#N)cn2)C1
Temperature: 130 °C
Yield: 50.9 %

Procedure:
Pyrrolidine-3-carboxylic acid methyl ester (100 mg, 0.77 mmol) was dissolved in dry DMF (0.5 MI) in a shield tube. 6-Bromonicotinonitrile (140 mg, 077 mmol) was added to the reaction mixture, followed by 2,2,6,6-tetramethylpiperadine (110 mg, 0.77 mmol) and the mixture was heated to 130° C. for 3 h, cooled to room temperature, and diluted with EtOAc. The organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petroleum ether) to afford methyl 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylate (90 mg, yield 70%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 7.62-7.59 (dd, J=8.9 Hz, J=2.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 3.78-3.77 (m, 2H), 3.75 (s, 3H), 3.67 (m, 1H), 3.56-3.52 (m, 1H), 3.28-3.23 (t, J=7.1 Hz, 1H), 2.37-2.30 (q, J=7.1 Hz, 2H). MS (ESI) m/z: Calculated for C12H13N3O2: 231.10. found: 232.2 (M+H)+
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][N:38]([CH2:46][CH:47]=O)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].[BH3-]C#N.[Na+]>CO.C1COCC1.CC(O)=O>[C:41]([O:40][C:39]([N:38]([CH3:37])[CH2:46][CH2:47][N:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[CH2:27][O:26][C@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:33]([O:35][CH3:36])=[O:34])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1)COc1ccccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1CCN(C)C(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution (0.02 M) of methyl (7S)-14-cyclohexyl-7-(pyrrolidin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in MeOH/THF (2/1), AcOH (cat.) was added followed by tert-butyl methyl(2-oxoethyl)carbamate (2 eq, prepared as described in Tetrahedron 2002, 58, 1719-1737). The reaction was stirred at RT for 30 min at which point NaCNBH3 (2 eq) was added and the mixture was stirred at 40° C. for 1 h. Additional tert-butyl methyl(2-oxoethyl)carbamate (1 eq) and NaCNBH3 (5 eq) were added and the reaction was stirred for further 30 min at 40° C. The reaction was quenched by adding sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc and the combined organics washed with brine before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used in the subsequent step without further purification. (ES+) m/z 646 (M+H)+
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:35])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)(=O)[NH2:6]>C(#N)C>[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:35])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)#[N:6]
Reactant: NC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: N#CC1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Yield: 85.4 %

Procedure:
75 ml of thionyl chloride and 150 ml of acetonitrile were added to 3.8 g (0.0086 mol) of 2-(4-carbamoylpiperidino)-4-(3, 4-methylenedioxybenzyl)amino-6-chloroquinazoline. The mixture thus obtained was heated under reflux for one hour. The reaction mixture was distilled under a reduced pressure to remove the solvent. A saturated aqueous solution of sodium hydrogencarbonate and triethylamine were added to the residue and the resultant mixture was etracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by a silica gel column chromatography (ethyl acetate-n-hexane) and recrystallized from chloroform-n-hexane to give 3.1 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29]([OH:31])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][NH2:33]>>[CH:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]([NH:13][C@@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C@H:9]([CH2:28][C:29]([NH:33][CH3:32])=[O:31])[CH2:10]2)=[O:15])=[N:17]1)([CH3:27])[CH3:26]
Reactant: CN
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Product: CNC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and methylamine.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)([O-:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N+:2]([O-:4])=[O:3])[N:12]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3[N+](=O)[O-])cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(2-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.47 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted twice with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid and boiling there separated, upon cooling, 0.58 g of 4-methyl-N-[4-(2-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][CH2:17][O:18][CH3:19])[CH:15]=1)[C:9](OC)=[O:10].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:13]=[C:14]([CH2:16][CH2:17][O:18][CH3:19])[CH:15]=1
Reactant: COCCOc1cc(CCOC)cc(C(=O)OC)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COCCOc1cc(CO)cc(CCOC)c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(2-methoxyethoxy)-5-(2-methoxyethyl)benzoate (1 eq.) from the previous step in THF (0.1 M) at −78° C. was added DIBAL-H (3 eq.). The reaction was warmed to −50° C. for 1 h, and then stirred at 0° C. for an additional 30 min. The reaction was quenched with an aqueous solution of Rochelle's salt and EtOAc. After stirring vigorously at rt for 1 h, the layers separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to give [3-(2-methoxyethoxy)-5-(2-methoxyethyl)phenyl]methanol as an oil. This intermediate (1 eq.) was dissolved in DCM and added to a solution of DMSO (2.5 eq.) and oxalyl chloride (2.5 eq.) in DCM, premixed at −78° C. for 25 min. After 5 min, triethylamine (5 eq.) was added, and the reaction was warmed to rt over 30 min. The reaction was quenched with 1 N aqueous HCl and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 30% EtOAc in Hex) to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13].C(OC(C)C)(C)C>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][NH:7][C:6]3[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: COc1ccc(N)cc1
Solvent: CC(C)OC(C)C
Product: COc1ccc(NCC(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 4-methoxy-aniline (Aldrich) and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 141-143° C. (diisopropylether)
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].CC(C)([O-])C.[K+].C(OP([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(OCC)=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:2](/[C:1](/[C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1)=[CH:32]\[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:3]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\CC)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The ketone thus prepared was subjected to the Horner-Emmons reaction. That is, potassium t-butoxide (19 g) was added to a solution of ethyl diethylphosphonoacetate (36 ml) in tetrahydrofuran (400 ml). The obtained mixture was stirred at room temperature for 30 minutes, followed by the addition of a solution of the above ketone (21.1 g) in tetrahydrofuran (40 ml). The obtained mixture was stirred at 55° to 65° C. for 1.5 hours to complete a reaction. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride to give 22.7 g of t-butyl 4-(1-ethyl-2-ethoxycarbonyl-E-ethenyl)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:13][CH2:12][CH2:11][C:10]=2[C:14]#[N:15])=[CH:4][CH:3]=1>[Ti](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>[NH2:15][C:14]1[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=[C:9]2[CH2:13][CH2:12][CH2:11][C:10]=12
Reactant: N#CC1=C(Nc2ccc(F)cc2)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3ccc(F)cc13)CCC2
Temperature: 140 °C

Procedure:
Under nitrogen, titanium tetrachloride (1.2 ml, 11 mmol) was added to the above enamine (Example 20) (2.0 g, 10 mmol) and the stirred mixture was heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxide solution (20 ml) was added and the mixture heated under reflux for 1 hour. After being allowed to cool, this mixture was filtered and the solids washed with dichloromethane. Any organics in the filtrate were also extracted into dichloromethane. All extracts were combined, dried (Na2SO4), filtered and the solvent evaporated. Kugelrohr distillation (175° C., 0.05 mmHg) gave the product as an off-white powder.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:33][CH3:34])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)/[CH:40]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])CCC.[Cl-].[Li+]>CN(C)C=O.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>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:20]=[CH:21][C:22](/[CH:40]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])=[CH:23][CH:24]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:33][CH3:34])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(c3ccc(OS(=O)(=O)C(F)(F)F)cc3)=C1c1ccc(OC)cc1C2
Reactant: CCCC[Sn](/C=C/C(=O)OC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(c3ccc(/C=C/C(=O)OC)cc3)=C1c1ccc(OC)cc1C2
Temperature: 90 °C
Yield: 96.4 %

Procedure:
A mixture of 9a-butyl-7-methoxy-4-[4-(trifluoromethane-sulfonyloxy)-phenyl]-1,2,9,9a-tetrahydro-3H-fluoren-3-one (98.9 mg, 0.2 mmol), methyl (E)-3-tributylstannyl-acrylate (112.5 mg, 0.3 mmol) and lithium chloride (25.4 mg, 0.6 mmol) in anhydrous dimethylformamide (1.0 mL) was purged with nitrogen and treated with bis(triphenylphosphine)palladium(II) chloride (7.0 mg, 0.01 mmol). The resulting mixture was purged with nitrogen then stirred under a nitrogen atmosphere with heating in an oil bath at 90° C. for 60 minutes. After cooling, the solvent was evaporated under vacuum. The residue in EtOAc (10 mL) was washed with water (2×5 mL) and brine (5 ml), dried over MgSO4, filtered, and evaporated under vacuum to a gum (194 mg). The crude product was purified by preparative layer chromatography (PLC) on two 0.1×20×20 cm silica gel GF plates, developing with 4:1-hexanes-EtOAc. The major UV visible band at Rf 0.15-0.25 was eluted with EtOAc and the solvent evaporated under vacuum to afford methyl (2E)-3-[4-(9a-butyl-7-methoxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-4-yl)phenyl]-2-propenoate (83 mg) as a pale yellow solid. NMR showed approximately 7-8% of a Bu3SnX impurity.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cscn1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cscn1
Yield: 44.6 %

Procedure:
The title compound was prepared using the method of Example 54 but starting from thiazole-4-carboxylic acid (50 mg; 0.38 mmol) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg; 0.38 mmol). Crude product was purified by chromatography (CombiFlash, silica C18 column, eluent: 0-100% ACN/water) to obtain 63 mg (44%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 4.30-4.52 (m, 3H), 6.95 (d, 1H), 7.85 (d, 1H), 7.95-8.04 (m, 2H), 8.14 (s, 1H), 8.27 (d, 1H), 8.77 (d, 1H), 9.22 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28]>CS(C)=O.O>[CH3:24][N:23]1[C:19]([C:17]([NH:16][C:11]2[CH:10]=[C:9]([CH:14]=[C:13]([CH3:15])[CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:18])=[CH:20][C:21]([CH3:25])=[N:22]1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc(N)nc2)c1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(C)cc(NC(=O)c3cc(C)nn3C)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (2.23 g, 5.43 mmol) in DMSO (30 mL) was added ethyl isothiocyanatoformate (770 μL, 6.52 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→50/50) to give the title compound (2.65 g, 88%) as a pale-yellow oil.