Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 10.2 %

Procedure:
2-Hydroxy-5-methoxyacetophenone (11.1 g), 4-chloro-6,7-dimethoxyquinoline (5.00 g), and 4-dimethylaminopyridine (8.10 g) were suspended in o-dichlorobenzene (40 ml) to prepare a suspension which was then stirred at 120° C. for 48 hr. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give 1-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone (802 mg, yield 10%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][C:22]=1[O:36][CH3:37].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]([CH2:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:36][CH3:37])[CH:23]=3)[CH2:32][CH2:31]2)=[O:35])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Reactant: CC(C)c1n[nH]c(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(C)C)c(Cl)c3C(F)(F)F)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-isopropyl-5-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.45) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.19–7.22 (d, 2H), 6.38–6.48 (m, 2H), 5 (s, 2H), 3.86 (s, 3H), 3.62–3.78 (m, 4H), 3.08–3.18 (m, 4H), 2.98–3.04 (m, 1H), 1.35–1.41 (d, 6H). 13C NMR (400 MHz, CDCl3): 163.8, 154.8, 150.5, 130, 109.8, 102, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26.8, 20.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(N(CC)CC)C.Br[CH2:44][C:45]([NH2:47])=[O:46]>C(Cl)Cl.CO.O>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: NC(=O)CBr
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CC(N)=O)CC3)ccc1-2
Reaction time: 42 h
Yield: 72.1 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 375 (250 mg, 0.49 mmol) in DCM (2.5 mL) was added triethylamine (157 μL, 1.13 mmol) followed by 2-bromoacetamide (81 mg, 0.59 mmol). The reaction mixture was stirred for 42 hours before being diluted with MeOH and water. The DCM was removed in vacuo to give a suspension. The solid was filtered off and washed with MeOH then ether to give 475 as an off-white solid (160 mg, 72%). LCMS: RT=3.17 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.23 (1 H, d, J=8.20 Hz), 8.05 (1 H, s), 7.17 (1 H, s), 7.08 (1 H, s), 7.07-7.02 (1 H, m), 6.90 (1 H, d, J=1.75 Hz), 5.81-5.71 (1 H, m), 4.35-4.28 (2 H, m), 3.37 (2 H, s), 2.90-2.79 (4 H, m), 2.13 (2 H, dd, J=8.92, 8.51 Hz), 1.77-1.67 (4 H, m), 1.50 (6 H, d, J=6.58 Hz). 1 Proton obscured by solvent peaks
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3[C:18]4[NH:22][C:21](=[O:23])[NH:20][C:19]=4[CH:24]=[CH:25][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:12][CH:13]3[O:26][C:17]4[C:16](=[CH:25][CH:24]=[C:19]5[NH:20][C:21](=[O:23])[NH:22][C:18]5=4)[O:15][CH2:14]3)[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)C1CCN(CC2COc3ccc4[nH]c(=O)[nH]c4c3O2)CC1
Temperature: 90 °C

Procedure:
A mixture of 0.60 g (1.6 mmole) of (8R)-1,3,7,8-tetrahydro-8-[[[(4 methylphenyl)sulfonyl]oxy]methyl]-2H-[1,4]dioxino[2,3-e]benzimidazol-2-one and 1.7 g (8.0 mmole) of 4-(4-fluorobenzoyl)piperidine in 30 mL of DMSO was heated at in 90° C. under nitrogen for 5 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 500 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform as eluant and the product fractions evaporated to give the free base as a colorless oil. This was recrystallized from ethanol with the addition of 4 N isopropanolic HCl to give 0.13 g of the (S)-enantiomer of the title compound. A second recrystallization from ethanol gave 0.095 g of the product as a white solid hydrochloride, hydrate, m.p. 250-256° C. (d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-:19].[K+]>C(O)(C)(C)C.Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]([NH2:11])=[O:19])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(CC#N)c1ccc(-c2ccccc2)c(F)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(CC(N)=O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 70 °C
Yield: 75 %

Procedure:
To a solution of 3-(2-fluoro-biphenyl-4-yl)butyronitrile in tert-butyl alcohol was added 1.87 g of finely powdered potassium hydroxide. The resulting suspension was stirred and heated to 70° C. for 2.5 hours and cooled to room temperature. The reaction suspension was diluted with 1.0 N HCl solution (100 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were combined and washed with 5% bicarbonate solution (100 mL) and then with H2O (100 mL). The organics were then dried over MgSO4, and concentrated to a white solid which was re-crystallized several times with EtOAc/Hex to give white flaky prisms (1.62 g, 75% yield).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[CH2:13]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:13]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](=[NH:22])[O:21][CH2:6][CH3:7])[CH2:14][CH2:15][CH3:16]
Reactant: CC[O+](CC)CC
Reactant: CCCCOc1ccccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCCOc1ccccc1C(=N)OCC
Reaction time: 20 h
Yield: 54.5 %

Procedure:
A solution of triethyloxonium fluoroborate (32.4 g., 0.171 mole) in methylene chloride (75 ml.) was added to a stirred solution of 2-n-butoxybenzamide [J. Pharm. Pharmacol., 4, 872 (1952)] (33.0 g., 0.171 mole) in methylene chloride (200 ml.) at 25°. The mixture was stirred at 25° for 20 hours. The solution was concentrated to about 1/15 of the original volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether to give ethyl 2-n-butoxybenzimidate fluoroborate (28.7 g.), m.p. 82°-88°. To a stirred, cooled (ice-water) suspension of the fluoroborate (28.7 g.) in ethanol (75 ml.) was added 8% ethanolic ammonia (150 ml.). The mixture was stirred at 25° for 20 hours. The ethanol was removed and the residue partitioned between ether and 5N sodium hydroxide (100 ml.). The ether layer was washed with brine, dried over sodium sulfate, and then concentrated. A solution of the residual oil in ether was treated with hydrogen chloride to precipitate the title compound (16.8 g.), m.p. 150°-155°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]2[CH2:10][CH2:11][O:12][C:13](=[O:14])[CH:7]2[CH2:6]1.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([OH:39])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1.C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([O:39][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH:8]5[CH2:10][CH2:11][O:12][C:13](=[O:14])[CH:7]5[CH2:6]4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:27]=1
Reactant: O=C1OCCC2CN(CCCCl)CC12
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CC2CCOC(=O)C2C1
Temperature: 90 °C
Reaction time: 10 h
Yield: 37.3 %

Procedure:
To a solution of 2-(3-chloropropyl)hexahydropyrano[3,4-c]pyrrol-4(2H)-one (0.25 g) in DMF (8 mL) was added K2CO3 (3.0 eq), 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.38 g) and tetrabutylammonium iodide (0.1 eq). The reaction mixture was heated to 90° C. and stirred for 10 h. To the mixture was added CH2Cl2 (100 mL). The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the product (0.20 g, 32.50%), HPLC: 97.35%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 467.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.06-2.12 (m, 4H), 2.35 (d, J=2.92 Hz, 1H), 2.51-2.58 (m, 3H), 2.76-2.79 (m, 2H), 2.97-3.02 (m, 1H), 3.49-3.50 (m, 1H), 3.52 (s, 1H), 4.00 (s, 3H), 4.18 (d, J=1.80 Hz, 1H), 4.21-4.24 (m, 1H), 4.35-4.40 (m, 1H), 7.13 (t, J=8.80 Hz, 1H), 7.24 (d, J=9.48 Hz, 1H), 7.41 (s, 1H), 7.68 (m, 2H), 7.95-7.98 (m, 1H), 8.28 (s, 1H), 8.63 (s, 1H) ppm.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].CC#N.CCOC(C)=O>O>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: C[C@H](CI)Cn1c(=O)ccc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC1CCN(C[C@@H](C)Cn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 43.7 %

Procedure:
A 4mL vial was charged with crude (S)-1-(3-iodo-2-methyl-propyl)-1H-quinolin-2-one (0.66 g), 4-butylpiperidine (0.43 g, 3.0 mmol) and dry CH3CN (1 mL). The mixture was shaken at 50° C. for 72 h and then poured onto The compound EtOAc (50 mL) and water (25 mL). The water phase was extracted (2×25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 1:4) and then cation-exchange CC producing the title compound (0.300 g, 44%). 1H NMR (CD3OD) δ 7.88 (d, J=9.2 Hz, 1H), 7.73-7.66 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 4.42-4.26 (m, 2H), 2.90 (brd, J=11.4 Hz, 1H), 2.74 (brd, J=11.4 Hz, 1H), 2.40-2.16 (m, 3), 1.94-1.78 (m, 2H), 1.64-1.54 (m, 2H), 1.35-1.00 (m, 9H), 0.96-0.85 (m, 6H); 13C NMR (CD3OD) δ 163.7, 140.2, 139.5, 130.8, 129.1, 122.5, 121.4, 120.4, 115.3, 64.0, 55.1, 54.2, 46.8, 36.3, 35.8, 32.4, 32.3, 29.8, 28.9, 22.8, 16.1, 13.2.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:18]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.CCOCC>C1COCC1>[CH:11]1([CH2:10][CH2:9][C:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C(CCC1CCCCC1)Sc1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)C1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3-Cyclohexyl-thiopropionic acid S-pyridin-2-yl ester (1.43 g, 5.74 mmol) from Step 1 above was dissolved in dry THF (28 mL) and cooled to −78° C. A solution of cyclopentylmagnesium bromide in Et2O (2.0 M, 3.01 mL, 6.02 mmol) was added dropwise. After stirring 1 h, the cooling bath was removed. The reaction mixture was quenched with 1 N HCl and extracted with EtOAc (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (1% EtOAc in hexanes) to give the product (0.99 g, 83%) as clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12](Cl)=[O:13].Cl.[C:16](=[NH:26])([O:23][CH2:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([N:26]=[C:16]([O:23][CH2:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: CCOC(=N)c1ccccc1
Reactant: O=C(Cl)c1cccc2c(Br)cccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=NC(=O)c1cccc2c(Br)cccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the procedure of Soto et al, Synthesis, 483 (1983), a solution of 5-bromo-1-naphthoyl chloride (10.7 g, 39.8 mmol) in dry toluene (30 mL) was added dropwise to a mixture of ethyl benzimidate hydrochloride (7.4 g, 39.8 mmol) and triethylamine (8.9 g, 12.2 mL, 87.6 mmol) in dry toluene (100 mL). The mixture was stirred for 18 hours at room temperature, then heated to 70° C. for 60 hours. The mixture was cooled to room temperature and the preciptated salt removed by filtration and washed with toluene. The filtrate was concentrated in vacuo to give a red oil which crystallized upon drying in vacuo (15.2 g, guant.). This material was of sufficient purity to be used in the subsequent reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([CH:17]=[O:18])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1COCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([CH2:17][OH:18])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc(C=O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1nc(CO)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a cooled (−78° C.) colorless solution of 3-ethyl-1-formyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (19.9 mg; 0.044 mmol) in anhydrous toluene (2 ml) was added dropwise 1M DIBAL in THF (88 μl; 2 eq.). The resulting yellow homogeneous solution was further stirred at −78° C. for 10 min., and then at rt for 1 h. The resulting crude mixture was purified by preparative HPLC to give the pure product 3-ethyl-1-hydroxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (16 mg; 0.035 mmol; 80%). LC-MS: tR=0.91 min.; [M+H]+=454.27 g/mol.
Reaction SMILES: O(C1C=CC(O)=CC=1)C1C=CC=CC=1.C(I)C.[OH-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:24]C(Cl)C.[F:28][C:29]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:30]=1[C:31](O)=[O:32].S(Cl)(Cl)=O>O>[F:28][C:29]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:30]=1[C:31]([Cl:24])=[O:32]
Reactant: CC(Cl)Cl
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: Oc1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCI
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Yield: 60.4 %

Procedure:
Into a 250 ml three-neck flask, which was equipped with an additional funnel and calcium chloride drying tube, were placed 4-ethoxydiphenyl ether (3.5 g), which was synthesized from p-phenoxyphenol with ethyl iodide in the presence of sodium hydroxide, aluminum chloride (5.4 g) and dried dichloroethane (30 ml). The solution of 2,3,4,5,6-pentafluorobenzoyl chloride (3.7 g), which was synthesized from 2,3,4,5,6-pentafluorobenzoic acid with thionyl chloride, and dried dichloroethane (10 ml) was slowly dripped into flask while stirring. After the addition was complete, the reaction mixture was stirred overnight at room temperature. Small amount of water was added very slowly to the reaction mixture and continued stirring for 15 min. The reaction mixture was then poured into 250 ml of water, which was extracted with dichloromethane. The organic layer was collected, washed with water, dried over sodium sulfate, filtered and evaporated. Recrystallization from methanol with charcoal yielded white crystal of 4-ethyoxy-4′-(2,3,4,5,6-pentafluorobenzoyl) diphenyl ehter (EPDE) (yield 60.4%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[CH2:26]=O>C(O)=O>[CH3:26][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: C=O
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Solvent: O=CO
Product: CN1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (25 g, 61 mmol) in 140 mL of formic acid (96%) was added 50 g of formaldehyde (37%). The solution was stirred at 75° C. for 48 h and was cooled to room temperature. The excess formic acid was removed under reduced pressure and the residue was dissolved in 100 mL of water. The solution was added to concentrated NH4OH/H2O and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (1×250 mL) and was dried over Na2SO4. The solution was filtered and concentrated to leave a white solid. The solid was triturated with ether and was filtered to afford the title compound: MS (M+H): 353 (base peak).
Reaction SMILES: [CH3:1][C:2]1([C:5]2O[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)[CH2:4][CH2:3]1.[OH-].[NH4+:13]>>[CH3:1][C:2]1([C:5]2[NH:13][CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(c2cc(=O)cco2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC1(c2cc(=O)cc[nH]2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-(1-methyl-cyclopropyl)-pyran-4-one (Step 1.6) (66.6 mmol) and a 28-30% aqueous solution of ammonium hydroxide (182 mL) was stirred for 1 h at 65° C. After cooling to rt, the reaction mixture was decanted to remove a dark brown solid and then concentrated. The residue was diluted with MeOH and re-concentrated (3×) to afford the title compound as a brown-orange solid. HPLC: tR=3.56 min (method B); LC-MS: tR=0.87 min, [M+H]+ 151; TLC: Rf=0.18 (9:1 CH2Cl2/MeOH).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.CCOCC.[C:12]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1COCC1>[C:12]1([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Brc1ccsc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccsc2)cc1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
To a mixture of 1.0 mL (10.6 mmol) of 3-bromothiophene, 20 mL of anhydrous ether, 60 mg (0.11 mmol) of 1,3-[Bis(diphenylphosphino)-propane]dichloronickel(II)[NiCl2 (dppp)] under N2 with stirring at 0° C. was slowly added 7.0 mL (14 mmol) of 2.0 M PhMgCl in THF. The reaction was slowly warmed to room temperature. Note that a vigorous exothermic reaction may occur if the Grignard reagent is added too fast or if the reaction is allowed to warm to room temperature to rapidly. After stirring for 3 h, the mixture was warmed to reflux for 2 h, poured into 20 mL of 5% HCl solution, and extracted with 2×20 mL of ether. The combined organic phases were washed with 15 mL of H2O and 15 mL of brine, dried (MgSO4) and concentrated. Crystallization from hexanes provided 0.58 g (34% yield) of 3-phenylthiophene.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH2:11]Cl)=[CH:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:38])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([CH3:29])[CH3:28])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:38])[C:27]([O:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:11][C:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)=[CH:35][CH:36]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A solution of 367 mg (1.11 mmol) 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 115C]) and 250 mg (1.11 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] in 4 ml DMF was treated with 436 mg (1.34 mmol) cesium carbonate. The reaction mixture was stirred for 24 h at RT and then it was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to provide 344 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester.