Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[CH:11]=1.C=O.Cl>C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:17][CH:18]=1)[C:14](=[O:16])[O:15][CH2:2][CH2:19]2
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: C=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OCCc2cc(Br)ccc21
Reaction time: 0.17 h

Procedure:
LDA (12 ml, 17 mmol) was dissolved in THF (50 ml) at −78° C. then 4-Bromo-2-methylbenzoic acid (1.0 g, 4.6 mmol) in 10 ml THF was added. The mixture was stirred for 10 minutes then paraformaldehyde (0.56 g, 18.6 mmol) was added. The reaction was stirred at RT for 4 hours. When LC-MS showed the product M+1=229, the reaction was poured into 1N HCl and extracted with ether. The organic layer was washed with brine, dried and evaporated to dryness. The residue was flashed through an Analogix 115 g column and eluted with 0-100% ethyl acetate/hexane to yield 6-bromo-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15](Cl)[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[K+].[K+].[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][C:35]2[C:36](=[O:42])[NH:37][C:38](=[S:41])[NH:39][CH:40]=2)[CH:31]=[N:30]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([S:41][C:38]3[NH:39][CH:40]=[C:35]([CH2:34][C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[C:36](=[O:42])[N:37]=3)[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: CC(Cl)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Sc1nc(=O)c(Cc2cnn(C)c2)c[nH]1)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 130 °C
Yield: 5.6 %

Procedure:
To a suspension of 1-chloro-4-{[4-(1-chloroethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (150 mg, 0.448 mmol) and K2CO3 (124 mg, 0.895 mmol) in DMF (3 mL) was added 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (99 mg, 0.448 mmol). The mixture was heated with a microwave reactor at 130° C. for 15 min. Purification via reverse phase flash chromatography and MDAP then afforded the title compound (13 mg, 5.58% yield). LCMS: rt=3.65 min, [M+H+]=521
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][N:12]=[N+]=[N-])[CH2:5][CH2:4]1)=[O:2].[H][H].[ClH:17]>[Pd].O.C(OCC)(=O)C>[ClH:17].[CH:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1)=[O:2]
Reactant: [N-]=[N+]=NCCCC1CCN(C=O)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NCCCC1CCN(C=O)CC1

Procedure:
To a suspension of 10% palladium-on-carbon catalyst (3 g) in water (100 ml), a solution of N-formyl-4-(3-azidopropyl)-piperidine (19.6 g) in ethyl acetate (100 ml) was added. Hydrogen was passed through the mixture, and the pH was maintained at 3.0 by simultaneous addition of 1 N hydrochloric acid. When the consumption of acid ceased, the catalyst was filtered off, and the two layers separated. The aqueous phase was extracted twice with 25 ml portions of ethyl acetate, and thereafter evaporated to dryness in vacuo. The residue was dissolved in propanol-2, filtered, and the filtrate taken to dryness. The residue was treated with acetonitrile, and the crystals were filtered off and washed with acetonitrile followed by ether to give the title compound with m.p. 141°-143° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][C:9]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:28]([O:37]C(OC(C)(C)C)=O)[C:27]([C:45]([F:48])([F:47])[F:46])=[CH:26][CH:25]=1>>[C:33]([O:32][C:30]([C:29]1[C:28]([OH:37])=[C:27]([C:45]([F:46])([F:47])[F:48])[CH:26]=[CH:25][C:24]=1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3[N+](=O)[O-])cc2)ccc(C(F)(F)F)c1O
Yield: 7 %

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from methyl (4′-hydroxy-2-nitro-1,1′-biphenyl-4-yl)acetate (1.71 g, 3.76 mmol) obtained in Example (37-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (1.08 g, 3.76 mmol) obtained in Example (28-5), the title compound was obtained as a yellow oil (138 mg, three-step total yield: 7%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15](OC)=[O:16])[CH3:7].O.[Cl-].[Na+]>C(O)C>[NH2:3][CH2:2][CH2:1][NH:4][C:15]([C:11]1[S:12][CH:13]=[CH:14][C:10]=1[N:9]=[N:8][N:6]([CH3:7])[CH3:5])=[O:16]
Reactant: COC(=O)c1sccc1N=NN(C)C
Reactant: NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)N=Nc1ccsc1C(=O)NCCN
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To an ice cold (0-5° C.) solution of ethylenediamine (5 mL) in ethanol (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (250 mg) in ethanol (5 mL) for 5 min and stirred at rt for 24 h. The solution was poured into ice cooled water and saturated with sodium chloride. The solution was extracted with THF (3×100 mL). The combined THF layer was washed with brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (90:10) as eluents to give the product as an off-white solid (60 mg, 22%), mp 98-100° C. 1H NMR (400 MHz, CDCl3): δ 8.65 (1H, br s), 7.30 (1H, d, J=5.2 Hz), 7.28 (1H, d, J=5.2 Hz), 3.50-3.57 (5H, m). 3.24 (3H, br s), 2.91 (2H, t, J=6.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][N:28]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][N:28]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)nc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)nc1

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and (4-isopropylphenyl)[(5-methoxypyridin-2-yl)methyl]amine (0.38 g) as starting materials, N-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This is dissolved in ether, and 4 mol/L-hydrochloric acid/dioxane (0.40 mL) was added. The solvent was evaporated, and ether was added to the residue. The precipitated crystals were collected by filtration to give N-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ hydrate (0.54 g). melting point: 108-110° C.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[C:19]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1[CH2:45][CH2:44]OCC1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([CH3:17])[C:18]2[C:19]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[N:20][C:21]([N:22]3[CH2:45][CH2:44][N:16]([CH3:14])[CH2:18][CH2:23]3)=[N:22][CH:23]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1Oc1nc(S(C)(=O)=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1COCCO1
Product: Cc1ccccc1Oc1nc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 97.2 %

Procedure:
To a solution of 0.22 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2-methanesulfonyl-4-o-tolyloxy-pyrimidin-5-yl)-N-methyl-isobutyramide in 10 ml dioxane 0.106 ml (0.96 mmol) I-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml sat. NaHCO3-solution. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.11 g (48%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyloxy-pyrimidin-5-yl]-isobutyramide as a white foam, MS (ISP): 596.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[C:26]([OH:27])=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39](I)[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[C:26]([O:27][CH2:39][CH3:40])=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[N:23][N:22]4[C:32]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: COC(=O)c1cc(O)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was in a manner analgous to that described for Intermediate Example Int-18 (0.16 g, 0.32 mmol), ethyl iodide (0.50 mL, 0.63 mmol, 2.0 equiv.) and cesium carbonate (0.31 g, 0.94 mmol, 3.0 equiv.) in DMF (6 mL) was stirred for 1 h at room temperature, followed by 3 h at 50° C. The reaction mixture was then added to ice water (20 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (2×25 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 80% hexane/20% EtOAc 3.0 min, gradient to 55% hexane/45% EtOAc 2.0 min, 55%/45% EtOAc 3.0 min, gradient to 4% hexane/96% EtOAc 5.5 min, gradient to 100% EtOAc 0.5 min, 100% EtOAc 7.2 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.072 g, 42%):
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]3)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:30])=[CH:7][CH:8]=2)[N:3]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH:32][CH3:31])=[O:28])[CH2:22]3)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:30])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1cc(N2CCN(C(=O)NC3CCCC(C(=O)O)C3)CC2)c2ccc(Cl)cc2n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)C1CCCC(NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of 3-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylic acid (30 mg, 0.069 mmol), HATU (100 mg), methylamine (1.0M in THF, 3 mL) and diisopropylethylamine (0.5 mL) in DMF (3 mL) was stirred at rt for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with sat. NaHCO3 solution and water, and dried over Na2SO4. Concentration in vacuo followed by flash chromatography afforded the title product. LC-MS: 445 (M++1). 1H NMR (CD3OD) δ 1.10–1.35 (m, 4H), 1.65–1.90 (m, 4H), 2.20 (m, 1H), 2.65 (s, 3H), 3.08 (m, 4H), 3.60 (m, 5H), 5.80 (d, 1H), 6.15 (s, 1H), 7.10 (d, 2H), 7.45 (s, 1H), 7.65 (a, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1cc(-c2ccc(F)cc2)ccc1F

Procedure:
5-Bromo-2-fluorobenzoic acid (250 mg, 1.14 mmol) was coupled to 4-fluoro-phenylboronic acid (192 mg, 1.37 mmol) using Method E to give the title compound. No chromatography was necessary.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([F:24])[C:20]=2[O:22][CH3:23])[C:15](=[O:26])[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13]1>>[F:25][C:18]1[CH:17]=[C:16]2[C:21](=[C:20]([O:22][CH3:23])[C:19]=1[F:24])[N:12]([NH:11][CH:1]=[O:2])[CH:13]=[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:15]2=[O:26]
Reactant: CCOC(=O)c1cn(N)c2c(OC)c(F)c(F)cc2c1=O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(NC=O)c2c(OC)c(F)c(F)cc2c1=O
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A solution was prepared by dropping 1.5 ml (0.04 mole) of formic acid onto 3.8 ml (0.04 mole) of acetic anhydride, whilst ice-cooling, and then stirring the mixture at the same temperature for 15 minutes and then at 50° C. for 15 minutes. This solution was added dropwise to a solution of 0.6 g (0.002 mole) of ethyl 1-amino-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XV) [prepared as described in Step (D1) above] dissolved in 4.2 ml (0.11 mole) of formic acid, whilst ice-cooling. The mixture was stirred at room temperature for 9 hours. At the end of this time, the solvent was distilled off under reduced pressure from the mixture. The residue was washed, in turn, with water and diethyl ether, to give 0.6 g of ethyl 6,7-difluoro-1-(formylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVI) as a pale yellow powder.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:36]=[CH:35][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:32]4[CH2:31][CH2:30][N:29]([CH2:28][C:27]5[CH:26]=[CH:25][C:24]([C:23]([F:37])([F:38])[F:22])=[CH:36][CH:35]=5)[CH2:34][CH2:33]4)=[O:19])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: FC(F)(F)c1ccc(CN2CCNCC2)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Yield: 94 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.3 g, 1.04 mmol) and 1-(4-(trifluoromethyl)benzyl)piperazine (0.255 g, 1.04 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl) ethanone as a white solid (0.501 g, 93.3% yield).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[H-].[Na+].C([Li])CCC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>CCOCC.CCCCCC>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:4]#[C:3][CH:2]([OH:5])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(C)O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(O)C#C[Si](C)(C)C

Procedure:
Referring to Flowchart II, 3-butyn-2-ol (formula 21) is treated in step H with sodium hydride in ether at -20° C. and then with 2.0 n-butyllithium in hexane, followed by chlorotrimethylsilane, to produce (+)-4-trimethylsilyl-3-butyn-2-ol (formula 22), which is then reacted in step I with lithium aluminum hydride in ether at reflux for several hours, basified and distilled, to produce (±)-trans-4-(trimethylsilyl)-3-buten-2-ol (formula 23). The reaction in step J of (23) in ether with a mixture of sodium dichromate hydrate and sulfuric acid at <5° C. or below produces trans-4-(trimethylsilyl)-3-buten-2-one (formula 24), which upon distillation with selected solvents gives trans-4-(trimethylsilyl)-2-acetoxy-1,3-butadiene (formula 25).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](Cl)=[N:7][OH:8])#[N:2].[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[CH:14].N>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:13]2[O:8][N:7]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[CH:14]=2)[CH:16]=1
Reactant: N#Cc1cccc(C(Cl)=NO)c1
Reactant: C#Cc1cccnc1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 18B (91 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.64 (dd, J=7.5, 4.4 Hz, 1H), 7.80 (t, J=7.5 Hz, 1H), 7.89 (s, 1H), 8.04 (dt, J=7.7, 1.3 Hz, 1H), 8.21-8.34 (m, 2H), 8.38 (t, J=1.4 Hz, 1H), 8.74 (dd, J=4.8, 1.6 Hz, 1H), 9.13 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:8])[CH2:6][NH2:7].C[N:15](C)[CH:16]=[CH:17][C:18]#N>C(O)C>[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:8])[CH2:6][NH:7][CH:18]=[CH:17][C:16]#[N:15]
Reactant: CN(C)C=CC#N
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Agent: Cl
Solvent: CCO
Product: N#CC=CNCC(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
20.0 g of 2,3-dichlorophenacylamine hydrochloride and 10.0 g of 3-dimethylaminoacrylonitrile are heated for 1 hour under reflux in 300 ml of ethanol. After cooling it to room temperature, the reaction solution is poured into a mixture of ice/dilute hydrochloric acid. After extraction with ethyl acetate, the combined extracts are dried over sodium sulfate, filtered, and the filtrate is concentrated. The oily residue is purified by column chromatography (silica gel: elution with a 4:1 mixture of toluene/ethyl acetate). M.p. 125°-127° C. IR (solid/KBr) in cm-1 : 3380 (NH), 2200 (CN), 1715 (CO) 1625 (C=C). 1H-NMR (DMSOd6) in ppm: 4.09 (d, J=15 Hz, 1H); 4.46 (d, J=7 Hz, 2H); 7.2 (q, 1H); 7.4 (broad s, 1H); 7.45-7.85 (m, 3H). Mass spectrum: molecular peak at 254.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]2[O:9][CH:8]([C:10]3([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:17]=1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]2[O:9][CH:8]([C:10]3([OH:16])[CH2:11][CH2:12][N:13]([C:20]4[N:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][N:21]=4)[CH2:14][CH2:15]3)[CH2:7][C:6]=2[CH:17]=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: OC1(C2Cc3cc(Br)cc(F)c3O2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(O)(C3Cc4cc(Br)cc(F)c4O3)CC2)nc1
Temperature: 90 °C
Yield: 52.7 %

Procedure:
A mixture of 4-(5-bromo-7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidin-4-ol (0.17 g, 0.531 mmol), 2-chloro-5-propylpyrimidine (0.11 g, 0.691 mmol) and K2CO3 (0.22 g, 1.594 mmol) in DMF (2.6 mL) were heated in 90° C. oil bath for 10 hours. At the conclusion of this period, the reaction mixture was cooled to room temperature, quenched with H2O (5 mL), and then extracted with EtOAc (3×5 mL). The combined organic layers were washed with H2O (3×5 mL) and brine (5 mL), dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 30 to 40% EtOAc) to afford Compound 1H as a light yellow solid (0.122 g, 52.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (s, 2 H), 6.99-7.10 (m, 2 H), 4.67 (t, J=9.2 Hz, 1 H), 4.47-4.62 (m, 2 H), 3.23-3.41 (m, 3 H), 3.10 (dd, J=15.8, 9.2 Hz, 1 H), 2.39 (t, J=7.6 Hz, 2 H), 1.84-2.00 (m, 2 H), 1.74 (td, J=13.1, 4.8 Hz, 1 H), 1.46-1.66 (m, 4 H), 0.93 (t, J=7.3 Hz, 3 H). LC/MS (m/z)=437 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:6][C@H:5](/[CH:7]=[CH:8]/[C:9](=[O:16])[CH:10]([CH3:15])[CH2:11][C:12]#[C:13][CH3:14])[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:3]1=[O:27].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[F:28][C:2]1([F:1])[CH2:6][C@H:5](/[CH:7]=[CH:8]/[CH:9]([OH:16])[CH:10]([CH3:15])[CH2:11][C:12]#[C:13][CH3:14])[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:3]1=[O:27]
Reactant: CC#CCC(C)C(=O)/C=C/[C@H]1CC(F)(F)C(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC#CCC(C)C(O)/C=C/[C@H]1CC(F)(F)C(=O)N1CCCCCCC(=O)OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To a −40° C. solution consisting of methyl 7-((5R)-3,3-difluoro-5-((E)-4-methyl-3-oxooct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate (76 mg, 0.20 mmol) in methanol (5 mL) was added cerium chloride heptahydrate (75 mg, 0.20 mmol) in one portion. The reaction mixture was stirred for 15 minutes, and cooled to −78° C. for 20 minutes. Sodium borohydride (15 mg, 0.40 mmol) was added and the reaction was stirred for 3 hours, quenched with equal parts water and saturated ammonium chloride and warmed to room temperature. The reaction mixture was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated to a cloudy white oil. The residue was purified by silica gel chromatography. Elution with methanol-dichloromethane (1:200 v:v) to afford the title compound (70 mg) as a clear oil. Rf 0.50 (solvent system: 5:95 v/v methanol:dichloromethane).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:5]=1[O:6][C:7]1[CH:19]=[CH:18][C:10]2[C@@H:11]3[C@@H:14]([C:15]([NH2:17])=O)[C@@H:12]3[O:13][C:9]=2[CH:8]=1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:5]=1[O:6][C:7]1[CH:19]=[CH:18][C:10]2[C@@H:11]3[C@@H:14]([C:15]#[N:17])[C@@H:12]3[O:13][C:9]=2[CH:8]=1
Reactant: NC(=O)[C@H]1[C@@H]2Oc3cc(Oc4ccc(C(F)(F)F)cc4OC(F)F)ccc3[C@@H]21
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#C[C@H]1[C@@H]2Oc3cc(Oc4ccc(C(F)(F)F)cc4OC(F)F)ccc3[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the corresponding amide (Example 21, 386 mg, 0.96 mmol) in DMF (5 mL) was added cyanuric chloride (89 mg, 0.48 mmol). The reaction was stirred at room temperature for 2h. After aqueous workup, the crude product was purified on a silica gel column, eluting with ethyl acetate (0-30%) in hexanes. The final product was collected as colorless oil.