Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Oc3cccc(Cl)c3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 3-chlorophenol (0.23 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(3-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.58 g, 83%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][N:25]2[NH2:28])=[CH:21][CH:20]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:30][C:18]([F:17])([F:29])[C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][N:25]2[NH:28][C:14]([C:10]2[C:11]([CH3:13])=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Nn1ccc2ccc(C(F)(F)F)cc21
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2ccc(C(F)(F)F)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic acid (258 mg, 1.2 mmol) and 6-trifluoromethyl-indol-1-ylamine (200 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 0.5 h. The mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with Et2O/heptane overnight. The precipitate is collected by filtration, washed with H2O (50 mL) and heptane (50 mL), and dried in vacuo to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (6-trifluoromethyl-indol-1-yl)-amide (160 mg, 40%). MS: 398 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.13 (s, NH, 1H), 9.36 (s, 1H), 8.82 (d, 1H), 8.48 (d, 1H), 8.04 (m, 1H), 7.83 (m, 3H), 7.60 (m, 1H), 7.44 (d, 1H), 6.74 (d, 1H), 2.80 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:31][C:32]1[C:41]([CH3:42])=[CH:40][C:39](Br)=[CH:38][C:33]=1[C:34]([NH:36][CH3:37])=[O:35].[CH3:44][N:45](C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Zn].[C-]#N.[Zn+2].[C-]#N.C(O)(=O)C>[NH2:31][C:32]1[C:41]([CH3:42])=[CH:40][C:39]([C:44]#[N:45])=[CH:38][C:33]=1[C:34]([NH:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: CC(=O)O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 130 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A flask purged with dry nitrogen was charged with palladium(II) acetate (370 mg, 1.64 mmol), 1,4-bis(diphenylphosphino)butane (850 mg, 2 mmol), activated zinc powder (500 mg, 7.64 mmol), zinc(II) cyanide (51 g, 434 mmol), and 2-amino-5-bromo-N,3-dimethylbenzamide (i.e. the product of Step A) (200 g, 820 mmol). Then freshly degassed N,N-dimethylformamide (500 mL) was added, and the mixture was heated at 130° C. for 25.5 h. Then the temperature was reduced to 95° C., and acetic acid (200 mL) was added. The mixture was sparged with nitrogen to remove hydrogen cyanide through scrubbers charged with aqueous sodium hydroxide and sodium hypochlorite solutions while cooling to room temperature. Then water (1500 mL) was added over 1.5 h, and sparging with nitrogen was continued overnight. Then the mixture was filtered, and the solids were washed with water and dried in a vacuum oven to afford the title compound as fluffy, light yellow solids, 141.5 g (90.9% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>C1(C)C=CC=CC=1>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:28][C@@H:26]2[CH2:25][N:22]3[C:23](=[O:24])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C@@H:17]4[CH2:30][C@@:18]4([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:19][C:20](=[O:29])[C@@H:21]3[CH2:27]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: C1CN2CCN1CC2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Reaction time: 0.25 h

Procedure:
A solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate and DABCO in toluene was stirred at room temperature (rt). To this solution was added a solution of 4-bromobenzene-1-sulfonyl chloride in toluene. After the addition was complete the reaction mixture was quenched with 10% aqueous sodium carbonate and the mixture stirred for 15 min. Tetrahydrofuran was added and the mixture was washed with 0.5 M HCl, water, and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure and dried to provide the title compound.
Reaction SMILES: [C:1](/[C:3](=[C:12](/OCC)\[CH3:13])/[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:19]=1[NH2:20]>C(O)C>[C:1](/[C:3](=[C:12](/[NH:20][C:19]1[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])\[CH3:13])/[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Cc1cccc(C)c1N
Reactant: CCOC(=O)NC(=O)/C(C#N)=C(/C)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)/C(C#N)=C(/C)Nc1c(C)cccc1C

Procedure:
α-Cyano-β-ethoxy-N-ethoxycarbonylcrotonamide (0.05 mol) is reacted with 2,6-dimethylaniline (0.05 mol) in hot ethanol using the procedure of Example 1 to yield α-cyano-β-(2,6-dimethylanilino)-N-ethoxycarbonylcrotonamide, which is cyclized by heating in tetralin to yield 5-cyano-1-(2,6-dimethylphenyl)-6-methyluracil, m.p. 302°-303°.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:6]([C:7]#[CH:8])[O:5][C:4](=[O:9])[NH:3]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](I)[CH:20]=2)[N:15]=[CH:14][N:13]=1.C(NC(C)C)(C)C>C1COCC1.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.[Cu](I)I>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:8]#[C:7][CH:6]2[O:5][C:4](=[O:9])[NH:3][C:2]2([CH3:10])[CH3:1])[N:13]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: C#CC1OC(=O)NC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)NC(=O)OC1C#Cc1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol), 4chloro-6-iodoquinazoline (1.63 g, 5.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (200 mg, 0.28 mmol), copper iodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30 mL) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH2Cl2 (80 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) of yellow solid: 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H), 5.57 (brs, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=2.0 Hz), 9.05 (s, 1H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:12]([NH:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6].O>C(O)C.[Pd]>[NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reaction time: 5 h

Procedure:
Z-Glu(Val-Gly-OBzl)-OBzl described above (6.20 g, 10.03 mmol) was suspended in ethanol (200 ml), 10% palladium/carbon (1.50 g) was added to the suspension, and a reduction reaction was performed under a hydrogen atmosphere at 55° C. for 5 hours. During the reaction, 100 ml in a total volume of water was gradually added. The catalyst was removed by filtration using a Kiriyama funnel, and the filtrate was concentrated under reduced pressure to a half volume. The reaction solution was further filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. After the residue was dissolved in a small volume of water, ethanol was added to precipitate a crystal, and the crystal was collected by filtration and dried under reduced pressure to obtain γ-Glu-Val-Gly as a white powder (2.85 g, 9.40 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH:21]([CH2:23][CH3:24])[CH3:22])[N:12]2[N:11]=1)[CH3:2].[S:26](Cl)([Cl:29])(=[O:28])=[O:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH:21]([CH2:23][CH3:24])[CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1ccccc1-c1nn2c(CC(C)CC)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(CC(C)CC)nc(C)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 7.23 g (0.12 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-ethylpropyl)-1H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 18A). This gives 8.56 g (91.9%) of sulphonyl chloride as a white solid which is directly reacted further.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.[C:13]([O-])([O-:15])=[O:14].[Na+].[Na+]>O1CCOCC1.O.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH3:10][C:8]1[NH:7][C:6]2[CH:11]=[C:2]([C:13]([OH:15])=[O:14])[CH:3]=[C:4]([CH3:12])[C:5]=2[N:9]=1
Reactant: Cc1nc2c(C)cc(Br)cc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Mo]
Agent: [Pd]
Agent: [C-]#[O+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c(C)cc(C(=O)O)cc2[nH]1
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 56.7 %

Procedure:
To a solution of 6-bromo-2,4-dimethyl-1H-benzimidazole (200 mg, 0.90 mmol) in degassed dioxane (2 mL) was added ((trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II))) (30 mg, 0.05 mmol), molybdenum hexacarbonyl (120 mg, 0.45 mmol) and a solution of Na2CO3 (283 mg, 2.67 mmol) in degassed water (2.4 ml). The mixture was stirred for 20 seconds and then heated at 165° C. for 15 minutes in a microwave reactor with absorption set at very high for 20 minutes. The reaction vessel was vented and filtered through diatomaceous earth. The solution was extracted with EtOAc and the aqueous phase was back extracted with additional EtOAc (2×). The combined organic extracts were set aside. Water (5 mL) was added to the aqueous extract which was then acidified with 0.5 M HCl to pH 3. The resulting solids were air dried to provide the title compound (97 mg, 57%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[C:42]([CH2:59][OH:60])=[N:43][N:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:41]2[C:42]([CH2:59][OH:60])=[N:43][N:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:50][CH2:51]3)[CH:45]=2)[CH:13]=[N:12][C:11]=1[N:25]([C:26]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:32])[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(CO)n2)CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nc5ccccc5o4)c3)c(CO)n2)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
Tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (237 mg), tert-butyl 4-(4-bromo-3-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (159 mg), potassium phosphate (225 mg) and trisdibenzilideneacetone dipalladium (20.19 mg) and tricyclohexylphosphine (12.37 mg) were weighed out in a microwave vial, sealed and 1,4-dioxane (4 ml) and water (400 μl) were added. Argon was bubbled through the suspension at 25° C. for 5 minutes. The mixture was stirred at 120° C. for 2 hours. The reaction mixture was allowed to cool down, Dicalite Speed Plus (Acros Chemicals) was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 50 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (150 mg). The N-tert-butoxycarbonyl groups on the resultant product were removed by conventional treatment with trifluoroacetic acid to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (49.0 mg) as a solid.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([C:17]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([CH3:46])[CH:40]=1)([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]([OH:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])=[C:22]([CH3:38])[CH:21]=1)[CH2:18][CH3:19])[CH3:16].Cl>O1CCCC1>[CH2:15]([C:17]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([CH3:46])[CH:40]=1)([C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:37])([C:33]([F:34])([F:35])[F:36])[C:29]([F:32])([F:31])[F:30])=[C:22]([CH3:38])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt % solution in toluene, 17 mL, 56.74 mmol) was added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenol (Example 25-(1); 8.67 g, 18.91 mmol) in tetrahydrofuran (100 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for one hour. The reaction mixture was then poured into 1 N hydrochloric acid aqueous solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 and 4:1) to give the target product as a colorless oil (6.11 g, 70%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:53]=[N:54][CH:55]=[C:56]([O:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:57]=1>CN(C=O)C.O>[Cl:51][C:52]1[CH:57]=[C:56]([O:58][CH:59]2[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:61][CH2:60]2)[CH:55]=[N:54][CH:53]=1
Reactant: Clc1cncc(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 12.71 %

Procedure:
DIPEA (387 mg, 3.0 mmol) was added a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (247 mg, 1.0 mmol) in DMF (2 mL) followed by HOBt (162 mg, 1.2 mmol) and EDCI.HCl (229 mg, 1.2 mmol). After 2 minutes 3-chloro-5-(piperidin-4-yloxy)-pyridine hydrochloride (prepared according to the method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) to afford 56 mg (12.71% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.14, 95.7%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (m, 2H), 8.0 (m, 1H), 7.8 (m, 3H), 7.4 (m, 4H), 7.1 (m, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([F:8])[C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:35])([F:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:28][CH2:27][CH2:26][N:25]2[N:29]=[C:30]([CH:32]=[CH2:33])[N:31]=[C:24]12.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[F:8][C:6]1[N:7]=[C:2](/[CH:33]=[CH:32]/[C:30]2[N:31]=[C:24]3[CH:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:16]([F:34])([F:15])[F:35])[CH2:28][CH2:27][CH2:26][N:25]3[N:29]=2)[CH:3]=[CH:4][C:5]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cn(-c2ccc(Br)nc2F)cn1
Reactant: C=Cc1nc2n(n1)CCCC2c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCCC4c3ccccc3C(F)(F)F)nc2F)cn1
Temperature: 120 °C
Reaction time: 1.3 h
Yield: 22.8 %

Procedure:
6-Bromo-2-fluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine (156 mg) and 8-(2-trifluoromethylphenyl)-2-vinyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (179 mg) were dissolved in toluene (5 ml). Tris(dibenzylideneacetone)dipalladium (167 mg), tri-o-tolylphosphine (111 mg) and triethylamine (340 ul) were added and the reaction solution was heated and stirred in a nitrogen atmosphere at 120° C. for 1.3 hours. After leaving to cool, ethyl acetate and water were added. The reaction solution was filtered through celite and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain a racemate of the title compound (65 mg). The resulting racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=6:4) to obtain the title optically active compound with positive optical rotation (20 mg, >99% ee) and the title optically active compound with negative optical rotation (20 mg, >99% ee).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12](O)[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][CH3:5])=[O:2].C(O)=[O:20].C([O-])=O.[Na+].C1(C=CC(O)=CC=1)O>O1CCOCC1.O>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:13]([OH:17])[CH:14]=[CH:15][C:16]1=[O:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=CO
Reactant: CCOC(=O)CCCCCCC(O)c1ccco1
Agent: O=C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCC1C(=O)C=CC1O

Procedure:
A stirred mixture of 2.0g (7.87 mmol) of α-(6-carbethoxyhexyl)furfuryl alcohol (Example 4), 5.93 ml of 97% formic acid, 268 mg of sodium formate, 10 mg of hydroquinone, and 40 ml of 3:2 dioxane-water is stirred at reflux for 18 hr. The solution is cooled, saturated with salt, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give an amber oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11](I)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1>O1CCOCC1.CCOC(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>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([B:19]2[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C)(C)OC(=O)c1c(F)cccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1c(F)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a degassed mixture of tert-butyl 2-fluoro-6-iodobenzoate (161 mg, 0.5 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.1 mL, 0.6 mmol) and TEA (0.25 mL, 1.5 mmol) in 2 mL dioxane, was added Pd(PPh3)2Cl2 (7 mg, 0.01 mmol). The mixture was stirred at 165° C. for 10 min in a microwave oven. The mixture was diluted with EtOAc, washed with sat. NH4C1, H2O and brine, dried over (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-10% EtOAc/hexanes gradient) to afford 50 mg (45%) of Intermediate 436.2.