Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:30])[CH:16]([NH:25][C:26](=[O:29])[CH2:27]O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:13][O:14][C:15](=[O:30])[CH:16]([NH:25][C:26](=[O:29])[CH2:27][O:9][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: O=C(O)COc1ccc(O)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)COC(=O)COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (4-hydroxy-phenoxy)-acetic acid 12 (10 grams, 59.52 mmol) and 2-(2-hydroxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester 3 (15 grams, 59.28 mmol) in anhydrous dichloro methane (100 mL) under an nitrogen atmosphere at 0° C. is added to a solution of 1,3-dicyclohexyl carbodiimide (31 grams, 150.24 mmol) in dichloro methane (75 mL) drop wise. Later it is stirred at room temperature for 6 hours. The solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 13, which can be purified in appropriate solvent.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=2)=[CH:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)=[CH:16][C:17]#[N:18])[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2cccc(OCc3ccccc3)c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(O)c2)c1
Yield: 63.5 %

Procedure:
3-(3-Benzyloxyphenyl)-3-(3,5-dimethoxyphenyl)acrylonitrile (3.45 g), 20% palladium hydroxide on charcoal (0.103 g, 3% w.t.), cyclohexene (12 ml), and ethanol (24 ml) were heated to reflux overnight. The black suspension was cooled, filtered through a Celite pad, and concentrated to an oil, which was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 30 min.) to give 3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-acrylonitrile as an off-white solid (1.66 g, 64%): mp, 127-129° C.; 1HNMR (DMSO-d6) δ 9.73 (s, 0.67H, OH of one isomer), 9.65 (s, 0.26H, OH of the other isomer), 7.33-7.23 (m, 1H, Ar), 6.92-6.62 (m, 4H, Ar), 6.46 (d, J=2 Hz, 2H, Ar), 6.32 (s, 0.73H, double bond proton of one isomer), 6.27 (s, 0.27H, double bond proton of the other isomer), 3.77 (s, 1.85H, 2OCH3 of one isomer), 3.73 (s, 4.29H, 2OCH3 of the other isomer), isomer ratio 27.6%:72.4%; 3C NMR (DMSO-d6) δ 161.5, 160.4, 157.4, 157.2, 139.9, 138.7, 138.1, 129.7, 119.7, 118.7, 118.0, 117.5, 116.7, 115.7, 115.0, 107.1, 106.6, 101.8, 101.0, 96.3, 96.0, 55.4; Anal. Calcd. For C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.40; H, 5.26; N, 4.85.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]([Si:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:20]2[CH2:19][CH:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC1CN(C(=O)Cc2ccc(Br)cc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 4-bromophenyl acetylchloride (300 mg, 1.28 mmol) in CH2Cl2 (5 mL) was added 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine (399 mg, 1.28 mmol), DIPEA (670 μL, 3.85 mmol) and the reaction stirred at RT for 2 h. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 80% EtOAc/isohexane to obtain 2-(4-bromo-phenyl)-1-[3-(tert-butyl-diphenyl-silanyloxy)-azetidin-1-yl]-ethanone as a colourless glass (632 mg, 97%).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.[C:29](=O)(O)[O-:30].[K+].O>CO>[OH:1][C@@H:3]1[C@@H:2]([O:30][CH3:29])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2α,3α-Epoxy-5α-pregn-16-en-20-one (500 mg.) in methanol (30 ml.) was treated with concentrated sulphuric acid (0.1 ml.). The reaction solution was stirred at room temperature for 10 minutes, and then potassium bicarbonate solution (10%, 6 ml.) and water were added and the precipitate was extracted into chloroform. The chloroform solution was evaporated to an oil which was purified by preparative TLC in ethyl acetate/petrol (1/2), to give, as the major product title compound (255 mg) as colourless plates (from ethyl acetate/petrol), m.p. 186°-189°, [α]D (c, 0.82) + 62° , λmax (EtOH) 239 nm (ε 8370).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].O[CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[O:14][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)phenol (1.4 g, 6.7 mmol) in benzene (50 ml) was added (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.4 g, 6.7 mmol) and triphenylphosphine (1.78 g, 6.7 mmol). Then diisopropyl azodicarboxylate (1.4 g, 6.7 mmol) was added dropwise to the mixture at RT. The resulting mixture was stirred at RT overnight and then solvent was removed under vacuum. The product was purified by flash column chromatography on the silica gel (EtOAc/hexane=5→25%) resulting in an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25]2)=[CH:20][CH:19]=1>>[CH3:30][N:29]([CH3:31])[CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:16])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was then treated by method G. This resulted in the product with the molecular weight of 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=12.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH:4]=[N:3][C:2]=2[Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=1
Reactant: Cc1ccc2c(I)ncn2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(C)ccc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 1-iodo-6-methyl-imidazo[1,5-a]pyridine (97 mg, 0.38 mmol) was dissolved in THF (3 ml). The solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0M solution in THF, 0.23 ml, 0.46 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.12 ml, 0.44 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to provide 6-methyl-1-tributylstannanyl-imidazo[1,5-a]pyridine as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[CH2:14]Br)=[O:4].[CH3:16][O:17][C:18](=[O:31])[CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[CH2:14][N:20]([CH2:19][C:18]([O:17][CH3:16])=[O:31])[S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)(=[O:23])=[O:22])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (363 mg, 1.07 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (260 mg, 1.07 mmol), sodium iodide (321 mg, 2.14 mmol) and potassium carbonate (296 mg, 2.14 mmol) in DMF (10 mL) was stirred at r.t. for 16 h. Brine (30 mL) was added and the mixture was extracted with EtOAc. The organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-70% EtOAc/hexanes) to give 292 mg of the title compound. MS: (+) m/z 501.13, 503.08 (M+1, 79/81Br).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]([O:14]C)=[O:13])[CH2:7][CH2:6]1.COC(C=C1CCN(C(OC(C)(C)C)=O)CC1)=O>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][C:8](=[CH:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:10]1
Reactant: COCCN1CCC(=CC(=O)OC)CC1
Agent: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Product: COCCN1CCC(=CC(=O)O)CC1

Procedure:
The title compound was prepared following the procedure for the preparation of intermediate 3a except that methyl 2-(1-(2-methoxyethyl)piperidin-4-ylidene)acetate was substituted for tert-butyl 4-((methoxycarbonyl)methylene)piperidine-1-carboxylate.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1>O1CCCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:18][CH:19]=2)[NH2:12])=[CH:7][CH:6]=1
Reactant: NNc1ccc(F)cc1
Reactant: BrCc1coc(-c2ccccc2)n1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1coc(-c2ccccc2)n1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) was added in portions. After 5 minutes, the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 4-(bromomethyl)-2-phenyloxazole (586 mg, 2.46 mmol; Anichem) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 267 (M+H−NH3)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([F:18])[C:13]([C:16]#[N:17])=[N:14][CH:15]=1.[I:19]I>C1COCC1>[Cl:9][C:10]1[C:11]([I:19])=[C:12]([F:18])[C:13]([C:16]#[N:17])=[N:14][CH:15]=1
Reactant: II
Reactant: N#Cc1ncc(Cl)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ncc(Cl)c(I)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a cooled (−78° C.) solution of LDA (34.9 mmol, 1.1 equiv) in dry THF (200 mL) was added dropwise 5-chloro-3-fluoropicolinonitrile (5 g, 31.9 mmol) in dry THF (100 mL) over 15 minutes. The resulting mixture was stirred at −78° C. for an additional 15 minutes. A cooled (−78° C.) solution of iodine (12 g, 47 mmol, 1.5 equiv) in dry THF (72 mL) was poured rapidly into the reaction, and the resulting mixture was removed from the cold bath and stirred for 20s. The reaction was then quenched by the addition of saturated aq. NaS2O3. The reaction mixture was diluted with ethyl acetate, and organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5% EtOAc, 95% hexanes) provided the title compound as a yellow solid (7.4 g, 82%) which was characterized by HNMR.
Reaction SMILES: C[Si]([NH-])(C)C.[Li+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[C:25]2[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=2)[NH:19][N:18]=1.[CH2:30](Br)[CH:31]=[CH2:32].C(O)C>O1CCCC1.CN(C)C=O.C1(C)C=CC=CC=1>[CH2:32]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[C:17]([C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[O:8][CH3:7])=[N:18]1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Temperature: -12.5 °C
Reaction time: 0.75 h

Procedure:
Under an atmosphere of nitrogen, a 1.3 M tetrahydrofuran solution of lithium(trimethylsilyl)amide (1.26 L, 1.63 mol) was added to a cold (−15 to −10° C.) stirred solution of 3-(2,4-dimethoxyphenyl)-7-trifluoromethyl-1H-indazole (0.250 kg, 0.766 mol) in tetrahydrofuran (1.66 kg, 1.87 L) and dimethylformamide (0.227 kg, 0.240 L). The addition was carried out over 40-50 min and the temperature of the reaction mixture was maintained at −15 to −10° C. during the course of the addition. The reaction mixture was then warmed to 15-20° C. over about 1 hour. Allyl bromide (0.282 kg, 0.202 L, 2.33 mol) was added over 20-30 min. The temperature of the reaction mixture was maintained at 15-25° C. for 40-50 h. Anhydrous 2B alcohol (anhydrous ethanol with 0.5 to 0.6% by weight of toluene as a denaturant, 04.08 kg, 0.500 L) was then added to the reaction mixture. The resulting solution was concentrated by distillation (under atmospheric pressure) to a volume of about 2.1 L. An additional 0.408 kg (0.500 L) of anhydrous 2B alcohol was then added to the concentrate. The resulting solution was concentrated by distillation under atmospheric pressure to a volume of about 0.95 L. The stirred concentrate was first cooled to 15-20° C. over 3 h and then to 5-10° C. over 1 h. The mixture was stirred for 2 h at 5-10° C. The product mixture (1-allyl-3-(2,4-dimethoxyphenyl)-7-trifluoromethyl-1H-indazole and 2-allyl-3-(2,4-dimethoxyphenyl)-7-trifluoromethyl-1H-indazole) crystallized during this period. The product was then isolated by filtration, washed with cold (5-10° C.) 2B alcohol (2×0.3 L), and dried to a constant weight under reduced pressure (≦30 mm Hg) at 40-50° C. The yield of 1-allyl-3-(2,4-dimethoxyphenyl)-7-trifluoromethyl-1H-indazole was 0.18 kg (64% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[CH2:28][CH2:29][C:30]#[N:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].Cl.C(N(CC)CC)C.CN1CCCC1=O>O>[C:1]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[CH2:28][CH2:29][C:30]2[NH:36][N:35]=[N:34][N:31]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2CCC#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2CCc2nnn[nH]2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 18.1 %

Procedure:
A mixture of 3-{4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-yl}propionitrile (227 mg, 0.5 mmol), sodium azide (98 mg, 1.5 mmol), triethylamine hydrochloride (103 mg, 0.75 mol) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 150° C. for 4 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (45 mg, 18%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C2CCC(=O)CC2)n1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-2-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[Br-].[CH2:19]([Zn+])[CH:20]([CH3:22])[CH3:21]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:3][C:4]=2[O:16][CH3:17])[N:8]=1
Reactant: COc1cc(Br)ccc1Oc1cccc(F)n1
Reactant: CC(C)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: COc1cc(CC(C)C)ccc1Oc1cccc(F)n1
Temperature: 105 °C
Yield: 19.6 %

Procedure:
To a suspension of Pd(PPh3)4 (0.025 mmol; 17 mg) under argon, in anhydrous, degased dioxane (2 mL), sheltered from light, were added 2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.51 mmol; 151 mg), then isobutyl zinc bromide (1.0 mmol; 2.0 mL). The reaction was heated to 105° C. for 24 hr. The mixture was then hydrolysed with water (3 mL), extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over MgSO4, concentrated under reduced pressure. The crude was then purified by preparative chromatography (cyclohexane/dichloromethane) to yield the desired product as a clear oil (28 mg; 0.10 mmol; 20%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].ClCCl.Cl[CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl>CCCCCC.C(OCC)(=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][C@H:4]([N:5]1[CH2:18][CH:17]=[CH:16][CH2:15]1)[C:3]([O:2][CH3:1])=[O:10]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: ClC/C=C\CCl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)N1CC=CC1
Yield: 84.5 %

Procedure:
From L-leucine methyl ester (520 mg, 3.56 mmol), dichloromethane (1 ml) and cis-1,4-dichloro-2-butene (135 mg, 1.08 mmol). Flash chromatography: silica gel, gradient hexane:ethyl acetate (3:1 to 1:1) afforded the product (180 mg, 84%) as yellow oil.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([OH:5])=O.C(Cl)Cl.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31]>N1C=CC=CC=1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31])=[O:5]
Reactant: O=C(O)C(Br)c1ccc(F)cn1
Reactant: NC(=O)c1ccccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1NC(=O)C(Br)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0.5 M solution of 2-bromo-2-(5-fluoropyridin-2-yl)acetic acid in 99:1 DCM/DMF is added oxalyl chloride (1.2 equiv) and the mixture is allowed to stir at rt for 30 min or until the reaction is substantially complete. The mixture is then cooled to 0° C. and 2-aminobenzamide (1 equiv) in pyridine (2 mL) is added slowly, and the mixture is allowed to warm to rt over ca. 1 h. The mixture is concentrated under reduced pressure and the residue is purified by chromatography to afford 2-(2-bromo-2-(5-fluoropyridin-2-yl)acetamido)benzamide.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[N:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C1COCC1>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:3]3[CH:17]=[CH:16][CH:15]=[N:14][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=2)[NH:20][N:21]=1
Reactant: Clc1nc(-c2ccccc2)nc2ncccc12
Reactant: Cc1cc(N)n[nH]1
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(-c3ccccc3)nc3ncccc23)[nH]n1
Temperature: 65 °C
Yield: 50.7 %

Procedure:
To a solution of 4-chloro-2-phenyl-pyrido[2,3-d]pyrimidine (J. Pharm. Belg., 29, 1974, 145-148)(109 mg, 0.45 mmol) in THF (15 mL) was added 3-amino-5-methyl pyrazole (48 mg, 0.5 mmol) and the resulting mixture heated at 65° C. overnight. The mixture was cooled to room temperature and the resulting suspension was filtered and washed with Et2O. The solid was dissolved in a mixture EtOH:water and the pH adjusted to pH 7. The aqueous was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, 50%): mp 234° C.; 1H NMR (DMSO) δ 2.14 (3H, s), 5.99 (1H, s), 7.20-7.40 (3H, m), 7.40-7.50 (3H, m), 8.60 (1H, d), 8.79 (1H, d), 12.82 (1H, br s); IR (solid)2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M+H)+.