Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13]C(=O)C(C)(C)C)=O.[H-].[Li+].[F:22][C:23]([F:32])([F:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)C>CS(C)=O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[NH:13][CH:24]([C:23]([F:31])([F:32])[F:22])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:1]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1C=O
Agent: [H-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 30 °C
Yield: 1.1 %

Procedure:
To a suspension of N-(2-formyl-4-(trifluoromethylphenyl)-2,2-dimethyl propanamide (Step 2) (921 mg, 3.7 mol) and lithium hydride (115 mg, 14.5 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 4,4,4-trifluorocrotonate (2.83 g, 16.8 mmol) and the contents warmed to 30° C. for 4 hours. After the addition of ethyl acetate (50 mL), the reaction was washed with water (2×30 mL), saturated ammonium chloride solution (2×30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, eluant: ethyl acetate-hexanes, 1:9) to yield, upon concentration of the appropriate fractions, ethyl 6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (65 mg, 5%): mp 138-139° C. 1H NMR (CDCl3/300 MHz) 7.67 (s, 1H), 7.26 (s, 1H), 7.04 (d, 1H, J=6.6 Hz), 6.62 (m, 1H), 5.14 (m, 1H), 4.60 (brs, 1H), 4.32 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). ESHRMS m/z 338.0592 (M−H Calc'd 338.0616). Anal. Calc'd for C13H11F3NO2: C, 49.57; H, 3.27; N, 4.13; Found: C, 49.23; H, 2.81; N, 3.93.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12]Cl.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 70 °C

Procedure:
A mixture of 12.8 g (0.06 mol) of 2-quinolinylmethyl chloride HCl, 7.5 g (0.06 mol) of 3-hydroxybenzyl alcohol, and 18 g of potassium carbonate in 50 ml of DMF is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2-quinolinylmethyloxy)benzyl alcohol.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:25]([NH:24][CH2:22][CH3:23])=[O:26])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Solvent: ClCCl
Product: CCNC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)aniline 1 (102 mg, 0.35 mmol) in 1 mL of dry CH2Cl2 was added ethyl isocyanate (95%, 35 μL, 1.2 eq.) at room temperature. After being shaken at room temperature for overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of the CH2Cl2 afforded N-(1-Boc-piperidin-3-yl-methyl)-N-phenyl-N′-ethylurea (2) (120 mg, 95%). LRMS 285 (M−100)+ 261.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:42])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3)c2)cc1
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3)c2)cc1

Procedure:
The compound of Example 40 was prepared in accordance with the same procedures as in Example 37, using the compound prepared in Example 23 and meta-chloroperbenzoic acid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:35]2[CH:34]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:38]=[CH:37][N:36]=2)[CH:40]=1)(=[O:46])=[O:47])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CC(C)(N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 62.9 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of 2-amino-2-methyl-1-propanol (0.097 g, 1.09 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.135 g, 63%). MS (ISP) 597.3 [(M+H)+]; mp 221° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:25])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:25])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 5-bromo-2-(2-(3-(trifluoromethyl)phenyl)acetamido)benzoate (3.86 g, 9.28 mmol, Intermediate 5: step b) in THF (100 mL) at −78° C. was added KHMDS (0.5 M in toluene, 55.6 mL, 27.8 mmol) over 8 minutes. The resulting light yellow solution was stirred at −78° C. for 5 minutes, then was transferred to an ice bath and stirred for 1 hour 15 minutes. The mixture was diluted with water and extracted once with EtOAc. The aqueous phase was acidified to pH 2 by addition of 1 N aqueous HCl solution. A white precipitate formed upon acidification and was collected by vacuum filtration and air dried to afford the title compound as a white powder.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8]/[C:9](/[NH:20][C:21]2[NH:25][N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:22]=2)=[N:10]/[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8]/[C:9](/[NH:20][C:21]1[NH:25][N:24]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:22]=1)=[N:10]/[C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: CC1(C)OCC(CN/C(=N/C(=O)c2ccc(F)cc2)Nc2cc(C(F)(F)F)n[nH]2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/N=C(/NCC(O)CO)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of (Z)—N-((((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)-4-fluorobenzamide (300 mg) in THF (7 mL) was added para-toluenesulfonic acid (p-TsOH) (133 mg, 1 equiv). The reaction mixture was shaken at room temperature overnight. The solution was then treated with triethylamine (100 μL), concentrated onto silica gel, and purified by silica chromatography (3:1 hexanes:EtOAc to EtOAc) to provide the title compound (115 mg (91% purity), 42% yield). MS (EI+) m/z: 389.93, 411.89; HPLC (Method B): 5.19 min
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22].O>CC(C)=O>[CH3:22][C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:20][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(OCC=C(C)CCC=C(C)C)cc1
Yield: 92.2 %

Procedure:
Methyl 4-hydroxyphenylacetate (6.00 g, 36.11 mmol) was dissolved in acetone (90 ml), and then potassium carbonate (9.98 g, 72.22 mmol) and geranyl bromide(14.34 ml, 72.22 mmol) were added thereto. After being refluxed for 4 hours, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride water and saturated brine successively, and dried over MgSO4. The solvent was evaporated out and the obtained residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give methyl 2-{4-[(3,7-dimethyl-2,6-octadienyl)oxy]phenyl}acetate (10.07 g, 92%).
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[C@@H:8]([OH:16])[CH2:7]1)=O.[CH2:19](O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)[CH:20]=[CH2:21]>>[CH2:21]([O:16][C@H:8]1[C:9]2[C:14](=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C@@H:6]([NH2:5])[CH2:7]1)[CH:20]=[CH2:19]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Reactant: Cc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Product: C=CCO[C@@H]1C[C@H](N)c2cc(C)ccc21
Yield: 75 %

Procedure:
Step BK (2): The product from Step BK (1) was N-deprotected by a procedure analogous to Step U (2) to afford 480 mg (75% yield) of (1S,3R)-3-(allyloxy)-6-methyl-2,3-dihydro-1H-inden-1-amine as a white solid. LC-MS (M+H)+=204.13 1H NMR (500 MHz, CDCl3) δ ppm 7.28 (d, 1H) 7.18 (d, 1H) 7.08 (d, 1H) 6.01-5.94 (m, 1H) 5.32 (d, 1H) 5.18 (d, 1H) 4.77 (t, 1H) 4.16-4.19 (m, 3H) 2.80-2.75 (m, 1H) 2.36 (s, 3H) 1.75-1.70 (m, 3H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:17]2[CH:26]=[CH:25][C:24]3[C:23](=[O:27])[CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=2)[N:10]=[CH:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)n1cnc(CCO)c1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
A solution of 1-N-Boc-4-(2-hydroxyethyl)imidazole (1.06 g, 5.0 mmol), 6-hydroxytetralone (0.811 g, 5.0 mmol), and triphenylphosphine (1.44 g, 5.5 mmol) in 10 mL of freshly distilled THF was cooled in an ice bath for 10 minutes and then treated with neat diethyl azodicarboxylate (0.87 mL, 5.5 mmol) added via syringe through a rubber septum. The ice bath was permitted to melt and the reaction continued at room temperature for 5 hours. The solvent was removed in vacuo and the residue was chromatographed (silica gel, 500 g; 1:1, EtOAc:hexanes), and the pure fractions were pooled to afford 0.61 g (33%) of the title compound as a clear, colorless, viscous oil: CI-MS m/e 357 (M++1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.N>O>[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(NCc3ccccc3)c2c1
Agent: N
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]nc(NCc3ccccc3)c2c1
Yield: 28.1 %

Procedure:
5-Amino-3-benzylamino-1H-indazole can be obtained as described in Example 4 from 0.6 g of 3-benzylamino-5-nitro-1H-indazole, 22 ml of ethanol, 4.5 g of ferrous sulfate, 7 ml of water and 5.4 ml of 32% aqueous ammonia. 0.15 g of 5-amino-3-benzylamino-1H-indazole is thus obtained in the form of a brown powder melting at 196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][NH:7][C:8]1[CH:13]=[C:12](I)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH2:38])O1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH2:38])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=1
Reactant: COc1ccc(CNc2cc(I)cc(C(F)(F)F)n2)cc1OC
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(CNc2cc(-c3ccncc3N)cc(C(F)(F)F)n2)cc1OC
Yield: 38 %

Procedure:
Method 26 was followed using N-(3,4-dimethoxybenzyl)-4-iodo-6-(tri-fluoromethyl)pyridin-2-amine (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (3 equiv.), Pd(dppf)Cl2 DCM (0.10 equiv.) in DME/2M Na2CO3 (3:1, 0.07 M) at 50° C. for 45 min. Purification via reverse phase HPLC afforded N2-(3,4-dimethoxybenzyl)-6-(trifluoromethyl)-4,4′-bipyridine-2,3′-diamine in 38% yield. LCMS (m/z): 402.1 (MH+); LC Rt=3.0 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7](=[O:14])[CH2:6][C:5]2([CH3:16])[CH3:15].CC(C)=[O:20].O.C1C(=O)N(Br)C(=O)C1>C(#N)C>[CH3:15][C:5]([C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:17])([CH3:16])[CH2:6][C:7]([OH:20])=[O:14]
Reactant: CC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)C(C)(C)CC(=O)O2
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Yield: 96 %

Procedure:
To the solution of 6-hydroxy-4,4,5,7,8-pentamethylchroman-2-one (15 g, 0.064 mol) in a mixture of acetonitrile (600 ml), acetone (50 ml) and water (300 ml), NBS (11.4 g, 0.064 mol) was added. The resultant mixture was stirred for 30 minutes at room temperature. After removing most of the organic solvent, the yellow solid was collected by filtration, washed by water and dried over vacuum to afford a yield of 96%. 1H NMR (300 MHz, CD2Cl2) δ 3.0 (s, 2H, CH2), 2.13 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.92 (s, 3H, CH3), 1.44 (s, 6H, CH3); MS (m/e): 251 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][CH2:25][CH2:26][OH:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][CH2:25][CH:26]=[O:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(F)c(-c2ccc(OCc3cccc(CCCO)c3)cc2CC(C)(C)C)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(CCC=O)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propan-1-ol (357 mg) and triethylamine (0.68 mL) in DMSO (5.0 mL) was added sulfur trioxide pyridine complex (390 mg), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 0.50N hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (167 mg) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH3:12][O:13][Na]>CO>[CH3:12][O:13][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: CO[Na]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with CH3OH (50 mL), 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (8.8 g, 40 mmol) and CH3ONa (4.3 g, 80 mmol). The reaction mixture was heated at reflux for 2 h. After this time the reaction was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate (60 mL) and water (60 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with brine (50 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to afford 176a as a yellow oil (6.1 g, 90%). LCMS: [M+H]+ 172.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)=[O:2].Cl[CH2:13][C:14](=[O:16])[CH3:15].C(N(C(C)C)CC)(C)C>C(O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:13]([C:14](=[O:16])[CH3:15])=[CH:8][C:7]=2[CH:10]=1)=[O:2]
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: CC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)c1cc2cc(C=O)ccc2o1
Reaction time: 5 h

Procedure:
About 5.0 g (1.0 equivalent) of 5-formylsalicylaldehyde was dissolved in about 15 ml of ethanol, and about 3.25 g (about 1.05 equivalents) of monochloroacetone was added thereto. Then, about 8.7 ml (about 1.50 equivalents) of diisopropylethylamine was added thereto at room temperature. The mixture was heated while being stirred for about 5 hours, and maintaining the reaction temperature at about 60° C. to 70° C. After confirming the completion of the reaction by TLC, the mixture was allowed to cool down. The produced solid matter was separated by filtering, and washed with ethanol. Then, the solid matter was recrystallized from ethanol so as to obtain about 5.8 g of the target 5-formyl-2-acetylbenzo[b]furan in the form of white crystal (yield: about 92.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:10])=[O:9].Br[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22]>>[C:2]1([CH3:1])[C:3]([S:8]([N:11]([CH2:20][C:21]([OH:23])=[O:22])[C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of 2-methyl-N-p-tolyl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH2:16][NH:15][CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9].Cl[C:18]1[C:19]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:31]=3[S:39][CH3:40])[C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:8]([C:11]1[CH2:16][N:15]([C:18]2[C:19]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[CH:32][C:31]=4[S:39][CH3:40])[C:20]=3[N:21]=[C:22]([CH3:24])[N:23]=2)[CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9]
Reactant: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(Cl)nc(C)nc21
Reactant: NC(=O)C1=CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(N3CCC=C(C(N)=O)C3)nc(C)nc21
Yield: 26.7 %

Procedure:
In 4 ml of ethanol, 0.27 g of 5-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate and 0.36 g of 4-chloro-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine were dissolved, and subsequently, 0.39 g of diisopiopylethylamine was added thereto. The reaction mixture was heated under reflux for 8.5 hours, and subsequently, a saturated aqueous solution of sodium hydrogencarbonate was poured therein to. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform—methanol=60:1), followed by crystallization from a mixed solvent of ethyl acetate-diethyl ether to yield 0.12 g of 4-(5-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.47 g, 2.2 mmol) (Example 1, step 2), trans-4-aminocyclohexanol (from Aldrich, 0.50 g, 4.4 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.6 mmol) in isopropyl alcohol (7.4 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.266 g, 41%). LCMS calculated for C13H16N3O3S (M+H)+: m/z=294.1. Found: 294.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[H][H]>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C=CC(=O)O)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCC(=O)O)ccc1F
Yield: 99 %

Procedure:
3-(4-Fluoro-3-methoxy-phenyl)-acrylic acid (6.2 g, 31.6 mmol) and Pd—C (10%, 620 mg) in ethyl acetate and methanol (1:1, 400 ml) was placed in a Parr apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the filtrate was concentrated in vacuo to give 6.2 g white solid (99% yield). LC-MS: m/e 197 (M−1)
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH3:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH3:18])[C:16]([CH3:15])=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(=O)C(C)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(C)c1C
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of 51.6 g (0.250 mol) of 3-amino-5-benzylthio-1,2,4-triazole and 28.5 g (0.250 mol) of 3-methyl-2,4-pentanedione in 350 ml of glacial acetic acid was heated at reflux for 17 hours. Upon cooling to room temperature, the reaction mixture was poured onto ice. The pale yellow solid which separated was collected by filtration, washed with water and dried in vacuo to yield 67.1 g (94%) of the desired product as a pale yellow solid, m.p. 133.5°-135° C. The IR and 1H NMR spectra were consistent with the assigned structure.