Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][CH:2]=[C:3]([CH3:10])[C:4]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nccc(C)c1C=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a stirred solution of 5-bromo-2-methoxy-4-methylpyridine (2.6 g, 13 mmol) in dry THF (40 mL) under argon at −70° C. was added 1.6M n-BuLi in hexanes (8.1 mL, 14 mmol) over ten minutes. The mixture was stirred at −70° C. for 30 minutes and then anhydrous DMF (1.2 mL, 15 mmol) was added portion-wise at a rate that kept the temperature at −70° C. When the addition was complete, the mixture was stirred at −70° C. for 30 minutes and then at RT overnight. The reaction was quenched with 1M hydrochloric acid (40 mL) and then extracted three times with TBME. The combined organic phases were washed with brine, dried, filtered and concentrated. Column chromatography with TBME-light petroleum ether (1:1) as eluent gave 1.8 g (91%) of the title compound as pale yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NCC(F)(F)F)on1
Yield: 62.9 %

Procedure:
As described for example 14e, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using 2,2,2-trifluoroethylamine (38 mg, 0.38 mmol) instead of isopropyl amine, to the title compound (77 mg, 64%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4). MS: m/e=383.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:8]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].[OH-].[K+]>CS(C)=O.CCOCC>[CH2:17]([N:7]1[CH:8]=[C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])[N:5]=[C:6]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: COC(OC)c1c[nH]c(-c2ccccc2)n1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-dimethoxymethyl-2-phenyl-1H-imidazole 208 (2.18 g, 10 mmol) and n-butyl bromide (2.74 g, 20 mmol) in anhydrous DMSO (15 mL) is added to a suspension of powdered potassium hydroxide (0.96 mg, 15 mmol) in DMSO (20 mL) at room temperature over 3 h. The mixture is then stirred at rt for 16 h. The mixture is diluted with ether and washed with water (three times), brine, and dried over anhydrous sodium sulfate. Removal of the solvent and purification of the residue affords the desired product. Yield: 2.5 g; LC-MS (MH+): 275.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21]C2CCCCO2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCOC2CCCCO2)cc1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCC(Cc1ccc(OCCO)cc1)C(=O)OCC
Yield: 75 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-butyl-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (2.47 g), which is the product of Reference example 6(d), and p-toluenesulfonic acid monohydrate (1.24 g) and the reaction mixture was treated to afford the desired compound (1.44 g) as a syrup.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][CH2:15][N:16]3[C:21](=[O:34])[CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])[CH:8]=[N:7]1.OS(O)(=O)=O>CC(C)=O>[CH3:33][C:27]1[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH2:24][CH2:23][CH2:22][C:21]([N:16]1[C:17]2[C:12](=[C:11]([C:9]3[CH:8]=[N:7][N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]1)=[O:34]
Reactant: COC(CCn1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)cn1)OC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(CCC=O)c4)cccc32)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 1-(5-(1-(3,3-dimethoxypropyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one (40 mg, 0.081 mmol) in acetone (0.8 mL) was added 9 M H2SO4. The reaction mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was partitioned between DCM and saturated NaHCO3, and stirred for 15 min. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (36 mg, 100% yield). 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 7.21-7.12 (m, 2H), 7.02 (t, J=7.9 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.09 (s, 1H), 4.48 (t, J=6.3 Hz, 2H), 3.94 (s, 2H), 3.81-3.75 (m, 2H), 3.14 (t, J=6.3 Hz, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.63 (s, 2H), 2.59 (d, J=4.3 Hz, 2H), 2.14 (s, 3H), 1.95-1.81 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=O.[CH3:13][O:14][N:15]=C1C2C(=CC(C(C)(C)C)=CC=2)OCC1>>[CH3:13][O:14][N:15]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: Cc1ccc2c(c1)C(=O)CCO2
Reactant: CON=C1CCOc2cc(C(C)(C)C)ccc21
Product: CON=C1CCOc2ccc(C)cc21

Procedure:
The title compound was prepared following the procedure as described in Example 1B, substituting 6-methyl-chroman-4-one for the product of Example 1B. MS (DCI) m/e 192 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12]I.O>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][CH3:12])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cccc(Br)n1
Temperature: 2.5 °C
Yield: 93 %

Procedure:
Add dropwise a solution of (6-bromo-pyridin-2-yl)-methanol (9.6; g, 51; mmol) in anhydrous tetrahydrofuran (29; mL) to a stirring suspension of sodium hydride (60% dispersion in oil, 2.45; g, 61; mmol) in anhydrous tetrahydrofuran (96; mL) cooled to 0-5° C. under nitrogen. After gas evolution ceases, add dropwise methyl iodide (10.9; mL, 77; mmol) and warm to room temperature over 1; hour. Add iced water (100; mL), dilute with brine (100; mL) and ethyl acetate (200; mL). Separate the layers. Extract the organic layer once with brine (100; mL), dry over sodium sulfate and decant the liquid. Concentrate to a pale yellow oil (11.1; g) and distill using a Kügelrohr apparatus to give the title product as a colorless liquid (10.1; g, b.p.=140-150° C. at 2.4; mbar, 93%). MS (m/z): 202, 204; (M+1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[O:40][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:42][CH:43]=1)[OH:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:38])[C:39]4[O:40][C:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:42][CH:43]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1ccc(-c2ccccc2)o1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc(-c2ccccc2)o1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
N,N-Diisopropylethylamine (0.17 mL) was added to a solution of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.183 g) and rac-2-(methylamino)-1-(5-phenyl-2-furyl)ethanol (Preparation 55, 0.217 g) in DMF (15 mL). The reaction mixture was heated to 90° C. for 2 h. The mixture was allowed to cool to room temperature, poured into water (50 mL), and was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 25/1) and crystallized from ethyl acetate/CH2Cl2/diethyl ether to afford 0.22 g of the title compound as a white solid. Physical characteristics. M.p. 115-119°C.; 1H NMR (400 MHz, DMSO-d6) δ 10.63, 8.40, 7.56, 7.42-7.30, 7.17, 6.89, 6.84, 6.37, 5.34, 4.74, 4.54, 3.80, 3.74, 3.67, 2.88, 2.68, 2.33; MS (ESI+) m/z 546 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=[O:18].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[O:18]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:6]1
Reactant: O=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(c2ccccn2)O3)c1
Temperature: 120 °C
Yield: 33.7 %

Procedure:
Pd(PPh3)2Cl2 (20 mg) in a 10 mL flask under Ar was treated sequentially with 6-bromo-2-(pyridin-2-yl)chroman-4-one (300 mg, 1 mmol) in [1,4]dioxane (40 mL), Cs2CO3 (2 N, 5 mL) and 3-cyanophenylboronic acid (250 mg, 1 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 3-(4-oxo-2-(pyridin-2-yl)chroman-6-yl)benzonitrile (110 mg, 60%). 1H-NMR (CDCl3): 3.13 (m, 2H), 5.61 (m, 1H), 7.13 (m, 1H), 7.27 (m, 1H), 7.49 (m, 1H), 7.58 (m, 2H), 7.68 (m, 1H), 7.79 (m, 3H), 8.09 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: [N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12](I)[C:11]=2[F:21])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][C:29]1[S:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[S:33][C:32]([C:12]2[C:11]([F:21])=[C:10]([N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH2:3][CH2:2]3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: Fc1c(I)nc2ccccc2c1N1CCc2cnccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1c(-c2ccc(Cl)s2)nc2ccccc2c1N1CCc2cnccc21
Temperature: 80 °C
Yield: 49.9 %

Procedure:
4-(2,3-Dihydro-pyrrolo[3,2-c]pyridin-1-yl)-3-fluoro-2-iodo-quinoline from step B (0.025 g, 0.063 mmol) was dissolved in tetrahydrofuran (5 ml) in a 25 ml round bottomed flask equipped with a magnetic stirrer. Sodium carbonate (0.06 g, 0.1 mmol) was added followed by 5-chlorothiophene-2-boronic acid (0.019 g, 0.08 mmol) and the mixture was degassed for 5 mins. Tetrakis(triphenylphosphine)-palladium(0) (5 mg, 5 mol %) was added followed by 0.5 ml water and the reaction mixture was heated to 80° C. for 4 hrs. The compound was extracted with ethyl acetate, dried and concentrated in vacuo. The title compound was purified by HPLC over a reverse phase column using a gradient of acetonitrile and water containing 0.1% trifluoroacetic acid to yield desired compound (0.012 g, 52%). MS (ES) 482.4 (M+H)+
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([C:18]1[C:19]([CH2:33][CH2:34][CH3:35])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[CH3:38][C:39]1([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=2)[NH:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>CN(C)C=O.O>[F:36][C:2]([F:1])([F:37])[C:3]([C:18]1[C:19]([CH2:33][CH2:34][CH3:35])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:41]3[C:40](=[O:45])[C:39]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=4)([CH3:38])[NH:43][C:42]3=[O:44])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(N2CCN(CCO)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCN(CCN3C(=O)NC(C)(c4ccc(OC(C)C)cc4)C3=O)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
2-(4-{5-[1,1,1,3,3,3-Hexafluoro-2-(4-methoxybenzyloxy)propan-2-yl]-4-propylpyridin-2-yl}piperazin-1-yl)ethanol (20 mg, 0.0373 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (34.3 mg, 0.138 mmol) and triphenylphosphine (34.5 mg, 0.132 mmol) were dried with a vacuum pump, dissolved in N,N-dimethylformamide (3 mL), added DEAD (51 μL, 0.111 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water (1.0 mL) and 2N aqueous solution of hydrochloric acid (1.0 mL), extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (30 mg (yield 99%)) was obtained as a yellow oil.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:13]=[C:12]([CH2:20]N(CC)CC)[C:11]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:27]1[N:28]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH2:44][OH:45])[CH:39]=[CH:38][C:37]=2[OH:46])[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:20]([C:12]1[CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[C:11]=1[OH:26])[C:38]1[CH:39]=[C:40]([CH2:42][CH2:43][CH2:44][OH:45])[CH:41]=[C:36]([N:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]3=[N:27]2)[C:37]=1[OH:46]
Reactant: CCN(CC)Cc1cc(CCCO)cc(-n2nc3ccccc3n2)c1O
Reactant: OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: OCCCc1cc(Cc2cc(CCCO)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Yield: 61.2 %

Procedure:
In 100 ml of xylene were dissolved 35.9 g (97.0 mmols) of crude 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 11 and 26.1 g (97.0 mmols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)phenol synthesized in Example 6. 5 ml of a methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. The subsequent treatment was carried out in the same manner as in Example 12, giving 33.0 g of 2,2'-methylenebis[6-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)phenol] as white crystals (yield 61.2%, purity 99.0%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH:7]([NH:21][CH3:22])[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH:7]([N:21]([C:29](=[O:30])[C:28]1[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=[C:26]([C:25]([F:24])([F:39])[F:40])[CH:27]=1)[CH3:22])[CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C=CC(NC)C(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 10.6 g (34.3 mmol) of 4-methylamino-5,5-diphenyl-pent-2-enoic acid ethyl ester in 110 ml of methylene chloride is added at 0° C. via a cannula to a solution of 6.7 ml (36.0 mmol) of 3,5-bistrifluoromethyl-benzoyl chloride in 110 ml of methylene chloride. 5.8 ml (41.1 mmol) of triethylamine and 0.4 g (3.4 mmol) of 4-dimethylaminopyridine are then added. After 1 hour the reaction mixture is diluted with ethyl acetate and washed twice with water and once with brine. The aqueous phases are back-extracted once with ethyl acetate. The combined organic phases are then dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride/methanol (100:0 to 98:2). The title compound is obtained in the form of a light-yellow foam. TLC: methylene chloride/methanol (98:2) Rf =0.38; Rt (HPLC)=22.4 min; 1H-NMR (400 MHz, d6 -DMSO, 120° C.) d 8.00 (br, 1H), 7.47-7.29 (m, 10H), 7.26-7.20 (m, 2H), 6.83 (dd, 1H), 5.96 (d, 1H), 5.89 (br, 1H), 4.65 (d, 1H), 4.10 (q, 2H), 2.68 (s, 3H), 1.18 (t, 3H); FAB-MS (M+H)+ =550.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][CH:2]([NH2:1])[CH2:3][NH2:4]
Reactant: N#CC(N)CCC(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCC(N)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 3.3 %

Procedure:
2-amino-5,5,5-trifluoropentanenitrile a5 (34 g, 2.2 mol, 1 eq) is dissolved in tetrahydrofurane (290 ml). Lithium aluminium hydride (25.5 g, 6.7 mol, 3 eq) is then added portionwise at 0° C. The reaction mixture is heated at 60° C. for 2 hours, then stirred overnight at room temperature. Disodium sulfate decahydrate (6 eq) is added portionwise and the mixture is stirred until the appearance of a white solid. The precipitate is filtered and the organic phase is condensed under vacuum to afford 11.2 g of 5,5,5-trifluoropentane-1,2-diamine a6 as orange oil.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1.OS(O)(=O)=O>C(OCC)C>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:19]([OH:20])[CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C(O)Cc2ccccc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a magnetically-stirred solution of freshly crushed magnesium turnings (36.54 mmol, 0.888 g) in anhydrous ethyl ether (20 mL) at room temperature is added a solution of benzyl bromide (36.54 mmol, 4.35 mL) in anhydrous ethyl ether (15 mL) dropwise via addition funnel. The addition is slow at first; only 2 to 3 mL of reagent is added and the reaction mixture is heated until gas evolution is observed. Dropwise addition of benzyl bromide is begun at this point, and the reaction mixture is diluted with ethyl ether (20 mL) to prevent dimerization of the Grignard reagent. Once the addition of benzyl bromide is complete, the reaction is allowed to stir at room temperature for 1 hour and then a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (30.00 mmol, 6.61 g) in anhydrous ethyl ether (30 mL) is added dropwise at room temperature. The reaction mixture is allowed to stir at room temperature for 30 minutes and then poured into a solution of ice water (500 mL) containing concentrated H2SO4 (7 mL). The aqueous mixture is extracted with ethyl acetate (2×300 mL) and the combined organic layers are washed with saturated NaHCO3 (300 mL). The organic layer is dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (25.97 mmol, 8.06 g; 86%) of sufficient purity to be used directly in subsequent transformation.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH:22][C:23](=O)[CH2:24][CH3:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[N:22]=[C:23]2[CH2:24][CH3:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc2cc(F)ccc2n1C1CCN(Cc2ccccc2)CC1
Yield: 96.3 %

Procedure:
N-[2-(1-Benzyl-piperidin-4-ylamino)-5-fluorophenyl]-propionamide (7 g) in glacial acetic acid (70 ml) was heated at reflux for 1 h. After cooling the residue was dissolved in ethyl acetate (100 ml) and water (50 ml) was then added. The mixture was made alkaline with K2CO3, and the organic layer separated, washed with water, then dried and concentrated in vacuo. The resulting oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 6.4 g of the title compound.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1)[CH2:3][C:4]#[N:5].C1(O)C=CC=CC=1.O[C@@H](C1C=CC=C(O)C=1)CCNC(=O)OC(C)(C)C>>[OH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1)[CH2:3][C:4]#[N:5]
Reactant: N#CCC(=O)c1cccc(OCc2cccs2)c1
Agent: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: N#CC[C@@H](O)c1cccc(OCc2cccs2)c1

Procedure:
Chiral reduction of 3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile following the method used in the preparation of phenol (7, Intermediate I) gave after flash column chromatography (R)-3-hydroxy-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a white solid. Yield (2.6 g, 82%); 1H NMR (400 MHz, DMSO-d6): δ 7.55 (d, J=4.8 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.21 (d, J=3.2 Hz, 1H), 7.06-6.99 (m, 3H), 6.94 (dd, J=8.0, 2.0 Hz, 1H), 5.95 (d, J=4.4 Hz, 1H), 5.27 (s, 2H), 4.85 (dd, J=11.2, 4.8 Hz, 1H), 2.92-2.77 (m, 2H). Yield (2.6 g, 92%); MS: m/z 260.06 [M+H]+.