Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3OCC[O:11]3)[N:5]=2)[CH2:3][CH2:2]1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>CC(C)=O.O>[CH:1]1([C:4]2[N:5]=[C:6]([CH:10]=[O:11])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CC2)nc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cccc(C2CC2)n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of 2-cyclopropyl-6-[1,3]dioxolan-2-yl-pyridine (0.9 g, see subpart (b) above) and a catalytic amount of TsOH hydrate in a mixture of acetone (10 mL) and water (2 mL) was heated to reflux overnight until most of the starting materials were consumed according to TLC. It was then cooled down to room temperature and concentrated. The residue was dissolved in diethyl ether and washed with saturated sodium carbonate, and then water, and then dried over MgSO4 and concentrated. The concentrate was purified on silica gel column with 100% CH2Cl2 to yield 6-cyclopropyl-pyridine-2-carbaldehyde as a bright liquid (0.65 g, 94%). 1H NMR (CDCl3, 300 MHz), δ 9.90 (s, 1H), 7.58(m, 2H), 7.23 (m, 1H), 2.01 (m, 1H), 1.02-0.92 (m, 4H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1)(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[C:7]([F:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)c(F)c1
Reactant: NNC(N)=S
Product: CC(=O)Nc1ccc(C=NNC(N)=S)c(F)c1
Yield: 45 %

Procedure:
4-Acetamido-2-fluorobenzaldehyde 20 then is reacted with thiosemicarbazide to form 4-acetamido-2-fluorobenzaldehyde thiosemicarbazone 17 in 45% yield. An exemplary scheme for this reaction is shown below.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[NH:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[NH2:11]>CCO>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: NNc1cccnc1
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(N)n(-c2cccnc2)n1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
Using the procedure described in Example 308A Step 1, to a solution of 4-methyl-3-oxopentanenitrile (303 mg, 2.7 mmol) prepared as described in Example 122A Step 1, in anhydrous EtOH (13 ml) was added 3-hydrazinylpyridine hydrochloride (450 mg, 3.1 mmol) and the reaction mixture was heated at 80° C. overnight to afford 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (179 mg, 28%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.25 (d, J=7 Hz, 6H), 2.90-2.99 (m, 1H), 3.93 (brs, 2H), 5.50 (s, 1H), 7.36-7.38 (m, 1H), 7.96 (d, J=8 Hz, 1H), 8.49 (d, J=7 Hz, 1H), 8.67 (s, 1H); LC-MS (ESI) m/z 203 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[F:16])C.[OH-].[Li+]>>[CH2:14]([S:11]([C:9]1[CH:8]=[CH:7][C:6]([F:16])=[C:5]([CH:10]=1)[C:4]([OH:17])=[O:3])(=[O:12])=[O:13])[CH3:15]
Reactant: CCOC(=O)c1cc(S(=O)(=O)CC)ccc1F
Agent: [Li+]
Agent: [OH-]
Product: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B3(c) from 5-Ethanesulfonyl-2-fluoro-benzoic acid ethyl ester using lithium hydroxide instead of sodium hydroxide. White solid. MS (m/e): 232.1 (M+, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].O>CN1CCCC1=O>[NH:18]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:19]
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCOCC1
Reactant: NN
Solvent: O
Solvent: CN1CCCC1=O
Product: NNc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5 g of 4-fluorobenzenesulfonic acid morpholide were dissolved in 15 ml of N-methylpyrrolidone and mixed with 2.5 g of hydrazine hydrate, and the mixture was heated at 100° C. for 1 hour. After cooling to room temperature, 75 ml of water were added and the mixture was stirred at room temperature. After 2 hours, the solid was filtered off with suction and recrystallized from isopropanol.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[N:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])[CH3:12])[CH:6]=1)C.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:11]([CH3:12])[C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:39])=[O:3])=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[N:24]1
Reactant: CCOC(=O)c1cccc(N(C)Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1CN(C)c1cccc(C(=O)O)c1
Temperature: 70 °C

Procedure:
To a solution of 3-({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzyl}-methyl-amino)-benzoic acid ethyl ester (20 mg, 0.035 mmol) in THF (4.0 mL) and methanol (4.0 mL) is added 5 M NaOH (0.5 mL). The reaction mixture is heated to 70° C. for two hours and cooled to room temperature. A solution of 5 M HCl (0.5 mL) is added. The reaction mixture is concentrated and triturated with methanol and then water is added to precipitate the product. The title compound (10 mg, 53%) is collected by vacuum filtration as a white solid. LC-MS: 537.3 (M−1).
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[C:13]1([C:19]2[C:28]([CH:29]=[O:30])=[C:27]([CH:31]([CH3:33])[CH3:32])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:36])[CH2:22][C:23]([CH3:35])([CH3:34])[O:24]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:13]1([C:19]2[C:28]([CH:29]([OH:30])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[C:27]([CH:31]([CH3:32])[CH3:33])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:36])[CH2:22][C:23]([CH3:34])([CH3:35])[O:24]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(C3=CCCCC3)c1C=O)C(=O)CC(C)(C)O2
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.03 ml (1.02 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethyl)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 255 mg (780 μmol) of 5-cyclohex-1-en-1-yl-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 33A) in 6 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. A further 300 μl (193 μmol) of the above Grignard solution are added and stirring is continued for a further hour, the solution slowly thawing to 0° C. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is dissolved in a mixture of cyclohexane and ethyl:acetate (10:1), whereupon the target product crystallizes and is filtered off. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 20:1→10:1). The resulting target product is combined with the crystals. The compound is present in the form of atropisomers (1:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:6]=1.Br[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.[OH-].[K+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])[CH:6]=1)[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Reactant: BrCC1CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(CC1CCC1)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Reaction time: 16 h
Yield: 43.9 %

Procedure:
[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid methyl ester (33 g, 94.5 mmol) and (bromomethyl)cyclobutane (17 g, 114.1 mmol) were mixed in DMSO (50 mL) and KOH (6.4 g, 114.1 mmol) was added in portions over 15 min. The reaction mixture was stirred for 16 h and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (9:1-4:1) to give 15 g (40%) of the product as a yellow oil. (The synthesis was repeated with temperature kept at 40° C. over 16 h to give the product in quantitative yield). 1H NMR (300 MHz, CDCl3/TMS): δ 7.86 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.50 (q, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.55 (t, J=7.3 Hz, 1H), 2.22-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.55 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 172.9, 150.5, 146.4, 139.4, 126.0, 122.7, 122.6 (d, 1JCF=277.6 Hz), 116.0, 67.5 (q, 1JCF=36.7 Hz), 52.3, 49.6, 40.7, 33.9, 28.2, 27.9, 18.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10](=[CH:11][O:12]C)[CH2:9][CH2:8][N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:10]([CH:11]=[O:12])[CH2:9][CH2:8][N:7]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6]1)=[O:4]
Reactant: COC=C1CCN(Cc2ccccc2)CC1(Cc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of the compound of Example 200, Step B (3.02 g, 8.26 mmol) in THF (40 mL) and 10% aqueous HCl solution (40 mL) was allowed to stir at room temperature for 14 h. The solution was adjusted to pH 9 with 5N NaOH and extracted twice with CH2Cl2. The combined organic layers were washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 3-5% EtOAc/CH2Cl2 as the eluant afforded the compound of Example 200, Step C as a mixture of isomers (1.89 g): +APcl MS (M+1)+352; 1H NMR (400 MHz, CDCl3) δ: 9.82 and 9.81 (s, 1H), 7.02-7.45 (arom, series of m, 10 H), 3.64 and 3.60 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
According to General Method 1A, 28 g (132 mmol) of methyl 5-bromonicotinate and 30 g (158 mmol, 1.2 eq.) of 4-trifluoromethylphenylboronic acid were reacted. Yield: 32 g (85% of theory)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([NH:14][CH2:15][CH2:16][OH:17])([CH3:13])[CH3:12].C(N(CC)CC)C>O1CCCC1>[CH:11]([N:14]([CH2:15][CH2:16][OH:17])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)([CH3:13])[CH3:12]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(CCO)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chlorobenzoxazole (23.04 g) was added dropwise to an ice-cooled solution of 2-(isopropylamino)ethanol (15.45 g) and triethylamine (30.3 g) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 30 minutes, then heated at reflux overnight before being cooled and evaporated. The residue was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate solution (500 ml), water (3×1 l) brine (1 l), dried (MgSO4), filtered and evaporated. The title compound was obtained as an oil following chromatography on silica gel using 1.5% methanol-dichloromethane as solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:40])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.19 mmol) of the compound from Example 103 were introduced into 14 ml of dichloromethane at 0° C., 47 mg (0.19 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 74 mg (95% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]=[N+:18]=[N-:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methane sulfonate (930 mg, 3.70 mmol, Example 316) in dimethylformamide (20 mL), sodium azide (962 mg, 14.8 mmol, Aldrich) was added and the mixture was stirred at 90° C. overnight. The mixture was poured into water and extracted with ethyl acetate (5×10 mL) and the extracts were combined, washed with water, brine and dried with sodium sulfate. The solvent was removed to give a clear oil. 710 mg, 97%. The compound was directly used for the next step.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]([CH:9]1[C:13](O)([CH3:14])[CH:12]=[CH:11][C:10]1=[O:16])[CH2:5][CH2:6][CH2:7][CH3:8]>O1CCCC1>[CH2:4]([C:9]1[C:10](=[O:16])[CH2:11][CH:12]([NH:3][CH2:1][CH3:2])[C:13]=1[CH3:14])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCN
Reactant: CCCCCC1C(=O)C=CC1(C)O
Solvent: C1CCOC1
Product: CCCCCC1=C(C)C(NCC)CC1=O
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
Into a four-necked flask equipped with a stirrer and a thermometer, a 30% aqueous solution of monoethylamine (70 g) and tetrahydrofuran (18 g) were charged, and then 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (18.2 g) was dropwise added thereto at a temperature of 10° to 20° C. for 30 minutes. At the same temperature, the reaction mixture was kept for 2 hours. After completion of the reaction, the mixture was extracted with toluene, and the organic layer was washed with water. From the organic layer, toluene was evaporated off to give 2-n-pentyl-3-methyl-4-ethylamino-2-cyclopentenone (20.3 g). Yeild, 97%. The product was purified by alumina chromatography using toluene-ethyl acetate (10:1 by volume). nD20 1.4864.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: Cc1ncc(CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ncc(CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Reaction time: 4 h

Procedure:
To a solution of the benzyl ether from Step B (419 mg, 0.75 mmol) in 6 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (250 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 4 hours, another portion of Pd/C was added (250 mg). After 16 hours, the solution was filtered through celite. Concentration in vacuo provided the titled product which was used in the next reaction without further purification.
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([OH:41])=O)=[N:37][CH:38]=1.Cl.[N:43]1([CH2:49][CH:50]([N:54]2[CH:58]=[C:57]([C:59]3[C:60]4[CH:67]=[CH:66][N:65](COCC[Si](C)(C)C)[C:61]=4[N:62]=[CH:63][N:64]=3)[CH:56]=[N:55]2)[CH2:51][C:52]#[N:53])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([N:46]2[CH2:45][CH2:44][N:43]([CH2:49][CH:50]([N:54]3[CH:58]=[C:57]([C:59]4[C:60]5[CH:67]=[CH:66][NH:65][C:61]=5[N:62]=[CH:63][N:64]=4)[CH:56]=[N:55]3)[CH2:51][C:52]#[N:53])[CH2:48][CH2:47]2)=[O:41])=[N:37][CH:38]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCC(CN1CCN(C(=O)c2ccc(Br)cn2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
Triethylamine (72 uL, 0.52 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (39 mg, 0.103 mmol) were added to a solution of 5-bromopyridine-2-carboxylic acid (26 mg, 0.13 mmol) in THF (0.95 mL). After 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (51 mg, 0.086 mmol; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (20 mg, 44%). 1H NMR (400 MHz, d6-dmso): δ 12.10 (br s, 1H), 8.81 (s, 1H), 8.70 (dd, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 8.16 (dd, 1H), 7.60 (d, 1H), 7.52 (dd, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.61-3.54 (m, 2H), 3.37-3.28 (m, 2H), 3.24-3.19 (m, 2H), 2.86 (dd, 1H), 2.81 (dd, 1H), 2.63-2.54 (m, 1H), 2.52-2.40 (m, 2H), 2.39-2.31 (m, 1H); LCMS (M+H)+: 520.2/522.2.
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:25])=[CH:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH2:13][C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:5])C>[OH-].[Na+]>[C:4]([C:6]([CH3:25])=[CH:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH2:13][C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)=Cc1ccc(CCc2cccc3cncn23)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=Cc1ccc(CCc2cccc3cncn23)cc1)C(=O)O

Procedure:
5-[p-(2-Ethoxycarbonylprop-1-enyl)phenethyl]imidazo[1,5-a]pyridine (0.33 g) in 10 ml of 0.5N sodium hydroxide is refluxed for 3 hours, cooled and extracted with ether. The aqueous phase is adjusted to pH=6 and the resulting solid is filtered off to yield 5-[p-(2-carboxyprop-1-enyl)phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH2:11][OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:12][CH2:11][CH2:10][O:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][O:3]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCOC1CCCCO1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
3.64 g of sodium hydride (60%) are added batchwise to 13.00 g of 2-(tetrahydropyran-2-yloxy)-ethanol in 250 ml of tetrahydrofuran while cooling with an ice bath. Then the reaction mixture is heated to about 30-40° C. in a water bath and stirred for 15 minutes. It is then cooled again in the ice bath and combined with 15.60 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-7-fluoro-6-nitro-quinazoline in 50 ml of tetrahydrofuran. The reaction mixture immediately turns dark red. After 10 minutes the ice bath is removed and the reaction mixture is stirred for one hour at ambient temperature. Then a total of 1.00 g of sodium hydride is added and stirring is continued for a further 1.5 hours at 50° C. until the reaction is complete. For working up about 200 ml of tetrahydrofuran are distilled off using a rotary evaporator. The residue is added to 1 litre of ice-water and neutralised with citric acid. The aqueous phase is extracted thoroughly with ethyl acetate. The combined organic phases are washed with 250 ml of semi-saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. A yellow precipitate is formed, which is suction filtered and dried in the desiccator. The mother liquor is again evaporated down. The solid yellowish flask residue is triturated with tert.butyl methyl ether, suction filtered and also dried in the desiccator.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([OH:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28]O)=[CH:26][CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([O:19][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)=[CH:25][CH:26]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)cc2ccccc12
Product: CCOC(=O)C(C)(C)Oc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc2ccccc12

Procedure:
In analogy to the procedures described in example 4D] and 4E], 2-(3-hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester (example 14C]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1I]) to give 2-methyl-2-{3-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-naphthalen-1-yloxy}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][CH:10]=2.[CH2:18]1COCC1.C[Mg]Br>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH:16]([OH:17])[CH3:18])=[CH:11][CH:10]=2
Reactant: C1CCOC1
Reactant: COCCOc1cnc2ccc(C=O)cc2c1
Agent: C[Mg]Br
Product: COCCOc1cnc2ccc(C(C)O)cc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(3-(2-methoxyethoxy quinolin-6-yl)ethanol. 3-(2-methoxyethoxy)quinoline-6-carbaldehyde (1.7 g, 7.4 mmol) was dissolved in THF (29 mL, 7.4 mmol) and cooled to −78° C. To the solution was added methylmagnesium bromide (7.4 mL, 22 mmol), and the reaction was allowed to warm to RT. After 1 h, the reaction was quenched with sat. aq ammonium chloride. The material was extracted with DCM (×3) and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was then purified via MPLC (eluting with 0-100% 90:10:1 DCM:MeOH:NH4OH in DCM). 1-(3-(2-methoxyethoxy)quinolin-6-yl)ethanol was obtained.