Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19]>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[C:16]([O:17][CH2:18][CH3:19])=[O:20]
Reactant: Clc1cn2ccccc2n1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)nc2ccccn12
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 45.1 mL) was added to a solution of 2-chloroimidazo[1,2-a]pyridine (10 g) in THF (120 mL) at −78° C. After stirring for 30 min, ethyl chlorocarbonate (7.82 g) in THF (10 mL) was added to the mixture at the same temperature and stirred for 1 h and then 10 h at room temperature. The mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (13.20 g) as an off-white solid.
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[F:19][C:20]([F:31])([F:30])[CH:21]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[OH:22]>>[CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[N:14]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]([OH:22])[C:20]([F:30])([F:31])[F:19])=[CH:24][CH:25]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CS(=O)(=O)N1CCC2(CCNC2=O)CC1
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(O)C(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared In analogy to example 162 B) from 8-(isobutylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. White solid. MS (ESI): 449.17 MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[NH2:12][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[C:15]([CH2:14][OH:13])[CH:16]=[CH:17][CH:18]=2)[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: OCc1cccc(B(O)O)c1
Product: Cc1cc2nc(N)cc(-c3cccc(CO)c3)n2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J) and 3-(hydroxymethyl)phenylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.40 (s, 3H), 4.79 (s, 2H), 4.90 (br, 2H), 6.03 (s, 1H), 6.09 (s, 1H), 7.51-7.54 (m, 2H), 7.82-7.85 (m, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22]S(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]1[O:31][C:30]2[CH:32]=[C:33](O)[CH:34]=[CH:35][C:29]=2[O:28]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][C:33]2[CH:34]=[CH:35][C:29]3[O:28][CH2:27][O:31][C:30]=3[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)OC[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Fc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2COc2ccc3c(c2)OCO3)cc1
Yield: 64 %

Procedure:
To a solution containing 7.54 g (0.02 mol) of (+)-cis-1-benzyl-4-(4-fluorophenyl)-3-mesyloxymethylpiperidine in 120 ml of tertiary butanol, 3 g (0.022 mol) of sesamol and 3.35 g (0.03 mol) of potassium tertiary butoxide are added and the mixture is boiled under reflux for 12 hours. After completion of the reaction the mixture is evaporated and 100 ml of dichloromethane and 50 ml of water are added to the residue. After separation, the organic phase is washed with water until neutral, dried over a drying agent and after filtration the filtrate is evaporated to solvent-free. The evaporation residue is recrystallized from 25 ml of isopropanol. The precipitated product is filtered at 0° C. to obtain 5.37 g (64%) of title compound, m.p.: 98-100° C.; [α]D20−37.1° (c=1, chloroform).
Reaction SMILES: [Na+].[I-].Cl[CH2:4][CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[CH3:23][NH2:24]>>[N:13]1([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][NH:24][CH3:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: ClCCC(c1ccccc1)n1ccc2ccccc21
Reactant: CN
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CNCCC(c1ccccc1)n1ccc2ccccc21
Temperature: 100 °C
Yield: 90 %

Procedure:
A suspension of NaI (0.235 g, 1.56 mmol) and 1-(3-chloro-1-phenyl-propyl)-1H-indole (0.141 mg, 0.52 mmol) in ethanolic methylamine solution (33%, 2 mL) was heated at 100° C. for 1 hour under microwave irradiation (sealed tube). The reaction mixture was poured into water (30 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4), and evaporated under vacuum. Purification by chromatography (SiO2, CH2Cl2-MeOH—NH4OH, 18:1:0.1) gave 0.125 g (90% yield) of pure (3-indol-1-yl-3-phenyl-propyl)-methyl-amine as an oil. Treatment of this amino compound with an ethereal solution of HCl (2M, 0.26 mL) gave the corresponding hydrochloride salt (0.127 g) as a white powder: mp=218-219° C.; 1H NMR (DMSO) δ 2.53 (s, 3H), 2.60-2.89 (m, 4H), 5.86-5.91 (m, 1H), 6.585 (d, 1H, J=3.22 Hz), 6.98-7.12 (m, 2H), 7.20-7.34 (m, 5H), 7.52-7.54 (m, 2H), 7.71 (d, 1H, J=3.22 Hz), 9.0 (broad s, 1H); MS (EI) m/z 265 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[S:41][CH:42]=[CH:43][N:44]=2)[N:35]=1)(=O)=O>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.COCCOC>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:34]3[N:35]=[C:36]([C:40]4[S:41][CH:42]=[CH:43][N:44]=4)[CH:37]=[CH:38][CH:39]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1cccc(-c2nccs2)n1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc3nccc(OCc4ccccc4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: c1ccc(COc2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)cc1
Yield: 39 %

Procedure:
A solution of 4-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.0 equiv.), 6-(thiazol-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.1 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 120° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (EtOAc eluant) to yield 2-(6-(4-(benzyloxy)quinolin-6-yl)pyridin-2-yl)thiazole (39%). LC/MS=396.0 (M+H), LC=3.34 min.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:8]=1.[OH-].[Na+].CC(O)=O>O>[F:24][C:2]([F:1])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:8]=1
Reactant: CCOC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCC(=O)O)n1
Yield: 78.9 %

Procedure:
A mixture of ethyl 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate (1.03 g.) and a solution of sodium hydroxide (0.13 g.) in water (10 ml.) was heated under reflux for 1 hour and then cooled. The solution was acidified with glacial HOAc and the white solid which crystallised was collected to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyric acid (0.75 g.), m.p. 234°-236°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[N:11]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12]1.B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[CH3:17][C:13]1[CH:14]=[C:15]([CH3:16])[N:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[OH:2])[N:12]=1
Reactant: COc1ccc(-n2nc(C)cc2C)c(OC)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)n(-c2ccc(O)cc2O)n1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
118.4 mg of 1-(2,4-dimethoxyphenyl)-3,5-dimethyl-1H-pyrazol was dissolved in 2.3 ml of methylene chloride, and 1.7 ml of 1M solution of boron tribromide in methylene chloride was added at room temperature and stirred for 1 hour. The reaction mixture was added to 30 ml of water, neutralized with 1N-sodium hydroxide, and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:2) to yield 71.7 mg of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5[nH]ccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 62.8 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 56% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:38][NH2:39]>O>[CH3:38][NH:39][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)OCC
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)NC
Temperature: 80 °C

Procedure:
A mixture of ethyl 12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanoate (4.0 g, 9.1 mmol), THF (5 mL), and methylamine (available as a 40% solution in water, 8 mL) was sealed in a high-pressure vessel and heated at 80° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 3.8 g of N-methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:38])[C:15]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:12](F)[C:11]=2[F:40])[CH2:6]1)(=[O:3])[CH3:2].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:38])[C:15]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:12]([NH:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:11]=2[F:40])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccccc2OCOCCOC)c2cc(N3CCC(NC(C)=O)C3)c(F)c(F)c2c1=O
Reactant: NCc1ccccc1
Product: CCOC(=O)c1cn(-c2ccccc2OCOCCOC)c2cc(N3CCC(NC(C)=O)C3)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
Ethyl 7-(3-acetamidopyrrolidin-1-yl)-5,6-difluoro-1-(2-methoxyethoxymethoxyphenyl)-4-oxo-4H-quinoline-3-carboxylate is reacted with benzylamine by a procedure similar to that of Example 22 step 3 to prepare the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8](C(F)(F)F)[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3].FC1C=C([C:21]([F:24])([F:23])[F:22])C=CN=1>>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:21]([F:24])([F:23])[F:22])=[CH:6][N:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(C(F)(F)F)ccn1
Reactant: Fc1cc(C(F)(F)F)ccn1
Product: [N-]=[N+]=Nc1ccc(C(F)(F)F)cn1

Procedure:
The following were prepared analogously and analyzed by nmr spectroscopy: 2-azido-4-(trifluoromethyl)pyridine, off white crystals (from 2-fluoro-4-(trifluoromethyl)pyridine; and 2-azido-4,6-bis(trifluoromethyl)pyridine, pale yellow oil crystallizing on standing (from 2-chloro-4,6-bis(trifluoromethyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]\[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: COc1cccc(C(=C/C=C\C(=O)O)c2cccc(OC)c2)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(C(=C/C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A solution of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid (1.85 g) and 4-nitrophenol (0.912 g) in dichloromethane (25 mL) was treated with 1,3-dicyclohexylcarbodiimide (1.23 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 2.2 g of crude (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester contaminated with the corresponding (E)-isomer, purification of the product by HPLC (dichloromethane-hexane; 3:1) yielded 1.2 g of the (Z)-isomer (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: O=C(O)c1ccncc1NCc1ccc(C(F)(F)F)cc1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 4-(trifluoromethyl)-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297. Found 297.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([OH:29])=[O:28].C1C=CC2N(O)N=NC=2C=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:28][C:27](=[O:29])[CH:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:47]2
Reactant: COc1ccccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reaction time: 0.17 h
Yield: 116.8 %

Procedure:
PS-DCC (2.05 g, 2.57 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL) and shaken for few minutes. Then (2-methoxy-phenylamino)-phenyl-acetic acid hydrochloride (I36) (377 mg, 1.28 mmol) and HOBT (393 mg, 2.57 mmol) are added. After 10 minutes, (R)-quinuclidin-3-ol (490 mg, 3.85 mmol) is added and the mixture is shaken at RT for 16 hours (Conversion complete by UPLC/MS-UV). PS-DCC is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated to afford the title compound as a yellow oil (548 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.[C:16]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[OH:1]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reaction time: 1.25 h
Yield: 100 %

Procedure:
916 mg (5 mmol) of 2-hydroxy-4-nitro-benzoic acid is dissolved in a mixture that consists of 8 ml of methanol and 32 ml of toluene, and it is slowly mixed with a solution of trimethylsilyldiazomethane in hexane (2 molar). After the addition is completed, stirring is continued for 1.25 hours at room temperature. After the reaction mixture is concentrated by evaporation, 1 g (about 100% of theory) of 2-hydroxy-4-nitro-benzoic acid methyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:10]/[C:11](=[O:12])[CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1cccc(F)c1
Temperature: 65 °C
Yield: 112 %

Procedure:
To a mixture of 3-fluorobenzaldehyde (4.0 ml, 37.7 mmol) and acetone (8.86 ml, 121 mmol) in water (10 ml), was added 0.25 M sodium hydroxide (15.08 ml, 3.77 mmol). The reaction mixture was heated at 65° C. for 2 h. The mixture was poured into ice water and extracted with ethyl acetate (200 ml). The organic layer was dried, filtered, and evaporated to give (E)-4-(3-fluorophenyl)but-3-en-2-one as yellow oil. It was used for the next reaction without purification (6.92 g, 42.1 mmol, 112% yield). 1H NMR (CDCl3/400 MHz): δ (ppm) 7.46 (d, 1H), 7.40-7.34 (m, 1H), 7.33-7.29 (m, 1H), 7.26-7.21 (m, 1H), 7.12-7.06 (m, 1H), 6.70 (d, 1H), 2.38 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]Br)[CH2:9][CH2:8]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH2:9][CH2:8]1
Reactant: BrCCCCN1CCN(c2ncccn2)CC1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cccn3)CC2)nc1

Procedure:
A mixture of 4 g (13.3 mmol) of 1-(2-pyrimidinyl)-4-(4-bromobutyl)piperazine, 1.02 g (15 mmol) of pyrazole and 2.76 g (20 mmol) of potassium carbonate in 50 ml of dimethylformamide is heated to reflux for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the organic phase is washed with water, dried over sodium sulphate and evaporated under vacuum, and 3.5 g of an oil which is 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]([OH:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS([C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[OH:17][C@H:15]([CH3:16])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]4[N:22]=3)=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: C[C@@H](O)CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: C[C@@H](O)CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)CC1
Yield: 41.7 %

Procedure:
(R)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (129.1 mg, 0.5488 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (100.0 mg, 0.2744 mmol) and N,N-Diisopropylethylamine (0.1434 mL, 0.8232 mmol) were dissolved in 1-Methoxy-2-propanol (1.00 mL, 10.2 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The mixture was then reduced under nitrogen and the product was isolated and purified by Gilson prep HPLC to afford 61.36 mg of N-[2-(2-{4-[4-((R)-2-Hydroxy-propyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=536.1. 1H NMR (400 MHz, DMSO, d6) δ 9.51 (s, 1H), 9.24 (s, 1H), 8.95 (s, 1H), 8.01 (d, 1H, J=7.52 Hz), 7.65 (d, 1H, J=7.65 Hz), 7.50 (m, 4H), 6.97 (m, 2H), 6.85 (m, 2H), 4.12 (m, 1H), 3.66 (m, 4H), 3.17 (m, 3H), 3.08 (s, 3H), 2.95 (m, 3H), 2.89 (s, 3H), 1.13 (d, 3H, J=5.08 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])(C)(C)C.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[Br:1][C:2]1[C:3]2[C:8]([C:9]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C[Si](C)(C)Cl
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c2ccccc2c(Br)c2ccccc12
Temperature: -69 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
Under an argon atmosphere, the temperature of a solution of 9,10-dibromoanthracene (5 g, 15 mmol) in dry-THF (50 ml) was cooled to −69° C., and t-butyllithium (18 mmol) was dropped to the solution. After the mixture had been stirred for 3 hours, chlorotrimethylsilane (3 ml, 22.5 mmol) was added to the mixture, and the whole was stirred at −69° C. for an additional 3 hours. After the temperature of the resultant had been increased to room temperature, the resultant was quenched with sodium bicarbonate water, extracted with toluene, and dried with sodium sulfate. Then, the solvent was removed by distillation. The residue was dispersed and washed with hexane, the insoluble matter was removed, and the filtrate was condensed. The condensate was washed with ethanol, and was then subjected to silica gel column chromatography, whereby 1 g of 9-bromo-10-trimethylsilylanthracene was obtained.