Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=4[F:45])[CH2:32][CH2:31]3)=[C:20]([NH:25][CH:26]3[CH2:29][CH2:28][CH2:27]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:26]1([NH:25][C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[N:30]2[CH2:31][CH2:32][CH:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=3[F:45])[CH2:34][CH2:35]2)[CH2:29][CH2:28][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCNC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-benzyl-N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (85.2 mg, 0.135 mmol) and Pd(OH)2 on carbon (10 mg, 0.071 mmol) in THF (674 μL) was stirred at rt under an atmosphere of hydrogen gas (balloon). After 4 h, the mixture was filtered, washing with MeOH, and concentrated to afford the title compound as its TFA salt (73 mg, 100%) as a yellow solid, which was used without further purification. ESI-MS m/z [M+H]+ 428.4.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][CH:4]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[CH2:29][CH2:30][C:31](O)=[O:32])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C([N:37](CC)CC)C.ClC(OCC)=O.O.N>O1CCCC1.O>[O:22]([CH2:21][C:19]1[CH:18]=[CH:17][C:16]([CH2:29][CH2:30][C:31]([NH2:37])=[O:32])=[C:15]([C:13](=[O:14])[NH:12][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[CH2:3][CH:2]([CH3:34])[CH3:1])[CH:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(=O)O)c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(N)=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound prepared in Example 6(40) (150 mg) in tetrahydrofuran (2 ml) were added triethylamine (0.068 ml) and ethyl chloroformate (0.037 ml). The mixture was stirred at room temperature for 30 minutes under an atmosphere of argon. To the reaction mixture was added ammonia water and the mixture was stirred for 10 minutes. To the reaction mixture was added water and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with n-hexane-ethyl acetate to give the title compound (119 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ncc(Cl)cc1O
Temperature: 25 °C

Procedure:
5-Chloro-3-pyridinol (15.3 mmol) is dissolved in concentrated H2SO4 (15 ml). At 5° C. concentrated nitric acid (0.9 ml) is added. The reaction mixture is allowed to warm to room temperature over 6 days. The reaction solution is pored onto ice (50 ml) and diluted with water (200 ml). The precipitate is filtered, washed with water and dried at 40° C. in vacuo. 5-Chloro-2-nitro-pyridine-3-ol is obtained as yellow powder; mp. 97°; LC-MS (method B): 1.35 min, 175.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1>O>[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1
Reactant: CCOC(=O)COc1ccc(CNCCOC)cc1C
Reactant: FC(F)(F)c1ccc(-c2cncc(Br)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cncc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 100 °C
Yield: 19.3 %

Procedure:
A mixture of 2-bromo-6-[4-(trifluoromethyl)phenyl]pyrazine (0.5 g, 1.65 mmol), N,N-diisopropylethylamine (0.29 mL, 1.65 mmol) and ethyl (4-{[(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate (0.7 g, 2.47 mmol) was heated at 100° C. in a sealed reactivial for 20 h. The reaction mixture was then allowed to come to room temperature, and the residue was diluted with water (40 mL) and extracted CH2Cl2 (2×40 mL). The organic extract was passed through a hydrophobic frit and concentrated in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 1:19–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (0.16 g).
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][CH2:21][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]([OH:20])=[C:10]2[CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[C:28]1([O:27][C:25]([N:8]2[CH2:23][CH2:22][CH2:21][C:11]3=[N:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]([OH:20])=[C:10]3[CH2:9]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1c2c(nc3ccccc13)CCCN(Cc1ccccc1)C2
Product: O=C(Oc1ccccc1)N1CCCc2nc3ccccc3c(O)c2C1
Yield: 51 %

Procedure:
11-Hydroxy-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid phenyl ester was prepared analogous to Example 101 from 2-benzyl-11-hydroxy-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and phenyl chloroformate.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O>[O:25]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:9][CH:10]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccnc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2ccnc3ccccc23)cc1
Yield: 99.4 %

Procedure:
A mixture of alpha-oxo-4-[[2-(4-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.50 g) in hot methanol (10 mL) was treated with 1N sodium hydroxide (4.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was dissolved in water and chilled in ice. Cold 2N hydrochloric acid (2.0 mL) was added dropwise and the product was allowed to crystallize and was filtered, washed with water and dried to give 0.477 g of alpha-oxo-4-[[2-(4-quinolyloxy)ethyl]oxy]benzeneacetic acid as a colorless solid, mp 271° C. with decomposition.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([NH:12][CH3:13])[N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[CH3:2].C1C(=O)NC(=O)N([C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@@H:23]2[OH:30])C=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>C(#N)C.C(O)CC>[CH2:1]([C:3]1[N:11]=[C:10]([NH:12][CH3:13])[N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[CH3:2].[C@@H:22]1([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][C:10]([NH:12][CH3:13])=[N:11][C:3]=3[CH2:1][CH3:2])[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@@H:23]1[OH:30]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Agent: CCc1nc(NC)nc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CCCO
Solvent: CC#N
Product: CCc1nc(NC)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 37 °C
Yield: 157 %

Procedure:
6-Ethyl(methyl)aminopurine was prepared by nucleophilic displacement of the chlorine group on 6-chloropurine (Sigma Chemicals, St. Louis, Mo.) by ethylo(methyt)amine in acetonitrile. 6-Ethyl(methyl)aminopurine (2.8 mmoles, 0.5 g) and uracil arabinoside (5.6 mmoles, 1.38 g) were suspended in 575 ml of a 10 mM potassium phosphate, 0.04% potassium azide solution, pH of 7.4, containing 10% n-propanol (v/v). Purified uridine phosphorylase (6000 I.U.) and purine nucleoside phosphorylase (8400 I.U.) (Krenitsky, T. A. et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) were added and the solution stirred at 37° C. Nineteen days later the reaction was filtered and the filtrate chromatographed on a 2.5×13 cm column containing Dowex-1-hydroxide resin. The resin was eluted with 90% methanol/water (v/v). Fractions containing the product were combined and the solvent removed under vacuum. The residue was dissolved in 30% n-propanol/water (v/v) and chromatographed on BioRad P-2 column (7.5×90 cm). Product containing fraction were combined and after lyophilization yielded 0.680 g of 9-β-D-arabinofuranosyl-6-ethyl(methyl)amino-9H-purine. NMR and mass spectrometry were consistent with the structure. Anal. Calcd. for C13H19N5O4 : Calcd: C,50.48; H,6.19; N,22.64. Found: C,50.36; H,6.25; N,22.52.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)[CH:3]=[N:2]1>CN(C=O)C>[O:10]=[C:7]([CH3:8])[CH2:6][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)Oc1ccc2cn[nH]c2c1
Solvent: CN(C)C=O
Product: CC(=O)Cn1ncc2ccc(OC(=O)C(C)(C)C)cc21
Yield: 137.4 %

Procedure:
A solution of the product of Step A (1.5 g, 6.9 mmol) in DMF (10 ml) was treated by the procedure described for Example 1, Step B to give an oil (1.3 g, 62%): 1H NMR (CDCl3) δ 8.09 (d, J=0.8 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.01 and 6.96 (dd, J=2.0 and 8.6 Hz, 1H), 4.64 (s, 2H), 2.15 (s, 3H), 1.56 (s, 3H) 1.27 (s, 6H); MS(ES) m/z 275 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[C:3]1[C:17](OCC)=[O:18].CC(C)=O.C(=O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[C:3]1[CH2:17][OH:18]
Reactant: CCOC(=O)c1c(-c2ccccc2[N+](=O)[O-])c(C)cn1C
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cn(C)c(CO)c1-c1ccccc1[N+](=O)[O-]
Temperature: -78 °C

Procedure:
200 mg (7) are dissolved in 30 ml of anhydrous methylene chloride and the solution is cooled to -78° C. in a bath (acetone/dry ice). 2.8 ml (4 equivalents) of 1M dibal in toluene are added dropwise. Stirring is maintained for 2 hours at -78° C., the flask is then removed from the cooling medium and 50 ml of aqueous (10%) sodium carbonate solution are introduced. A substantial emulsion appears, and is removed by filtration on celite. The clear organic phase collected is washed with water saturated with sodium chloride and dried over sodium sulfate. The alcohol (12) is purified on a silica column (120 mg ; Yld 71%).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][CH2:6]1)=[O:3].N1C=CC=CC=1.[Cl:17][C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:17][C:18]([O:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:4][C:2](=[O:3])[CH3:1])=[O:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)O[C@@H]1CCC[C@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (1R,2R)-trans-2-acetoxy-1-cyclopentanol (1.0 g, 6.9 mmol) in dichloromethane (25 mL) at 0° C. under nitrogen atmosphere was added pyridine (0.88 mL, 10.4 mmol) followed by a solution of triphosgene (1.03 g, 3.5 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at 0° C. for 30 min. to provide the corresponding 2(R)-acetoxycyclopent-1(R)-yl chloroformate which was carried to next step without further purification.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1)(=[O:12])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(O)c1ccc(C(=O)OC)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCCC(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Pyridinium chlorochromate (1.25 g, 5.80 mmol) was added to a 0° C. solution of methyl 4-(1-hydroxybutyl)benzoate (602.5 mg, 2.89 mmol) in 9.6 mL dichloromethane. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. MgSO4 was added, and the solids removed by filtration. The filtrate was concentrated to give a brown solid. Purification by silica gel chromatography provided methyl 4-butyrylbenzoate (491.2 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3, δ): 8.08-8.13 (m, 2H), 7.97-8.01 (m, 2H), 3.94 (s, 3H), 2.96 (t, J=7.3 Hz, 2H), 1.77 (m, 2H), 1.00 (t, J=7.41 Hz, 3H).
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8]CCl.C([N-:18]CCC)(OC(C)(C)C)=O.[CH:22]1[CH:23]=[CH:24][C:25]([NH:32][C:33]2[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=2[Cl:39])=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:27]=1>C(OCC)C>[NH2:32][C:33]([NH2:18])([CH3:34])[CH3:38].[CH:22]1[CH:23]=[CH:24][C:25]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:27]=1.[ClH:8]
Reactant: CCC[N-]C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Agent: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(N)N
Reaction time: 2 h

Procedure:
Under ice-cooling, 20 mL of 4 M hydrochloric acid/ethyl acetate was added to 1 mL dichloromethane solution of 825.0 mg (1.82 mmol) of the Boc-propylamide-diclofenac obtained above, followed by stirring for 2 hours. Diethyl ether was added thereto for precipitation, and the precipitate was dried under reduced pressure to give 714.5 mg (101%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH2:23])[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH2:23])=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: C=C(c1ccccc1)c1nc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cnc1N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: C=C(c1ccccc1)c1nc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cnc1NC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(1-phenylvinyl)pyrazin-2-amine (7c) (543 mg, 1.35 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C., and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11c (292 mg, 448 μmol, 33.3%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.13 (s, 6H), 0.18 (s, 6H), 0.91 (s, 9H), 0.92 (s, 9H), 3.22 (s, 2H), 5.51 (s, 1H), 5.65 (s, 1H), 6.67-6.74 (AA′BB′, 2H), 6.90-6.97 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.19-7.26 (m, 2H), 7.26-7.31 (m, 3H), 7.91-7.98 (AA′BB′, 2H), 8.95 (s, 1H), 10.19 (s, 1H); 13C NMR (75.5 MHz, acetone-d6) δ −4.3 (4C), 18.6, 18.7, 26.0 (6C), 42.5, 118.8, 120.5 (2C), 121.1 (2C), 127.9 (2C), 128.4, 128.6, 128.78 (2C), 128.84 (2C), 130.1, 131.3 (2C), 138.4, 140.0, 144.2, 146.9, 148.7, 148.9, 155.1, 157.9, 169.7; IR (KBr, cm−1) 546, 696, 781, 806, 839, 914, 1007, 1082, 1169, 1261, 1362, 1420, 1435, 1472, 1508, 1605, 1670, 2857, 2886, 2930, 2955, 3030, 3055, 3231 HRMS (ESI+) m/z 652.3390 ([M+H]+, C38H50N3O3Si2+ requires 652.3385).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:10]([CH2:20][C:21]([O-:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:10]([CH2:20][C:21]([OH:23])=[O:22])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Agent: [Pd]
Product: O=C(O)Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1

Procedure:
1,49 Grams (3 mM) of the benzohydryl [1-(4-fluorophenyl)-4-(4-chlorophenyl)-1H-pyrazol-3-yl]-acetate are dissolved in 40 ml of tetrahydroflurane. To the solution 0,4 g of Pd on charcoal (10%) are added, then the mixture is hydrogenated at room temperature and pressure. At the end of the reaction the catalysator is filtered, the solvent evaporated and the product crystallized from acetic acid/ethanol. The title product is obtained in almost quantitative yield.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13]>C1COCC1>[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](=[O:13])[CH2:1][C:2]#[N:3]
Reactant: COC(=O)C(C)(C)C(F)(F)F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)CC#N)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
To a mixture of MeCN (3.32 mL, 97 mmol) in THF (300 mL) cooled to −78° C. was added n-BuLi (56.4 mL, 141 mmol). The mixture was stirred at −30° C. for 30 min. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (15 g, 88 mmol) dropwise. The mixture was stirred at 25° C. for 10 h. The mixture was quenched with aqueous NH4Cl and extraced with DCM/MeOH (10:1). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (5 g, 27.9 mmol, 31.7% yield): 1H NMR (400 MHz, CDCl3) δ: 3.75 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)c3)cccc2s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)c3)cccc2s1

Procedure:
A solution of 4-[5-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-benzothiazol-2-ylamine (12 mg, 0.031 mmol), acetic anhydride (10 uL, 0.074 mmol) and pyridine (1 mL) was heated at 60° C. for 18 h. The solution was concentrated under an N2 stream and the resulting mixture was purified by prep LC (10-90% CH3CN/H2O modified with 0.1% TFA) to give N-{4-[5-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-benzothiazol-2-yl}-acetamide as a white solid [MS (ESI, pos. ion) m/z: 430 (M+1)].
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[CH:19][N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([Br:27])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2ccc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncnn2c(Br)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: -20 °C
Reaction time: 2 h
Yield: 178.9 %

Procedure:
To a cooled (−20° C.) solution 5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (600 mg, 1.76 mmol) in THF (18 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (252 mg, 0.88 mmol) in 3 portions over 10 min. The mixture was stirred at −20° C. for 2 h. Saturated, aqueous Na2SO3 (20 mL) was added and the mixture warmed to rt. The mixture was extracted with ethyl acetate (2×20 mL). The combined organics were washed with 5% aqueous K2CO3 (2×20 mL), brine, dried (Na2SO4) and evaporated to provide 660 mg (89%) of the desired product, which contained trace impurities. ES-MS m/z 419.12 [M+H]+, HPLC RT (min) 3.00.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])#[N:2].N>CO.[Ni].CCO>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1ccc(C#N)c(N(C)S(C)(=O)=O)c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: Cc1ccc(CN)c(N(C)S(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
N-(2-cyano-5-methyl-phenyl)-N-methyl-methanesulphonamide (B-1a) (10.0 g, 44.6 mmol) is dissolved in 60 mL MeOH and 20 mL methanolic ammonia (7 M) in a hydrogenating autoclave and combined with Raney nickel in EtOH (1 g). The reaction mixture is then hydrogenated at 3 bar H2 and 80° C. for 16 h. After the reaction has ended the reaction mixture is filtered and the filtrate is mixed with ethanolic HCl (4.5 mL, 10 M). The precipitate formed is filtered off and the solid B-2a (HPLC-MS: tRet.=1.03 min; MS (M+H)+=229) is used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)Oc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C
Yield: 33.3 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.027 g, 0.09 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 μL, 0.10 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 60 (0.015 g, 0.03 mmol, 38%) as a white solid. LCMS m/z (%)=447 (M+H79Br, 98), 449 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.11 (s, 2H), 7.65 (dd, J=2.4, 8.9 Hz, 1H), 7.54 (dd, J=4.9, 8.7 Hz, 2H), 7.49 (s, 1H), 7.41 (d, J=2.6 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 4.40-4.52 (m, 1H), 3.70 (s, 3H), 1.26 (d, J=6.0 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H).