Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:13]([NH2:14])=[CH:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35].[NH4+].[Cl-]>C(Cl)Cl>[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:14][C:13]1[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[N:10][N:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)(=[O:36])=[O:35]
Reactant: Nc1cn(-c2ccccc2)nc1C(=O)N1CCOCC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1nn(-c2ccccc2)cc1NS(=O)(=O)c1ccccc1Br)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.3 %

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-1-phenyl-1H-pyrazol-4-amine (260 mg; 0.95 mmol; 1 eq.) in DCM (10 mL) is added pyridine (151 μL; 1.91 mmol; 2.00 eq.) and 2-bromobenzene-1-sulfonyl chloride (317 mg; 1.24 mmol; 1.30 eq.). The reaction is stirred for 48 h at room temperature. After this time, DCM is added to the reaction mixture which is ished with NH4Cl sat, dried over MgSO4 and purified by flash chromatography (AcOEt/heptane 4:1) to give 440 mg (94%) of the title compound as a white solid. 1H NMR (DMSO) δ 9.93 (s, 1H), 8.43 (s, 1H), 8.11-8.02 (m, 1H), 7.91-7.84 (m, 1H), 7.84-7.76 (m, 2H), 7.59-7.45 (m, 4H), 7.40-7.31 (m, 1H), 3.81-3.69 (m, 2H), 3.67-3.49 (m, 6H) HPLC (max plot) 94.6%; Rt 4.83 min. MS (ESI+): 493.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=2[CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C:13]2=[O:31])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(#N)C>[F:36][C:34]1[CH:33]=[CH:32][C:10]([CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=3)[C:13]2=[O:31])=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:7][CH:6]=2)[CH:35]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(F)cc1Nc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(F)cc1Nc1ccc(NS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
150 mg of compound 240.1 were dissolved in 5 ml of acetonitrile and admixed with 145 mg of cesium carbonate and 41 mg of methanesulfonyl chloride. Subsequently, the mixture was stirred at 60° C. for 6 h; the next day, a further 1.2 equivalents of methanesulfonyl chloride were added and the mixture was stirred at 60° C. for a further 8 h. For workup, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography (method [RP1]). N-(4-{5-Fluoro-2-[3-(4-fluoro-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]phenylamino}phenyl)methanesulfonamide was obtained. Molecular weight 582.13 (C26H23F5N4O4S); retention time Rt=3.88 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[O:13][C:14]([CH:17]([F:19])[F:18])=[CH:15][CH:16]=1)(=O)C>CO>[F:18][CH:17]([F:19])[C:14]1[O:13][C:12]([CH2:11][OH:10])=[CH:16][CH:15]=1
Reactant: CC(=O)OCc1ccc(C(F)F)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1ccc(C(F)F)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a suspension of potassium carbonate in anhydrous methanol (10%, 50 mL) was added (5-(difluoromethyl)furan-2-yl)methyl acetate (4.21 g, 22.16 mmol). The reaction mixture was stirred at ambient temperature for 20 minutes, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (3/7) to afford (5-(difluoromethyl)furan-2-yl)methanol as a yellow oil in 96% yield (3.15 g): 1H NMR (300 MHz, CDCl3) δ 6.55 (t, JH-F=54.2 Hz, 1H), 6.58-6.55 (m, 1H), 6.34-6.26 (m, 1H), 4.59 (d. J=5.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg]Br>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: C[Mg]Br
Reactant: CC(=O)c1c(F)ccc(F)c1F
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)ccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,3,6-trifluorophenyl)ethanone (1.74 g, 10 mmol) in THF (10 mL) was added methyl magnesium bromide (7 mL, 21 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride and was then extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 2-(2,3,6-trifluorophenyl)propan-2-ol. (74).
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[N:7]=1>O.[OH-].[Na+].O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH:2]([F:4])[F:1])[CH:9]=[C:8]([CH3:13])[N:7]=1
Reactant: Cc1cc(O)nc(N)n1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OC(F)F)nc(N)n1

Procedure:
Gaseous difluorochloromethane is introduced, over a period of 12 hours at a temperature of 70° to 75° C., into a solution of 62.5 g of 2-amino-4-hydroxy-6-methyl-pyrimidine in 500 ml of water, 100 ml of 40% sodium hydroxide solution and 100 ml of dioxane. There are added during this time, in each case at intervals of 1 hour and in equal portions, a total of 160 g of solid sodium hydroxide. The organic phase is separated, and concentrated to about 1/10 of its volume; the residue is poured into water, and the solid substance which has precipitated is removed. The yield is 39.9 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine, m.p. 136° to 137° C. (compound No. 1.1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:25](Cl)=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=2)[CH2:9]1
Reactant: CCOC(=O)c1cnc(N[C@@H]2CCCN(Cc3ccccc3)C2)c(Cl)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ccc(N[C@@H]2CCCNC2)nc1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate (6.75 g, 18.1 mmol) in ethanol (200 mL) were added ammonium formate (6.83 g, 108 mmol) and 10% Pd/C (20% w/w, 1.2 g) at ambient temperature and the mixture was heated to reflux with stirring for 8 hrs. After cooling, the catalyst in the reaction mixture was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (NH, CHCl3 only —CHCl3:MeOH/50:1-25:1) to give ethyl 6-[(3R)-3-piperidinylamino]nicotinate (4.5 g, 100%) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[N:4]=1.F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[N:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1nccc(-c2ccc(N)cc2)n1
Product: CN(CCOc1ccc(C=O)cc1)c1nccc(-c2ccc(N)cc2)n1
Yield: 51.3 %

Procedure:
The title compound (980 mg) was prepared by the same procedure as the preparation 3 except for using 2-[N-methyl-N-(6-(4-anilinyl)pyrimidinyl)amino]ethanol (1.34 g) and 4-fluorobenzaldehyde (1.13 g).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:24]=[N:25][N:26]([CH3:29])[C:27]=6[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)cnn1C
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)cnn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
A small screw cap test tube was charged with 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 134 mg, 0.333 mmol) and THF (3.3 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (64.2 mg, 0.336 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (˜5 mL) and the resulting solution was triturated with Hexanes (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜10 mL) to afford the title compound in 11% yield (0.021 g, 0.036 mmol).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([S:14](Cl)(=[O:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[CH:22]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH2:42])[CH2:35]2)[N:20]=1>C1COCC1>[NH2:18][C:19]1[N:20]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH:42][S:14]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)(=[O:16])=[O:15])[CH2:35]2)[CH:22]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[N:24]=1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)C2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 147.4 %

Procedure:
Triethylamine (41 μL, 0.30 mmol) and cylcohexanesulfonyl chloride (44 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (85 mg, 0.25 mmol) in THF (3 mL), and the mixture was stirred at room temperature under nitrogen for 22 hours. LC-MS indicated only about 25% conversion, so more triethylamine (0.15 mL, 1.08 mmol) and cyclohexanesulfonyl chloride (0.15 mL, 1.03 mmol) were added, and stirring continued at room temperature for another 26 hours. The mixture was then quenched with saturated aqueous NaHCO3 (25 mL) and extracted with EtOAc (3×15 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the crude title compound (180 mg, about 45% pure according to LC-MS) as a yellow foam. LC-MS (ES) m/z=489 [M+H]+.
Reaction SMILES: ClC(OCC)=O.C([N:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:17]3([CH2:16][CH2:15][NH:14][CH2:19][CH2:18]3)[CH2:23][C:22]=2[CH:24]=1
Reactant: Fc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Yield: 46.9 %

Procedure:
Ethyl chloroformate (65.6 mg, 0.604 mmol) was added to a solution of 1′-benzyl-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidine] (150 mg, 0.504 mmol) in toluene (2 mL) and the mixture was refluxed over night, cooled to room temperature, diluted by addition of toluene (10 mL), washed successively with saturated aqueous NaHCO3 solution and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in ethanol (3.5 mL), aqueous KOH (800 mg, KOH in 0.8 mL H2O) was added and the mixture was refluxed over night, cooled to room temperature, ethanol was removed in vacuo. Aqueous layer was extracted with diethyl ether. Combined ether layer is was washed with 3N aqueous HCl. Aqueous layer was adjusted to pH 10 by addition of aqueous 3N NaOH. The basic solution was extracted with ethyl acetate. Combined organic layer was washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC (10-55% CH3CN in H2O, 0.1% NH4OH) to give the title compound (49 mg). 1H-NMR (CD3OD, 400 MHz): δ 6.92-6.87 (m, 1H); 6.81-6.75 (m, 1H); 6.64 (dd, J=4.2, 8.7 Hz, 1H); 3.08-2.98 (m, 4H); 2.89-2.81 (m, 2H); 1.91-1.83 (m, 2H); 1.78-1.69 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:15])=[CH:8]2)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[Br:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([OH:4])=[CH:14][CH:13]=2
Reactant: CC(=O)Oc1ccc2ncc(Br)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1ccc2ncc(Br)cc2c1
Yield: 90.2 %

Procedure:
A solution of Intermediate A (1 g, 3.76 mmol) and K2CO3 (1.04 g, 7.52 mmol) in MeOH/H2O (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vacuum to give the title compound as white solid (760 mg, yield 86%). LCMS (method N): [M+H]+=224, tR=2.29 min.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[N:16][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].O1CCC[CH2:28]1>>[CH3:28][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[N:15]=[N:16][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: C1CCOC1
Reactant: CC(C)(C)NC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Agent: [H-]
Agent: [K+]
Product: CN(C(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-[1-Phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetra-hydropyridine-1-carboxylic acid tert-butylamide (15 mg) prepared in Example 74 was added to a solution of 35 mg of potassium hydride in 1 ml of tetrahydrofuran washed with hexane. After stirring at room temperature for 10 minutes, 20 μl of methyl iodide was added thereto and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution followed by extracting with chloroform. The resulting organic layer washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was separated and purified by a preparative thin-layer chromatography (chloroform/methanol=20/1+0.3% aqueous ammonia) to give 8.5 mg of the title compound as a white solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[OH-:25].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:25])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1
Reactant: FC(F)(F)c1nn2c(Cl)cc(Cl)nc2c1Cc1cccc(Cl)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-dichloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (0.83 g, 2.0 mmol) in THF (10 mL) and water (2.5 mL) was added 1.6 mL of 6N sodium hydroxide solution. Reaction mixture was stirred at 45° C. overnight. Reaction mixture was concentrated down to s small volume, and diluted with 10 mL of icy water. The pH of reaction solution was adjusted to ˜7, and extracted with ethyl acetate (35 mL×2). Combined organic layers were dried over anhydrous sodium sulfate, and concentrated to dryness. The crude material was purified with column chromatography. Product was obtained and used without further purification in the next step. (0.273 g, 34%); LC/MS: MS (ES+) m/e 396 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:20]([OH:21])[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][N:14]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(O)c1cnccn1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2cnccn2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.38 g 1-acetyl-2-indolinone, 3.41 g pyrazine-2-carboxylic acid, 8.83 g TBTU, 4.21 g HOBT-hydrate and 21.8 ml ethyldiisopropylamine are stirred in 70 ml DMF for 15 hours at ambient temperature. The mixture is poured onto 400 ml ice water and 10 ml of conc. hydrochloric acid and stirred for 1 hour. The precipitate is suction filtered, washed with water, stirred with methanol, suction filtered again, washed with methanol and dried at 100° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=[O:33])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:34]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=[O:33])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH2:10][CH2:9]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CC=C(c2cnc3[nH]cc(C(=O)Cc4cccc(F)c4F)c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(C3CCC(NCc4ccccc4)CC3)cc12
Yield: 162 %

Procedure:
A solution of the above carbamic acid tert-butyl ester (306 mg, 0.54 mmol) was dissolved in CH2Cl2 (1 ml), treated with TFA (3 ml) for 1 hour. The reaction was evaporated and the solid residue triturated with ether and hexane, and filtered to give the final desired product as a white solid (402 mg) in 80% overall yield. FIA-MS m/e=458.2 (M+H), 456.3 (M−H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[CH3:20][CH:21]([CH2:44][CH2:45][CH2:46][CH3:47])[C:22]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:23]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: CCCCC(C)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Yield: 101.8 %

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (3.88 g.) and 2-methylhexanoylmethylenetriphenylphosphorane (6.0 g.) in dry tetrahydrofuran (30 ml.) was heated to reflux under nitrogen for 18 hours. The solvent was removed in vacuo and the residue triturated with petroleum ether (b.p. 60°-80° C.), allowed to stand at 0° C., filtered to remove triphenylphosphine oxide and the filtrate evaporated to give 6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (5.56 g), νmax 1620 cm-1, 1660 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:27]1[CH2:26][CH2:25][C:20]2[N:21]([CH3:24])[C:22]3[CH:23]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][C:11]4=[O:29])[CH:16]=[CH:17][C:18]=3[C:19]=2[CH2:28]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Yield: 33.8 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (0.2 g, 0.5 mmol) in CH2Cl2 (6 mL) was added triethylamine (0.20 mL, 1.4 mmol) followed by acetyl chloride (50 μL, 0.71 mmol). The reaction was stirred at room temperature until complete. After the solvent was removed under reduced pressure, the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound (72.2 mg, 36%) as a yellow solid and as a mixture of rotamers: mp 225-230° C.; 1H NMR (500 MHz, CDCl3) δ 7.53-7.36 (m, 6H), 7.32-7.30 (m, 2H), 7.06-7.00 (m, 1H), 6.09 (d, J=3.0 Hz, 1H), 6.07-6.04 (m, 1H), 5.06 (s, 2H), 4.82 (s, 1H), 4.67 (s, 1H), 4.03 (t, J=5.5 Hz, 1H), 3.84 (t, J=5.5 Hz, 1H), 3.64 (s, 3H), 2.90 (t, J=5.5 Hz, 1H), 2.84 (t, J=5.5 Hz, 1H), 2.24, 2.22 (2×s, 3H); ESI MS m/z 428 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=16.8 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Sodium hydride (60%, 0.12 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.00 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C., which is stirred for 15 minutes. To the reaction solution is added dropwise a solution of 2-chloro-5-trifluoromethyl pyridine (0.60 g) in 1,2-dimethoxyethane (20 ml) at -5° C., which is stirred for 15 minutes. The reaction mixture is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.80 g of desired compound (refractive index: 1.5879).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(=O)(OCC=C)O[CH2:14][CH:15]=[CH2:16]>Cl[Pd]Cl>[CH2:16]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH:15]=[CH2:14]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: C=CCOC(=O)OCC=C
Agent: Cl[Pd]Cl
Product: C=CCN1C(C)(C)CC(O)CC1(C)C
Temperature: 110 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
2,2,6,6-tetramethyl-piperidin-4ol (0.5 g, 3.18 mmol), PdCl2 (20 mg, 0.11 mmol) and di-allyl carbonate (5 ml, 36 mmol) are charged, under inert atmosphere, into a 10 ml-flask equipped with a reflux condenser. The reaction mixture is then heated to 110° C. under stirring for about 6 hours. Gas-chromatographic analysis shows that the reaction afforded the desired 1-allyl-2,2,6,6-tetramethyl-piperidin-4ol in 85% yield (calculated on the starting piperidinol) and >98% selectivity.