Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:40])[CH:16]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C>C(O)C.Cl.C(OCC)(=O)C>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[O:31][C:27]1[CH:26]=[N:25][N:24]([CH:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:40])[C:29](=[O:30])[CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1ccn(CCO)n1)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A solution of N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (540.6 mg, 0.89 mmol) in ethanol (4.5 mL) at 25° C. was treated with concentrated aqueous hydrochloric acid (9 drops). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (150 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and then concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 1-10% methanol/methylene chloride) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (298 mg, 68%) as a white solid; ES+-HRMS m/e calcd for C23H25N5O5F2 [M+H+] 490.1897 found 490.1895. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.34 (m, 2H) 1.34-1.46 (m, 1H) 1.46-1.59 (m, 2H) 1.90 (ddd, J=13.6, 9.0, 4.3 Hz, 1H) 2.12-2.28 (m, 1H) 3.08-3.29 (m, 2H) 3.69 (q, J=5.5 Hz, 2H) 3.74-3.89 (m, 2H) 4.02 (t, J=5.5 Hz, 2H) 4.86 (t, J=5.5 Hz, 1H) 5.54 (dd, J=11.0, 4.3 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.32-7.43 (m, 2H) 7.43-7.53 (m, 1H) 7.56 (d, J=2.1 Hz, 1H) 8.29 (d, J=2.7 Hz, 1H) 10.84 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:21]([N:23]([CH2:27][CH2:28][CH2:29]Cl)[CH:24]([CH3:26])[CH3:25])[CH3:22]>O1CCOCC1>[CH2:21]([N:23]([CH2:27][CH2:28][CH2:29][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)[CH:24]([CH3:26])[CH3:25])[CH3:22]
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Reactant: CCN(CCCCl)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(CCCN1c2ccccc2N(C)C(=O)c2ccc(C)nc21)C(C)C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 4.5 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-one, 60 ml of dioxane and 1.27 gm of 50% sodium hydride in mineral oil was stirred at 90° C. for 1 hour. Thereafter, 4.3 gm of 3-(N-ethyl-N-isopropyl-amino)-propyl chloride were added dropwise, and the mixture was refluxed for 17 hours. The reaction solution was then evaporated in vacuo, and the residue was purified over a silica gel column and recrystallized from petroleum ether, yielding 36% of theory of the compound named in the heading, which had a melting point of 104°-105° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[O:11][C:10]([C:12]([O:14]CCCC)=O)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[NH3:19]>>[CH2:1]([N:3]([CH2:6][C:7]1[O:11][C:10]([C:12]([NH2:19])=[O:14])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCCCOC(=O)c1ccc(CN(CC)CC)o1
Reactant: N
Product: CCN(CC)Cc1ccc(C(N)=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.3 g (0.1 mole) of n-butyl 5-(N,N-diethylaminomethyl)-2-furoate is added to 50 ml of liquid ammonia in a pressure vessel. The mixture is held at 180° C. and 2000 pounds per square inch gage pressure for 8 hours. The mixture is cooled to ambient temperature and evaporated to dryness giving 5-(N,N-diethylaminomethyl)-2-furamide (m.p. 164°-165° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:25][CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(CC=Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 1.50 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 20 ml of 1,2-dimethoxyethane was added 0.3 g of a 50% sodium hydride (suspension in oil) under cooling, and then the mixture was stirred for 1 hour. To the mixture was added 1.18 g of cinnamyl bromide, and the mixture was heated under reflux for 5 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The ethereal layer was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.6 g of 2-cinnamyl-2-(1-naphthylmethyl)malonic acid diethyl ester as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:13][CH:12]=1)=[O:6]
Reactant: Brc1ccc(OCCOC2CCCCO2)cc1
Reactant: O=Cc1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccc(OCCOC3CCCCO3)cc2)c1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of 3-hydroxybenzaldehyde (1.27 g, 10.4 mmol), tetrahydro-2-(2-(4-bromophenoxy)ethoxy)-2H-pyran (6.26 g, 20.8 mmol), potassium carbonate (2.23 g, 16.12 mmol) and copper (330 mg, 5.2 mmol) in pyridine (10 mL) was refluxed for 5 days. It was then cooled to r.t., filtered through Celite, diluted with ethylacetate (50 mL), and washed with H2O (3×40 mL). The organic was dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 2:3) to afford tetrahydro-2-(2-(4-(3-formylphenoxy)phenoxy)ethoxy)-2H-pyran (3.09 g, 87%) as a pale yellow oil.
Reaction SMILES: COC(C[O:6][C:7](=[O:21])[CH:8]([NH:17][C:18](=[O:20])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=O.Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[C:18]([NH:17][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:15]=1)[C:7]([OH:6])=[O:21])(=[O:20])[CH3:19]
Reactant: COC(=O)CCl
Reactant: COC(=O)COC(=O)C(Cc1ccc(O)cc1)NC(C)=O
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(NC(C)=O)C(=O)O)cc1

Procedure:
To mixture of 2-Acetylamino-3-(4-hydroxy-phenyl)-propionic acid methoxycarbonylmethyl ester 5 (5 grams, 16.95 mmol) Potassium carbonate (9.4 grams, 68 mmol) sodium iodide (1 gram, 6.67 mmol) Disodium Phosphate (1 gram, 70.84 mmol) in acetone (50 mL) is added Methyl chloroacetate (2.2 grams, 20.27 mmol) and is refluxed till the reaction complies by TLC. Acetone is distilled, water is added and the crude 6 can be extracted into chloroform, dried over sodium sulphate and distilled.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH2:11]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC1CCCO1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([OH:9])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CC2O1
Agent: I[Cu]I
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3 g, 16 mmol), was dissolved in 2-methyl-tetrahydrofuran (5 mL) and added dropwise to a solution of phenylmagnesium bromide (1.5 eq, 24.3 mL of a 1.0 M solution) and copper iodide (0.05 eq) at 0° C. The reaction was allowed to warm to room temperature and stir for 18 h. Reaction was cooled to 0° C. and quenched with sat. NH4Cl solution and extracted with EtOAc. Organic was washed with NaHCO3 and brine and dried over Na2SO4 and the solvent removed. Residue was purified by column chromatography on SiO2 (15-40% EtOAc/HEptane) which gave the title compound Ia as a yellow oil (3.59 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[C-:21]#[N:22].[K+]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:18]1[CH:17]=[CH:16][C:3]([NH:4][C:5]2[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:19]=1)#[N:22]
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c(Nc2ccc(C#N)cc2F)cc1=O
Temperature: 110 °C
Yield: 7 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.20 g, 0.5 mmol) was added to potassium cyanide (0.23 g, 3.5 mmol), copper(I)iodide (excess) and tetrakis(triphenylphosphine)palladium(0) (excess) in DMF (30 ml) and heated at 110° C. for 4 h. The reaction mixture was allowed to cool to RT and filtered through Celite® to remove any solid. The Celite® pad was washed well with 5% MeOH/EtOAc. The filtrate and washings were combined and concentrated under reduced pressure. The residue was dissolved in 5% MeOH/EtOAc, then washed with water, brine, dried (Na2SO4), concentrated and triturated with EtOAc giving an approximately 1:1 mixture of 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide and 4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide. Further purification by preparative HPLC [90% (H2O/TFA)/(acetonitrile/TFA)—1% (H2O/TFA)/(acetonitrile/TFA) gradient elution 0.8 ml/min, pH 2.5-2.6] yielded 4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.01 g, 7%); m.p. 261-266° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.01 (s, 1H), 8.39 (s, 1H), 7.91 (dd and br s, J=11.2, 1.7 Hz, 2H), 7.72 (t, J=8.2 Hz, 1H), 7.66 (dd, J=8.6, 1.7 Hz, 1H), 7.52 (br s, 1H), 5.97 (s, 1H), 3.40 (s, 3H). HPLC 95.5% (254 nm). HRMS (FAB+) cald for C14H11FN4O2 286.0866 (M+), found 286.0864.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1.S(Br)([Br:20])=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:20])=[CH:12][CH:11]=1
Reactant: OCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To 4-(benzoxazol-2-yl)benzyl alcohol (20.9 g; 100 mmol) dissolved in CH2Cl2 (330 ml) and cooled to 0°-5° C. is added thionyl bromide (9.2 ml; 120 mmol) and allowed to warm to room temperature after removing the bath. After 11/2 hours, 2,6-lutidine (11.6 ml; 100 mmol) is added to the mixture and warmed to 30° C. The reaction mixture is then diluted with CH2Cl2, washed with H2O 1x , 0.2M HCl 1x, NaHCO3 2x, brine, dried (MgSO4) and concentrated to dryness. The residue is recrystallized from EtOAc to obtain 4-(benzoxazol-2-yl)benzyl bromide as white-orange needles which is used directly in Step C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)/[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([OH:28])=O.C(Cl)(=O)C([Cl:32])=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)/[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([Cl:32])=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(/C=C2/C(C)=C(CC(=O)Cl)c3cc(F)ccc32)cc(OC)c1OC

Procedure:
(Z)-5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylaceticacid (20.64 g, 54.70 mmol) in THF (150 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 35 ml; 70 mmol) under reflux conditions (24 h). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: C([C:3]1C=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=[N:29]C=CC=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:23]=[N:29][CH:3]=[CH:4][CH:5]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: ClCc1cccnc1
Product: COCOc1cc(SCc2cccnc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 3-chloromethylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[O:5].[CH:8]([Mg]Br)=[CH2:9].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]([OH:5])[CH:8]=[CH2:9]
Reactant: CC(C)(C)CC=O
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)CC(C)(C)C
Temperature: -20 °C
Yield: 15.3 %

Procedure:
A solution of 3,3-dimethylbutyraldehyde (5.0 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (0.780 g, 15%). 1H NMR (300 MHz, CDCl3): δ ppm 0.98 (m, 9 H) 1.45 (m, 2 H) 4.26 (m, 1 H) 5.06 (m, 1 H) 5.21 (m, 1 H) 5.90 (m, 1 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:14]([Cl:37])=[C:15]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH:29]4[CH2:31][CH2:30]4)[C:25]4=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:24]4[N:23]=3)[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=2)[CH2:9][C@H:8]1[O:38][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:37][C:14]1[C:15]([NH:21][C:22]2[N:27]=[C:26]([NH:28][CH:29]3[CH2:30][CH2:31]3)[C:25]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:24]3[N:23]=2)=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][C@@H:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C@H:8]([O:38][Si:39]([CH:43]([CH3:45])[CH3:44])([CH:46]([CH3:48])[CH3:47])[CH:40]([CH3:41])[CH3:42])[CH2:9]1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1NS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Methanesulfonyl chloride (7.5 μl, 0.10 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg, 0.040 mmol) and triethylamine (17 μl, 0.120 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 0-40% ethyl acetate/dichloromethane). N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)methanesulfonamide (28 mg) was obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16]>ClCCl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26]
Reactant: COC(=O)CN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Glycine methyl ester hydrochloride (15.0 g) was dissolved in dichloromethane, and to the solution triethylamine (26.48 g) was added at 0° C. A solution of 2-nitrobenzenesulfonyl chloride (23.57 g) in dichloromethane (50 mL) was then gradually added dropwise. After the mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The resultant mixture was washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14](COC)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].Cl.O.C(=O)([O-])O.[Na+]>CC(C)=O>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:11][CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13]1
Reactant: CCOC(=O)C(Cc1cn(COC)c2ccccc12)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1c[nH]c2ccccc12)OC(C)C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2.3 g of Ethyl 2-isopropoxy-3-(1-methoxymethyl-1H-indol-3-yl)propionate was dissolved in 25 ml of acetone, and 15 ml of 5N hydrochloric acid was added, and the mixture was stirred for 2 hours. The reaction solution was cooled with ice, treated with water and sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 20 ml of ethanol, and an aqueous solution containing 2 g of potassium carbonate was added, and the mixture was stirred at 50° C. for 3 hours. The reaction solution was cooled with ice, treated with water and ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was subjected to silica gel column chromatography (50% ethyl acetate-hexane), to give 0.75 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH:17]=O.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCCC(F)(F)F
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
0.097 ml of 4-tert-butylbenzylamine (0.55 mmol) and 110 mg 4,4,4-trifluoro-butyraldehyde (0.83 mmol) were dissolved in 2 ml methanol and stirred 30 min at rt and then refluxed for 2.5 h. After cooling down to rt, 25 mg (0.66 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was refluxed for 2¾ h. After cooling down to rt, the reaction mixture was treated with 1 drop 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 110 mg colorless viscous oil (73%). MS (ISP) 274.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:46][C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NC(C)(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A solution of Example C2 (0.100 g, 0.238 mmol) in DCM (5 mL) was treated with mCPBA (0.059 g, 0.238 mmol), stirred at RT for 2 h, treated with t-butylamine (0.4 mL, 3.81 mmol) and stirred at RT overnight. Additional t-butylamine (0.4 mL, 3.81 mmol) was added and the mixture stirred at RT for an additional 24 h. The mixture was concentrated to dryness, transferred to a sealed vessel with DMF (5 mL), treated with additional t-butylamine (0.4 mL, 3.81 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, the solids removed via filtration and washed with DCM. The filtrate was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were washed with 5% LiCl (3×), then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(tert-butyl)-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (69 mg, 65%). MS (ESI) m/z: 446.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].S(=O)(=O)(O)O.[CH3:16][C:17]([CH3:22])=[CH:18][CH:19](O)[CH3:20]>C(OC(C)C)(C)C>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]2[C:7]([CH:19]([CH3:20])[CH2:18][C:17]([CH3:22])([CH3:16])[O:9]2)=[C:6]([CH3:10])[CH:5]=1
Reactant: Cc1cc(O)c(C)c(O)c1
Reactant: CC(C)=CC(C)O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Product: Cc1cc(O)c(C)c2c1C(C)CC(C)(C)O2
Yield: 60 %

Procedure:
13.8 g. of 2,5-dimethyl resorcinol were dissolved in a mixed solution comprising 70 ml of isopropyl ether and 5 ml of concentrated sulfuric acid. Then, 10 g. of 4-methyl-3-pentene-2-ol were added dropwise to the solution at the temperature of about 60° C. for about 30 minutes. The resulting solution was cooled, and washed with water, with 1 N sodium hydroxide solution, and again with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ether/n-hexane, to obtain 13.2 g. (yield: 60%) of the subject compound. Melting point: 88°-89° C.