Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15][C:16]#[N:17])(=O)OCC)C.O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1.O>[C:16]([CH:15]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Temperature: 0 °C

Procedure:
To a three necked round bottom flask equipped with a mechanical stirring bar was added potassium tert-butoxide (263 mL, 263 mmol, 1.0 M in THF) and THF (200 mL). The mixture was cooled to 0° C., followed by the addition of diethyl(cyanomethyl)phosphonate (43.7 mL, 276 mmol) slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of tert-butyl 4-oxopiperidine-1-carboxylate (50.0 g, 251 mmol) in THF (150 mL) over 30 minutes. After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water (800 mL) and extracted with EtOAc (700 mL×2). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a light pink solid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:5]([F:16])=[C:4]([F:17])[N:3]=1.C([Li])CCC.[Cl:23][C:24]1[C:29]([CH:30]=[O:31])=[C:28]([Cl:32])[N:27]=[CH:26][N:25]=1>C1COCC1>[Si:9]([C:6]1[C:5]([F:16])=[C:4]([F:17])[N:3]=[C:2]([CH:30]([C:29]2[C:24]([Cl:23])=[N:25][CH:26]=[N:27][C:28]=2[Cl:32])[OH:31])[C:7]=1[F:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(Br)c1F
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(O)c2c(Cl)ncnc2Cl)c1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 37.2 %

Procedure:
To a solution of (2-bromo-3,5,6-trifluoro-4-pyridyl)-tert-butyl-dimethyl-silane (2.5 g, 7.66 mmol) in THF (15 mL) cooled at −78° C. was added butyllithium (2.5M in hexanes) (3.22 mL of 2.5 M, 8.05 mmol) at a rate which maintained the temperature below −70° C. On complete addition, the reaction mixture was stirred at −78° C. for 40 minutes and then a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.43 g, 8.05 mmol) in THF (25 mL) was added at a rate which maintained the temperature below −70° C. The reaction mixture was stirred at −78° C. for 1.5 hours. After this time, the reaction mixture was quenched with water and extracted with EtOAc (3×). The organics were combined, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 80 g column, eluting with 0-5% EtOAc/petroleum ether) to give the sub title compound as a cream solid (1.21 g, 37.2% Yield). H1 NMR (400 MHz, DMSO) δ 8.91 (1H, s), 6.69 (1H, s), 6.48 (1H, s), 0.88 (9H, s) and 0.39 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O-:34])=[O:33])[CH2:28][CH2:27]2)=[CH:22][C:21]=1[O:35][CH3:36]>C(O)CCC>[C:5]([O:33][C:32]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:6]3[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[C:21]([O:35][CH3:36])[CH:22]=2)[CH2:27][CH2:28]1)=[O:34])([CH3:9])([CH3:6])[CH3:4]
Reactant: COc1cc(N2CCN(C(=O)[O-])CC2)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
2,4-dichloro-5-(trifluoromethyl)pyrimidine (800 mg) and potassium carbonate (510 mg) were dissolved in n-butanol (15 ml), dropwisely added with a reaction solution, in which 4-(4-amino-3-methoxyphenyl)piperazin-1-carboxylate (1.13 g) was dissolved in n-butanol (5 ml), and stirred at room temperature overnight. Then, the mixture was distilled under reduced pressure to remove the solvent, added with ethyl acetate, and washed with saturated brine. The washed organic layer was dried with sodium sulfate, and concentrated under reduced pressure. The concentrated mixture was purified by column chromatography to obtain a target compound (430 mg).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].CC1C([N+]([O-])=O)=CC=CC=1C[N:34]1[C:38](=[O:39])C2=CC=CC=C2C1=O>>[C:38]([C:7]1[CH:6]=[CH:5][C:4]([N+:8]([O-:10])=[O:9])=[C:3]([CH2:11][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[CH:2]=1)(=[O:39])[NH2:34]
Reactant: Cc1cccc([N+](=O)[O-])c1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)cccc1[N+](=O)[O-]
Product: NC(=O)c1ccc([N+](=O)[O-])c(CN2C(=O)c3ccccc3C2=O)c1

Procedure:
N-(2-methyl-6-nitrophenyl)methyl-phthalimide, mixed with N-(2-methyl-3-nitrophenyl)methyl-phthalimide. M.p. 100°-124° C.
Reaction SMILES: [Na].[CH2:2]([SH:6])[CH2:3][CH2:4][CH3:5].[CH3:7][C:8]1([CH3:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:19][CH2:20][CH2:21][CH2:22]Cl)[C:9]1=[O:24]>C(O)C>[CH3:7][C:8]1([CH3:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:19][CH2:20][CH2:21][CH2:22][S:6][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]1=[O:24]
Reactant: CCCCS
Reactant: CC1(C)C(=O)N(CCCCCl)C(=O)c2ccccc21
Agent: [Na]
Solvent: CCO
Product: CCCCSCCCCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
1 gm of sodium was dissolved in 100 ml of ethanol, 3.7 gm of n-butylmercaptan were added dropwise to the solution, and a solution of 12 gm of 4,4-dimethyl-2-(4-chloro butyl)-2H,4H-isoquinoline-1,3-dione was slowly added. After refluxing the mixture for 3 hours, the precipitate was filtered off, the filtrate was evaporated, the residue was poured into ice water, and the aqueous mixture was acidified and extracted with chloroform. The chloroform phases were evaporated, whereby an oily crude product was obtained (13.0 gm, 98% of theory), which was purified by chromatography on silicagel (eluant: chloroform).
Reaction SMILES: CS([O:5][C@@H:6]([CH3:16])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.CC(C)([O-])C.[K+].CS(C)=O.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[N:32][C:33]=1[O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:45][C:46]1[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=1>O>[Si:9]([O:8][CH2:7][C@@H:6]([CH3:16])[O:5][C:30]1[CH:29]=[C:28]([Cl:27])[C:33]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][N:39]=[C:38]3[NH:45][C:46]2[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=2)=[N:32][CH:31]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)n1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 33.1 %

Procedure:
(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl methanesulfonate (79 mg, 0.29 mmol) and potassium tert-butoxide (55 mg, 0.49 mmol) were added to a dimethyl sulfoxide solution (3 ml) of 5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (90 mg, 0.24 mmol) obtained in Example 22, then stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to 0:1) to obtain 6-{[5-((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (43 mg, yield: 33%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: Cc1cc(CCCCCBr)no1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(C#N)cc2)no1
Yield: 53.6 %

Procedure:
A mixture of 5.1 g of 4-cyanophenol, 10 g of 3-(5-bromopentyl)-5-methylisoxazole, 8 g of potassium carbonate, 1 g of potassium iodide and 75 ml of acetonitrile was heated at reflux for 24 hours. The product was isolated and distilled, first at 115°-200° C. (0.1 mm) and then at 160°-190° C. (0.05 mm) to yield a yellow oil which crystallized upon cooling. Recrystallization from hexane-ether afforded 6.2 g of 3-[5-(4-cyanophenoxy)pentyl]-5-methylisoxazole, m.p. 61°-62° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: Nc1ccc(Br)cc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(Br)cc1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-bromoaniline and methyl chlorooxoacetate.
Reaction SMILES: B.O1CCCC1.[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[C:19]([CH2:22][CH:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])[CH:18]=[CH:17]2.CO>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[C:19]([CH2:22][CH:23]([CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25])[CH:18]=[CH:17]2
Reactant: COCCOc1cccc2ccc(CC(C(=O)O)C(C)C)cc12
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cccc2ccc(CC(CO)C(C)C)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3 ml of borane-tetrahydrofuran complex (1M in tetrahydrofuran) are added dropwise at 0° C. to the solution of 0.32 g of 2-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-3-methylbutyric acid in 2 ml of tetrahydrofuran. After 2 hours at room temperature, the reaction mixture is cooled to 0° C., admixed cautiously with 5 ml of methanol and subsequently stirred at room temperature for 1 hour. The reaction mixture is concentrated by evaporation—the residue is dissolved once again in methanol and concentrated by evaporation to dryness. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][CH2:17][Cl:16])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCCCCl
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C#CCCCCCl)n[nH]c2c(=O)[nH]1
Temperature: 60 °C
Yield: 166.9 %

Procedure:
To a solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (4.97 g, 15.62 mmol) in N,N-dimethylformamide (100 mL) was added bis(triphenylphosphine)palladium(II)dichloride (1.228 g, 1.750 mmol) and copper(I) iodide (0.595 g, 3.12 mmol). The solution was stirred and degassed with nitrogen for 5 minutes then the reaction mixture placed under a nitrogen atmosphere. A solution of 6-chloro-1-hexyne (3.64 g, 31.2 mmol) and triethylamine (4.36 mL, 31.2 mmol) in N,N-dimethylformamide (30 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at ambient temperature for a further 10 minutes then heated to 60° C. for 2.5 hours. The reaction mixture was concentrated in vacuo at 60° C. and the resulting residue partitioned between ethyl acetate (250 mL) and a 1:1 mixture of water:brine (500 mL). The organic layer was separated and the aqueous layer back extracted with ethyl acetate (250 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo to give a brown solid (8.0 g). The residue was dissolved in a 1:1 mixture of MeOH:DCM and absorbed onto Florisil. The solid was loaded and purified by chromatography on silica (330 g) using a 0-100% ethyl acetate-cyclohexane gradient over 10 column volumes followed by flushing with ethyl acetate for 9 column volumes. The appropriate fractions were combined and evaporated in vacuo to give a yellow solid (3.55 g). The solid was triturated with diisopropyl ether, filtered and dried in vacuo at 50° C. to give the title compound as a pale yellow solid (3.14 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N+:10]([O-:12])=[O:11])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1CCBr
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1CCN1CCN(c2ccccc2)CC1

Procedure:
A mixture comprising 0.1 mol 2-(2-bromoethyl)nitrobenzene, 0.23 mol N-phenylpiperazine, and 300 cc absolute ethanol was heated for 15 hr with agitation and refluxing of the ethanol. The alcohol was then removed by evaporation. The residue of the evaporation was dissolved in water. This was then extracted with ether. The ether phase was washed with fresh water, and then dried over sodium sulfate, after which the ether was evaporated off. The excess N-phenylpiperazine was removed by distillation. The distillation residue was recrystallized in methanol, yielding 2-(4-phenylpiperazinylethyl)nitrobenzene with m.p.=76° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11]
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)ccc1C
Yield: 84 %

Procedure:
A solution of (2,5-dimethylphenyl)acetic acid (3.0 g; 18.3 mmol) and H2SO4 (conc.; 0.1 mL) in EtOH (40 mL) was refluxed over 6 days. The solution was concentrated, ether (40 mL) was added, and the resultant mixture was washed with Na2CO3 solution (2×25 mL) and water (1×25 mL). The organic phase was dried (MgSO4) and evaporated, yielding 2.94 g (84%) of the sub-title compound a clear colourless liquid. Purity 97%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)(=O)C>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: CS(=O)(=O)OCC(F)(F)F
Product: Cc1cc(C#Cc2cn(CC(F)(F)F)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=280.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2,2,2-trifluoroethyl mesylate.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24]O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[N:4]1)[CH3:2].[CH3:38][CH2:39][N:40](CC)[CH2:41][CH3:42].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][N:40]5[CH2:41][CH2:42][CH2:38][CH2:39]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:30][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCN5CCCC5)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of N′-[4-(1-ethyl-4-{2-[3-(2-hydroxyethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea (210 mg, 0.42 mMol) in CH2Cl2 (15 mL) was added at 0° C. Et3N (120 uL, 0.86 mmol) and methanesulfonyl chloride (40 uL, 0.52 mmol). After stirring for 3 h, pyrrolidine (2 mL, 24 mmol) was added. The reaction was allowed to warm to RT, stirred for 18 h, and evaporated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (25%) as a pale yellow solid. ESMS [M+H]+: 548.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:15](=[O:18])[CH2:16][Cl:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22](=[O:27])/[CH:23]=[C:24](\[NH2:26])/[CH3:25])[CH3:20]>CCO>[NH2:26][C:24](=[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:27])[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15](=[O:18])[CH2:16][Cl:17])[CH3:25]
Reactant: CCOC(=O)C(=Cc1cccc(Cl)c1)C(=O)CCl
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C(=C(C)N)C(c1cccc(Cl)c1)C(C(=O)CCl)C(=O)OCC
Yield: 57.9 %

Procedure:
A solution of ethyl 2-(m-chlorophenylmethylen)-4-chloro-3-oxobutanoate (5 g) and ethyl-3-aminocrotonate (2.3 g) in EtOH (50 ml) is stirred at room temperature for four hours, then it is evaporated at reduced pressure, the residue dissolved in Et2O (70 ml) washed with water (3×20 ml), dried on Na2SO4 and purified by column-chromatography on silica gel (120 g; eluent hexane/AcOEt 60/40) to give 4.2 g of 2-amino-7-chloro-3,5-dicarboethoxy-6-oxo-4-(m-chlorophenyl)-2-heptene as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=O)=[C:11]([CH3:27])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:27][C:11]1[C:12]2[NH:18][C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:15][C:13]=2[CH:14]=[C:9]([OH:8])[CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1NC(=O)C1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(O)cc2nc(C3CCOCC3)[nH]c12

Procedure:
0.33 g (0.84 mmol) N-(4-(benzyloxy)-2-methyl-6-nitrophenyl)tetrahydro-2H-pyran-4-carboxamide were placed in 10 mL acetic acid and hydrogenated under a hydrogen atmosphere and with the addition of 0.10 g palladium/charcoal (10%) at 50° C. and a hydrogen pressure of 5 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])#[CH:15]>>[NH2:19][C:18]1[CH:17]=[C:16]([C:14]#[C:15][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CCc1ccc(I)cc1
Reactant: C#Cc1cccc(N)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc(N)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (100 mg, 0.34 mmol) and 3-ethynylaniline (0.04 mL, 0.38 mmol) according to the general procedure IC to give 89 mg (93%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.35 (EtOAc:hexanes, 1:1); 1HNMR (CDCl3) δ 7.44-7.42 (m, 2H), 7.18-7.09 (m, 3H), 6.93-6.91 (m, 1H), 6.83 (s, 1H), 6.66-6.63 (m, 1H), 3.66 (s, 3H), 2.98-2.93 (t, 2H, J=7.8 Hz), 2.65-2.60 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.1, 146.3, 140.7, 131.7, 129.2, 128.3, 124.0, 122.0, 121.3, 117.7, 115.2, 89.3, 88.6, 51.6, 35.4, 30.8; EI-MS m/z 279 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1(C)[CH2:25][O:24]1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:23]([CH3:25])([OH:24])[CH3:22])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC1(C)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)CN1CCC(Oc2ccc(Cl)nc2)CC1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirred solution of tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (1.0 g, 3.2 mmol) in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added at 0° C. and stirred for 3 h. The reaction mixture was concentrated in vacuo and resultant residue was dissolved in MeOH (5 mL), 2,2-dimethyloxirane (0.246 g, 3.2 mmol) was added and stirred at room temperature for 10-12 h. The reaction mixture was concentrated in vacuo to give the title product (0.775, 85%); MS: 285.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[O:10][C:11](=[O:23])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1.CCOC(C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:11]([O:10][C@H:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:32])[F:33])=[C:26]([O:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:25]=2)[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N+:4]([O-:40])=[CH:5][C:6]=2[Cl:39])=[O:23])=[CH:19][CH:18]=1
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(4-nitrobenzylcarbamoyloxy)ethyl)pyridine 1-oxide (200 mg, 0.334 mmol) in THF (10 ml), SnCl2 dihydrate (603 mg, 2.67 mmol) was added, and the mixture was stirred at 60° C. for 5 hours, then the mixture was diluted with NaHCO3 sat (pH=7) followed by the addition of EtOAc and filtered trough a celite pad. The inorganic phase was extracted with EtOAc. The combined organic layers were rinsed with brine, dried over Na2SO4 and evaporated affording the desired product (190 mg, 0.334 mmol, 100% yield, MS/ESI+ 568.3 [MH]+).