Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl-].[NH4+].C(O)C.O>[Fe].CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
4-Chloro-6-(4-nitrophenoxy)pyrimidine (2.52 g, 10.0 mmol), iron powder (2.79 g, 50.0 mmol) and ammonium chloride (5.35 g, 100 mmol) were suspended in an ethanol (100 ml)-water (25 ml) mixed solvent and the suspension was heated and stirred at 80° C. for 1 hour. Upon completion of the reaction, the reaction mixture was filtered with celite and washed in an ethanol-ethyl acetate mixed solvent. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=2:3), and the fraction containing the target substance was concentrated to obtain the title compound (1.74 g, 7.85 mmol, 79%) as colorless crystals.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].C(OCC)(=O)C>C(N(CC)CC)C>[C:1]([O:5][CH2:7][C:8]([O:10][CH3:11])=[O:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: COC(=O)CBr
Reactant: C=CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(=O)OC
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Into a five-liter, three-necked, round-bottom flash (equipped with a mechanical stirrer, a thermometer and a one-liter dropping funnel topped with a drying tube) were placed 527.9 mls. of acrylic acid, 662.7 mls. of methyl bromoacetate and 1750 mls. of ethyl acetate. The resulting solution was cooled to about 15° C. and 1073.2 mls. of triethylamine were added over a period of about one hour. An exotherm was noted and reaction temperature was maintained between 15° and 25° C. with an ice/salt cooling bath. Upon completion of the triethylamine addition, the cooling bath was removed and the reaction mixture was stirred at room temperature (25° to 30° C.) overnight. The resulting thick slurry was poured into 1750 mls. of distilled water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (two times, 500 mls. each) and the combined organic portions were washed successively with 500 mls. of 0.5N hydrochloric acid, 500 mls. of saturated aqueous sodium bicarbonate and, then, with 500 mls. of saturated aqueous sodium chloride. The organic solution (about 3.5 to 3.75 liters) was then dried (magnesium sulfate) and evaporated in vacuo (water aspirator) at ≤30° C. to provide a very pale-yellow product. The product was purified by addition of one gram of 2,6-di-tert-butyl-p-cresol as a free radical inhibitor and vacuum distilling through a distillation column. The purified product exhibited a boiling point of 50° C. (1.2 mm.) to 56° C. (1.9 mm.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:11][C:10]=2[Cl:20])[CH:7]=1.[Br-].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Zn+]>O1CCOCC1.O.[Pd+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:20][C:10]1[CH:11]=[C:12]([S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH:7]=1
Reactant: [Zn+]c1ccccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(Br)cc(CC(=O)O)c2)c(Cl)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [Br-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(-c3ccccn3)c2)c(Cl)c1

Procedure:
The product from example 55 step (vi) (0.45 g), 2-pyridyl zinc bromide (0.89 ml) and bisdiphenylphosphinoferrocene palladium (II) (0.04 g) in dry dioxane (20 ml) were heated to 90° C. for 20 h. Mixture diluted with water, extracted with DCM, dried (MgSO4) and evaporated under reduced pressure to an oil, which was purified by RPHPLC to give a white solid (3 mg).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH:30](=O)[CH2:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)(Cl)Cl.ClCCCl>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH3:32])[CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 2.75 h
Yield: 52.7 %

Procedure:
A solution of 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (75.1 mg, 0.191 mmol) in methanol and chloroform was treated with ethereal HCl, concentrated, treated sequentially with 32 mL of 1,2-dichloroethane, propionaldehyde (0.55 mL, 7.6 mmol in two portions) and acetic acid (0.55 mL, 9.6 mmol in two portions). The reaction mixture was stirred, under nitrogen, at ambient temperatures for 2.5-3 hours, treated with sodium triacetoxyborohydride (81.2 mg, 0.384 mmol), stirred 1.5-20 hours, diluted with chloroform and washed with 1.0 N sodium hydroxide and brine. (Methanol was added to the organic phase to aid in solubility.) The organic phase was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.3-0.8% ammonium hydroxide/3.0-8.0% methanol in chloroform to yield 3-(naphthalene-1-sulfonyl)-5-(1-propyl-pyrrolidin-3-yloxy)-1H-indazole as a light yellow foam (43.8 mg, 52.5%). The foam was dissolved in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo at 86° C. for 13 hours to give the title product as a light beige foam, 43.7 mg, Mass spectrum (+EI, [M+H]+) m/z 436. 1HNMR (500 MHz, DMSO-d6): δ14.20 (s, 1H), 10.29-10.62 (m*, 1H), 8.74 (d, 1H, J=8.54 Hz), 8.56 (d, 1H, J=6.95 Hz), 8.28 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.27 (s, 1H), 7.12 (dd, 1H, J=9.15 Hz and 2.32 Hz), 5.17-5.23 (m, 1H), 3.30-3.95 (m*, 3H), 3.11-3.23 (m*, 3H), 2.01-2.56 (m*, 2H), 1.60-1.69 (m, 2H), 0.87-0.90 ppm (m, 3H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[NH:8][C:7]2=[O:21].COC1C(N)=C(C=CC=1)C(N)=O.[H][H]>CO.[C].[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[NH:8][C:7]2=[O:21]
Reactant: [H][H]
Reactant: O=c1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc2c(O)cccc12
Agent: [Pd]
Agent: COc1cccc(C(N)=O)c1N
Solvent: CO
Product: Nc1ccc(-c2nc3c(O)cccc3c(=O)[nH]2)cc1

Procedure:
8-Hydroxy-2-(4'-nitrophenyl)quinazolin-4-[3 H]-one, prepared from 3-methoxy-2-aminobenzamide as in Example 5, (50 mg, 0.18 mmol) was suspended in methanol (20 ml) with palladium-carbon catalyst (20 mg) and the reaction vessel was placed under the atmosphere of hydrogen at ambient temperature and pressure. The reaction mixture changed from a yellow suspension to a clear, colourless solution, whereupon the catalyst was removed by filtration through Celite™. The solvent was removed under vacuum to leave a cream pale brown solid, which was recystallised from aq. methanol (25.7 mg, 0.1 mmol, 57%), m.p. >230° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(CCN)cc1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(CCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared as in Example 1a from 3-trifluoromethylphenyl glyoxal (3.85 g) and 2-(4-carbomethoxyphenyl) ethanamine (3.4 g), and crystallised from hexane m.p. 75-77.5. τ(CDCl3) 7.66 (2H, broad, replaceable by D2O), 5.9-6.5 (6H, m), 6.15 (3H,s), 5.3 (1H,m), 2.75 (2H,d,J=8 Hz), 2.3-2.6 (4H,m), 2.03 (2H,d,J=8 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.CCOCC>[NH:1]1[C:9]2[C:4](=[N:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc2[nH]ncc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid, methyl ester (420 mg, 2.37 mmol) was dissolved in THF (30 mL) and cooled to 0° C. LiAlH4 (360 mg, 9.48 mmol) was added in one portion. The mixture was stirred at 0° C. for 3 hr, and diluted with ether. 50% NaOH (5 mL) was added to quench the reaction, and the solid was filtered off through Celite. The filtrate was concentrated, and the residue was purified by flash chromatography to afford 1H-pyrazolo[4,3-b]pyridine-5-methanol (270 mg, 76.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>CC(C)CC(=O)C>[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[O:28])=[CH:24][CH:25]=1
Reactant: CCOC(=O)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)Oc1ccc(CC(=O)N(c2ccc(Cl)cc2)C2CCN(C(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To a stirred mixture of 7.5 parts of N-(4-chlorophenyl)1-(1-methylethyl)-4-piperidinamine and 80 parts of 4-methyl-2-pentanone are added dropwise 9 parts of [4-(2-chloro-2-oxoethyl)phenyl] ethyl carbonate. Upon completion, the whole is heated to reflux and stirring is continued for one hour at reflux temperature. After cooling, the precipitated product is filtered off and stirred for 30 minutes in a mixture of alkaline water and trichloromethane. The layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.5 parts of {4-[2-{(4-chlorophenyl)-[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl} ethyl carbonate as an oily residue.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C@H:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[N:12]=2)C=CC=CC=1.Cl>C1COCC1>[CH3:18][O:17][C:13]1[N:12]=[C:11]([CH2:10][C@@H:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:8])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)n1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](N)Cc1cccc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(diphenylmethylidene)-3-(6-methoxy-2-pyridinyl)alaninate (1.81 g, 4.66 mmol) and 5N hydrochloric acid (1.86 mL, 9.32 mmol), and THF (20 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo to give crude ethyl 3-(6-methoxy-2-pyridinyl)alaninate as a light-yellow tar, which was used without purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([O:8][N:9]=[CH:10][CH:11]=[N:12][OH:13])(=[O:7])[CH3:6]>>[C:5]([O:8][N:9]=[CH:10][CH:11]=[N:12][O:13][C:3](=[O:4])[NH:2][CH3:1])(=[O:7])[CH3:6]
Reactant: CC(=O)ON=CC=NO
Reactant: CN=C=O
Product: CNC(=O)ON=CC=NOC(C)=O
Reaction time: 4 h
Yield: 90 %

Procedure:
1 Part of methylisocyanate is added to a solution of 1 part of mono-O-acetylglyoxime (Example 1) in 5 parts of acetronitrile, and stirring carried out for 4 hours at 20°. The precipitated product is filtered off; mp. 138°; yield 90%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:25]1([CH2:24][CH2:23][CH2:22][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: BrCCCn1ccnc1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCCn1ccnc1
Yield: 37.5 %

Procedure:
Using General Procedure A: 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (91.3 mg, 0.341 mmol), 1-(3-bromo-propyl)-1H-imidazole (129 mg, 0.680 mmol), KI (5.6 mg, 0.034 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.4 mL) were stirred at 60° C. overnight. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 90:5:5) followed by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (48 mg, 38%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:11]=[CH:12][C:13](=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=CC(C)=O
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)C=CNCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of benzylamine (1.1 mL, 10 mmol) and 4-methoxybut-3-en-2-one (1 mL, 10 mmol) in chloroform (100 mL) was stirred at room temperature until complete conversion. Then, the solvent was evaporated to afford the desired product 30 in 70% yield which was used without additional purification.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=S>CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[N:1][NH2:2]
Reactant: S=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Reactant: NN
Solvent: CO
Product: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Reaction time: 24 h
Yield: 126.7 %

Procedure:
Hydrazine (0.32 ml, 10 mmol) was added to a suspension of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbothioamide (90 mg, 0.2 mmol) in 3 ml of methanol and the reaction mixture was stirred for 24 hour. The precipitate was filtered, washed with methanol and dried in vacuum to give N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbohydrazonamide (94 mg, 90%). MS: (ESI+)=371.1
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].C1N=[CH:36][N:35]([C:38](N2C=NC=C2)=[O:39])[CH:34]=1.CN>C1COCC1.CCOC(C)=O>[NH2:6][C:4]([C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:11][C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH2:23][CH2:24][N:25]3[C:38]([N:35]([CH3:36])[CH3:34])=[O:39])=[CH:21][C:20]=2[O:28][CH3:29])[NH:15][C:14]2=[N:30][CH:31]=[CH:32][C:13]=12)=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)N(C)C)CC2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
A mixture of of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (67 mg, 0.15 mmol) and CDI (30 mg, 0.18 mmol) in THF (4 mL) was stirred for 15 min, then treated with a solution of methylamine (2M in THF, 4 mL, 8 mmol) and was heated for 2 days in a sealed vessel at 80° C. More methylamine (2M in THF, 5 mL) was added and the reaction mixture was heated for 22 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL), washed with a saturated Na2CO3 solution (50 mL), water (50 mL) and a saturated NaCl solution (50 mL). The aqueous layers were back extracted with EtOAc (50 mL). The organic layers were combined and concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 6-[(4-{[2-(aminocarbonyl)-3-fluorophenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-N,N-dimethyl-5-(methyloxy)-2,3-dihydro-1H -indole-1-carboxamide as a yellow solid (43 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (s, 6H), 2.94 (t, J=8.06 Hz, 2H), 3.73-3.86 (m, 5H), 6.18-6.28 (m, 1H), 6.84-6.95 (m, 2H), 6.97 (s, 1H), 7.31-7.42 (m, 1H), 7.47 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H), 8.07 (s, 1H), 8.41 (d, J=8.24 Hz, 1H), 10.47 (s, 1H), 11.21 (s, 1H); ESIMS (M+H)+=505.15.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1nc(SC)nc(N2CCSCC2)c1[N+](=O)[O-]
Product: CCOc1nc(N2CCNCC2)nc(N2CCSCC2)c1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
23 gm (0.07 mol) of 6-ethoxy-2-methylthio-5-nitro-4-thiomorpholino-pyrimidine were added to 68 gm (0.8 mol) of molten piperazine, and the mixture was heated at 110°C for 1 hour. After cooling, ice water was added to the reaction mixture, and the yellow precipitate formed thereby was suction-filtered off, washed with water and recrystallized from isopropanol. Yield: 18 gm (70% of theory); m.p. 166.5°-168.5°C
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.CN1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13]([CH:10]2[CH2:12][CH2:11]2)=[O:14])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C(Cl)C1CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2CC2)cc1Br
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methylaniline (100 mg), cyclopropanecarbonyl chloride (98 mg) and N-methylmorpholine (0.12 ml) in dry dichloromethane (2 ml) was stirred at 20 C for 18 h. The mixture was then partitioned between saturated sodium bicarbonate solution and dichloromethane. The dried extracts were evaporated giving a solid which was used without purification in the next synthetic step (120 mg).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:18][N:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([CH:30]=O)[N:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOCC.C([O-])(O)=O.[Na+]>[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:18][N:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([C:30]#[CH:1])[N:21]=[N:20]1
Reactant: O=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Yield: 53.7 %

Procedure:
To the (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (794, 4.20 mmol) in 70 mL of methanol, add 1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbaldehyde (1.44 g, 3.60 mmol) as a solution in 5 mL of methanol. To this mix, add (995 mg, 7.20 mmol) of potassium carbonate and mix the solution for 18 hours. Dilute with ether, saturated NaHCO3 and extract with ether 3 times, wash the organics again with saturated NaHCO3, and dry the combined organics with MgSO4. Filter and concentrate. Purify by chromatography (silica gel, hexanes/EtOAc gradient) to provide 764 mg of the title compound. Exact Mass 395.09 spectrum (aspci): m/z=396.1 (M+1), 394.0 (M−1); 1H NMR (250 MHz, CDCl3) δ 7.73 (s, 1H), 7.55-7.40 (m, 3H), 7.42-7.30 (m, 3H), 5.52 (s, 2H), 3.21 (s, H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11][OH:12])[CH:5]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(Br)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 22, from 3-(3-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 11) and (3-methylsulfonylphenyl)boronic acid was prepared the title compound as a mixture of E and Z isomers (3:1) as a white foam, MS (ESI+): m/z=471.2 ([M+H]+).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][CH:21]=[N:22]4)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C(NC(C2C=CC=CC=2)C)=NC(C2C=CC=C3C=2C=CC=N3)=CC=1)([O-])=O.[CH2:55]([OH:57])C>[Pd]>[C:1]1([CH:7]([N:9]2[C:10]3=[N:11][C:12]([C:17]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:18]=4[CH:19]=[CH:20][CH:21]=[N:22]5)=[CH:13][CH:14]=[C:15]3[NH:16][C:55]2=[O:57])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CC(Nc1nc(-c2cccc3ncccc23)ccc1N)c1ccccc1
Agent: [Pd]
Agent: CC(Nc1nc(-c2cccc3ncccc23)ccc1[N+](=O)[O-])c1ccccc1
Product: CC(c1ccccc1)n1c(=O)[nH]c2ccc(-c3cccc4ncccc34)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
N2-(1-Phenylethyl)-6-(quinolin-5-yl)pyridine-2,3-diamine. A solution of 3-nitro-N-(1-phenylethyl)-6-(quinolin-5-yl)pyridin-2-amine (2.36 g, 6.37 mmol) in ethanol (175 mL) was purged with nitrogen for several min. Following addition of palladium on carbon (245 mg, 2.29 mmol), the flask was evacuated and a hydrogen filled balloon was placed on the reaction. After stirring at room temperature for 18 h, the reaction was filtered and the solvent removed under reduced pressure to afford the title compound (1.89 g, 87% yield). MS (ESI) m/z 341.3 [M+1]+.