Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cu][C:16]#[N:17].[C-]#N.[K+].C(Cl)Cl>O.Cl>[C:16]([C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)#[N:17]
Reactant: N#C[Cu]
Reactant: COc1cc(C(C)=O)cc(N)c1OC
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(C)=O)cc(C#N)c1OC
Reaction time: 3 h

Procedure:
A solution of 5.2 g of sodium nitrile in 20 ml of water is added dropwise at 0° within 20 minutes to 14.0 g of 5'-amino-3',4'-dimethoxyacetophenone dissolved in 155 ml of 1N hydrochloric acid. After stirring at -2° for 30 minutes the cold diazonium salt solution is added dropwise within 30 minutes at 5°-10° to a solution of 8.7 g of copper(I) cyanide and 5.45 g of potassium cyanide in 60 ml of water. After completion of the addition 200 ml of methylene chloride are added, and the reaction mixture is stirred at 23° for 3 hours and then filtered. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. There is obtained 5'-cyano-3',4'-dimethoxyacetophenone of m.p. 125°-126°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2nc(-c3ccc(O)cc3)cn2c1
Temperature: 110 °C
Yield: 29 %

Procedure:
432 mg (corresponding to 2.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 279 mg (corresponding to 2.0 mmol) of 2-amino-5-nitropyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 6 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 8 mL of water and 8 mL of methanol. Then, about 8 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 3 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 148 mg (corresponding to 0.580 mmol) of 2-(4′-hydroxyphenyl)-6-nitroimidazo[1,2-a]pyridine (FIG. 8, Step 2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)=[N:15]1>CN(C)C=O>[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:2]4[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)=[N:15]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc([N+](=O)[O-])nc4)cc23)n1
Temperature: 60 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
5-Bromo-2-nitropyridine (460 mg, 2.3 mmol) and sodium hydride (120 mg, 3.1 mmol) were added to an N,N-dimethylformamide suspension (10 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (500 mg, 2.1 mmol), and stirred at 60° C. for 14 hours. The reaction solution was cooled to room temperature, the precipitate was collected by filtration, washed with water. The obtained precipitate was dried, then purified by silica gel column chromatography (chloroform:methanol=96:4) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-[(6-nitropyridin-3-yl)oxy]quinazoline-4-amine (580 mg, yield: 77%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH:14]([C:17]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19](=[C:20]([CH3:30])[CH:21]=[C:22]2[CH:28]=O)[CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19](=[C:20]([CH3:30])[CH:21]=[C:22]2/[CH:28]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:28]/[C:22]3[C:23]4[C:19]([CH:18]=[C:17]([CH:14]([CH3:15])[CH3:16])[CH:26]=[CH:25][C:24]=4[CH3:27])=[C:20]([CH3:30])[CH:21]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)[CH:18]=1)([CH3:16])[CH3:15]
Reactant: Cc1cc(C=O)c2c(C)ccc(C(C)C)cc1-2
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: Cc1ccc2c(c1)O/C(=C\c1cc(C)c3cc(C(C)C)ccc(C)c1-3)C(=O)/C(=C/c1cc(C)c3cc(C(C)C)ccc(C)c1-3)O2

Procedure:
Calone is reacted with 5-isopropyl-3,8-dimethylazulene-1-carbaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(5-isopropyl-3,8-dimethylazulen-1-yl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])=[O:34].ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])=[O:34])[CH2:20]3)=[CH:13][C:12]2=[O:31])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)Oc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CCN(C(=O)Oc4ccccc4Cl)C3)cc2=O)cc1

Procedure:
Example 19 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)pyrrolidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 2-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=8.80 Hz, 2H), 7.61 (d, J=8.80 Hz, 2H), 7.43 (d, J=8.25 Hz, 1H), 7.23-7.31 (m, 3H), 7.14-7.19 (m, 1H), 6.10-6.21 (m, 2H), 3.38-4.14 (m, 6H), 3.10 (s, 3H), 2.77-2.93 (m, 1 H), 2.15-2.32 (m, 1H), 1.83-2.00 (m, 1H). MS (ESI) 503 (M+H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:35][CH2:34][CH2:33][N:32]3[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:27][CH:26]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:29][CH:30]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCNc1ccc2ncc(Br)n2n1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCCCCNc1ccc2ncc(-c3ccc(C4CCCN4C(=O)OC(C)(C)C)cc3)n2n1
Yield: 66.7 %

Procedure:
To 150 mg (0.530 mmol) of the 3-bromo-N-pentylimidazo[1,2-b]pyridazin-6-amine was added the tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate (237 mg, 0.636 mmol), K3PO4 (225 mg, 1.060 mmol), PdCl2(PPh3)3 (37 mg, 0.053 mmol), 3 mL of DME and 1 mL of water. This mixture was microwaved for 0.5 hr at 140° C. After cooling it was diluted with 25 mL of EtOAC, and washed with about 20 mL of brine. The organic layer was dried over MgSO4, and concentrated. The crude mixture was purified on a 12 g silica gel column (ISCO), eluting with 15-100% EtOAc/Hex to give 159 mg (67%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH3:16][N:17](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:17][CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
To a solution of (4-bromophenoxy)acetic acid (500 mg, 2.10 mmol) in N,N-dimethylformamide (15 mL) was added methylamine hydrochloride (320 mg, 5.10 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (570 mg, 3.00 mmol), 1-hydroxybenzotriazole (400 mg, 3.00 mmol) and N-methyl-morpholine (600 mg, 6.00 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), and then washed three times with ethyl acetate (20 mL). The combined organics was dried and concentrated to give the title compound (580 mg, 90% yield) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H), 6.79 (d, 2H), 6.56 (s, 1H), 4.46 (s, 2H), 2.91 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][CH2:16][O:17][C:18]([C:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19].C(N(CC)CC)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:52].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18]([C:20]3[C:32]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:52]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C(OCCBr)c1cccc2c1Cc1ccccc1-2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCN1CCN(c2cccc(Cl)c2)CC1)c1cccc2c1Cc1ccccc1-2

Procedure:
To a stirred solution of 2-bromoethanol (3.3 g, 0.026 mol) in 50 mL of methylene chloride, fluorene-1-carboxylic acid chloride (6 g, 0.026 mol) and triethylamine (5 g, 0.05 mol) were added. The reaction mixture was stirred at room temperature overnight. The methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 7 g of the intermediate fluorene-1-carboxylic acid bromoethyl ester. The title compound was prepared by stirring 4-(3-chlorophenyl)piperazine (2.6 g, 0.011 mol), fluorene-1-carboxylic acid bromoethyl ester (3.5 g, 0.011 mol) and triethylamine (2.5 g, 0.025 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf =0.68 in 30% methanol/ethylacetate system) was separated and converted to the dihydrochloride salt with ethanolic HCl (1.8 g, 31% yield), mp. 215°-217° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](N1C=CN=C1)([N:19]1C=CN=[CH:20]1)=O.C(N(CC)CC)C.Cl.CNC>CN(C)C=O>[CH3:17][N:19]([CH3:20])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.1 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (10 g, 43.6 mmol) in N,N-dimethylformamide (150 mL) was added 1,1′-carbonyldiimidazole (14.13 g, 87.23 mmol). The reaction mixture was stirred at room temperature for 10 min. Triethylamine (18.3 mL, 130.2 mmol) and dimethylamine hydrochloride (7.1 g, 87.2 mmol) were then added sequentially. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was treated with cold water and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography to afford (R)-tert-butyl 3-(dimethylcarbamoyl)piperidine-1-carboxylate (0.9 g, 80%). MS (ES+APCI) (M+H) 257.1; LCMS retention time: 2.829 min (Method D1)
Reaction SMILES: [C:1]([O:18][CH2:19][C:20](=[CH2:23])[CH2:21][OH:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[C:1]([O:18][CH2:19][C:20](=[CH2:23])[CH2:21][O:22][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)CCCCCCCBr
Reactant: C=C(CO)COC(=O)CCCCCCCCCCCCCCC
Product: C=C(COC(=O)CCCCCCCBr)COC(=O)CCCCCCCCCCCCCCC

Procedure:
Following the procedure described in Preparation 9, but replacing 3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with 3-hexadecanoyloxy-2-methylenepropan-1-ol (from Preparation 2), and replacing 6-bromohexanoic acid with 8-bromooctanoic acid, the desired product was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].CS(C)=O.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of indole (11.7 g, 0.1 mol) in THF is added to a stirred mixture of NaH (60% dispersion in mineral oil, 4.2, g 0.105 mol), DMSO and THF. The reaction mixture is stirred for 1 h at room temperature, cooled to 0° C., treated with phenylsulfonyl chloride (13.3 mL, 0.15 mol), stirred at ambient temperatures for 3 h, quenched with water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized in ethanol and filtered. The filtercake is air-dried to give 1-phenylsulfonylindole. A portion of this 1-phenylsulfonylindole (257 mg, 1.0 mmol) and cyclohexylcarbonyl chloride (0.175 mL, 1.3 mmol) in methylene chloride is treated with tin tetrachloride (97 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethylacetate. The extracts are combined and concentrated in vacuo to give a residue. The residue is suspended in isopropanol, treated sequentially with concentrated HCl (50 μL) and aminoguanidine bicarbonate (100 mg, 0.5 mmol), heated at 80° C. for 4 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product 37.7 mg (17% yield), identified by HPLC1 and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].NC1C=CC=CC=1C(F)(F)F>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccccc3C(F)(F)F)c2cn1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (300 mg, 1.56 mmol), 2-aminobenzotrifluoride hydrochloride (1.00 g, 5.06 mmol) and 2-aminobenzotrifluoride (2.00 g, 12.4 mmol) is stirred at 160° C. for 10 min. The resulting product is neutralized with excess NaHCl, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(2-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (194 mg, 41%) as a cream solid, mp (MeOH/CHCl3 /light petroleum) 126°-130° C. (dec.). 1H NMR (DMSO) δ 10.60 (1H, brs), 9.17 (1H, brs), 8.13 (1H, brs), 7.76, 7.69 (1H, 1H, m, m), 7.45 (2H, m), 6.66 (2H, brs), 6.36 (1H, s).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:19][C@H:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:21]([NH2:23])=[O:22])=[N:7][C:8]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[S:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:23][C:21](=[O:22])[C@H:20]([NH:19][C:6]1[N:7]=[C:8]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[S:12][CH:11]=2)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:24][CH:25]1[CH2:26][CH2:27]1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1csc2ncccc12
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1csc2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (78 mg, 0.293 mmol), thieno[2,3-b]pyridin-3-amine (60 mg, 0.400 mmol), K2CO3 (70 mg, 0.507 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(thieno[2,3-b]pyridin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (33 mg). The compound (R)-2-(5-cyano-6-(thieno[2,3-b]pyridin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (33 mg, 0.087 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (34 mg). MS 398.2 (M+H); UV 203.6, 224.8, 262.1, 294.1, 357.3 nm; t 0.532 min.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([C@@H:8]([CH2:42][CH3:43])[C@@H:9]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([I:40])[CH:35]=3)[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].CC(O)(C)C.[Cl:49]C1C(Cl)=C(I)C=CC=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([C@@H:8]([CH2:42][CH3:43])[C@@H:9]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([I:40])[CH:35]=3)[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@:14]2([Cl:49])[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC[C@H]1[C@@H](OC(=O)c2cccc(I)c2)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](OC(C)=O)C[C@@H]12
Reactant: Clc1cccc(I)c1Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC[C@H]1[C@@H](OC(=O)c2cccc(I)c2)[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(Cl)[C@H](C)CCC(=O)OC)[C@@]2(C)CC[C@@H](OC(C)=O)C[C@@H]12
Yield: 91.3 %

Procedure:
To a solution of 4 (3.5 g, 4.95 mmol) in CH2Cl2 (280 ml) containing 0.3 M tBuOH (8.2 ml), dichloroiodobenzene (3.38 g, 12.4 mmol) was added. The mixture was deoxygenated for 3 min by bubbling dry N2. Then the mixture was photolyzed at 0° C. using a tungsten lamps (200 W) for 1 h. The solvent was then evaporated under reduced pressure and the residue was quickly purified by flash chromatography eluting with petroleum ether/EtOAc (8:2, v/v) to yield 3.35 g (4.52 mmol, 92%) of the 17-chloro derivative 5 as white solid.
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=O)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH2:26][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1C=O)O2
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1CN1CCOCC1)O2
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 2 (34 mg, 0.060 mmol) in CH2Cl2 (3 ml) was added morpholine (0.016 ml, 0.180 mmol) and acetic acid (10.32 μl, 0.180 mmol) followed by sodium triacetoxyborohydride (38.2 mg, 0.180 mmol). The reaction was complete in 30 minutes at which stage it was quenched with water and extracted with dichloromethane. Purification by PTLC (40% EtOAc/hexane) provided the desired compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([NH2:30])[N:21]=1.O>CC(N(C)C)=O>[NH2:30][C:22]1[N:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:21]=1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)cc(C(F)(F)F)n1
Temperature: 90 °C

Procedure:
322 mg (1.38 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 2 mL dry dimethylacetamide under argon atmosphere, and 50 mg (2.1 mmol) NaH is added. 136 mg (0.69 mmol) 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine 24 is then added and the solution stirred at 90° C. over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 mL 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate: cyclohexane from 1:1 to 3:1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>C(#N)C>[Br:1][C:2]1[C:3]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Br
Temperature: 0 °C

Procedure:
An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 3.4 ml (24.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.82 g (12.1 mmol) of trans-2-aminocyclohexanol hydrochloride. After 16 hours at room temperature the batch is filtrated and the filtrate is concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1). 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained.