Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].[CH2:16]([OH:18])[CH3:17]>>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:18][CH2:16][CH3:17])([O-:5])=[O:4]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Into a 2-liter resin kettle, equipped with stirrer, reflux condenser and thermometer, was charged 632 g. ethanol. To the ethanol was added carefully, below 50° C., in 15-20 minutes, 42.0 g. sodium hydroxide. To this was added, in 15 to 20 minutes, 213 g. 2,4-dinitrochlorobenzene, with the temperature maintained below 50° C. The resulting mixture was heated to reflux and held at reflux for 3 hours to give an ethanol solution of 2,4-dinitrophenetole. After cooling to room temperature, the ethanolic reaction solution was treated with 340 g. iron powder and 200 ml. water, exhibiting a mild exotherm. A solution of 12 ml. hydrochloric acid, 12 ml. glacial acetic acid and 100 ml. water was added dropwise over 1 hour at a rate to maintain 62°-75° C. This reaction mass was refluxed under a nitrogen atmosphere for 3 hours, then cooled to 0° to 5° C., and assayed for 2,4-diaminophenetole by perchlorate titration. To the cooled reaction mass was added 80 g. sodium hydroxide (50% aqueous solution), and then an exact equivalent amount of acetic anhydride, about 90-94 g. acetic anhydride, depending on the perchlorate assay. The temperature was maintained at 0° to 5° C. during this addition. The acetic anhydride was added dropwise over a period of about 2.5 hours. Following the addition of the acetic anhydride, the pH was adjusted to 6.8-7.0. The reaction product was treated with 20 g. of activated charcoal and 10 g. of diatomaceous earth at 80° C. and filtered to clarify. The filter residue was washed three times with 50 ml. of hot 1:1 ethanol-water. The combined filtrate and washings was heated to distill off ethanol, until the pot temperature reached 98° C. The aqueous pot residue was cooled to 10°-15° C. and filtered to give substantially pure crystalline product, assayed at 126 g. of 3-amino-4-ethoxyacetanilide, 65-70% of theory, based on the 2,4-dinitrochlorobenzene starting material.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[N:8][CH:9]=2)[N:4]([CH3:21])[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1>>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[N:8][CH:9]=3)[N:4]([CH3:21])[N:3]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCN(CC)CCCCNc1ncc2c(Cl)nn(C)c2n1
Product: CCN(CC)CCCCNc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1

Procedure:
Prepared as described above in Example 15 starting from N′-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N,N-diethyl-butane-1,4-diamine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound N-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N′,N′-diethyl-butane-1,4-diamine; 1H-NMR (MeOH): δ 1.33 (m, 6H), 1.86 (m, 4H), 3.28 (m, 4H), 3.82 (m, 2H), 3.69 (m, 2H), 3.98 (s, 3H), 7.44 (d, 2H, J=8.4 Hz), 8.07 (d, 2H, J=8.4 Hz), 9.23 (s, 1H); LC/MS (m/e)=368.2 (MH+), Rt=1.20 min.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34](OC(=O)C)=[O:35]>>[CH:34]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC=O
Agent: Cl
Product: O=CN1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and acetic formic anhydride the title compound is obtained as colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:14][C:15]2[NH:16][C:17]([NH2:26])=[C:18]3[C:22]([N:23]=2)=[N:21][C:20]([O:24][CH3:25])=[N:19]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32]>>[Cl:32][CH2:31][CH2:30][CH2:29][CH2:28][N:21]1[C:20]([O:24][CH3:25])=[N:19][C:18]2[C:22]1=[N:23][C:15]([O:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:16][C:17]=2[NH2:26]
Reactant: ClCCCCBr
Reactant: COc1nc2nc(OC3CCCCC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclohexyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]4)=[CH:14][CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>C(OCC)(=O)C>[CH3:24][N:23]([CH3:25])[C@@H:20]1[CH2:21][CH2:22][N:18]([C:15]2[CH:16]=[CH:17][C:12]([N:7]3[C:8](=[O:11])[C:9]4[S:10][C:2]([N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:3][C:4]=4[N:5]=[CH:6]3)=[CH:13][CH:14]=2)[CH2:19]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(Br)sc4c3=O)cc2)C1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(N5CCCCC5)sc4c3=O)cc2)C1
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-3-[4-((R)-3-dimethylaminopyrrolidin-1-yl)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (40 mg) and piperidine (492 mg) was heated at 100° C. for 2 days. Water and ethyl acetate were then added, and the organic phase was washed twice with water. The ethyl acetate phase was dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The product with the molecular weight of 423.58 (C23H29N50S) was obtained in this way; MS (ESI): 424 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=2)[C:5](=O)[NH:4][CH:3]=1.O.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=2)[C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(Cl)c[nH]c(=O)c2c1
Solvent: O
Product: CCOC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reaction time: 18 h

Procedure:
Anal. Found: C, 57.02; H, 3.99; N, 5.53. Calc for C12H10ClNO3 : C, 57.27; H, 4.01; N, 5.57. ##STR168## Ethyl 4-chloro-1-oxo-1,2-dihydro-7-isoquinolinecarboxylate (500 mg, 1.99 mmol) was warmed in POCl3 (3 mL) until a clear solution formed, and was then allowed to stand at 23° C. for 18 h. The reaction mixture was poured into warm water, extracted with EtOAc (3×20 mL), and the combined organic extracts washed with water and saturated brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexane-EtOAc (90:10) as eluant followed by crystallisation from i-Pr2O to give ethyl 1,4-dichloro-7-isoquinolinecarboxylate (377 mg, 1.40 mmol) as a pale pink solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:20][C:19](=[O:21])[C:18]([C:22]#[N:23])=[C:17]([S:24]([CH3:26])=[O:25])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29]([NH2:31])=[O:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([O:21][CH2:28][C:29]([NH2:31])=[O:30])[C:18]([C:22]#[N:23])=[C:17]([S:24]([CH3:26])=[O:25])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)nc(OCC(N)=O)c1C#N
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
A mixture of 6-[2-(benzyloxy)phenyl]-4-(methylsulfinyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (2.97 g, 8.16 mmol), bromoacetamide (1.27 g, 9.21 mmol), and K2CO3 (1.43 g, 10.4 mmol) in DMF (30 mL) was stirred at 60° C. for 1.5 hrs. The reaction mixture was poured into water, and the resulting precipitates were collected by filtration. The solid obtained was washed with acetone to give 2-{[6-[2-(benzyloxy)phenyl]-3-cyano-4-(methylsulfinyl)-2-pyridinyl]oxy}acetamide as a solid (2.09 g, yield; 61%).
Reaction SMILES: CC([O:4][C:5]1[C:8](=[O:9])[C:7](=O)[C:6]=1[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])C.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:7]1[C:8](=[O:9])[C:5](=[O:4])[C:6]=1[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH3:25]
Reactant: CCN
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Product: CCCC[Sn](CCCC)(CCCC)c1c(NCC)c(=O)c1=O

Procedure:
Using the procedure described in Example 37 treatment of 4-(2-propoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2-dione with anhydrous monoethyl amine afforded the title compound as a dark viscous oil which crystallized.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[N:5]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:50][CH3:51].O>CN(C=O)C>[CH2:50]([O:1][CH2:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[N:5]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:4]=1)[CH3:51]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(CO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Yield: 100 %

Procedure:
The solution of (R)-1-(3-(hydroxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (124 mg, 0.224 mmol), cesium carbonate (146 mg, 0.448 mmol) and iodoethane (26.9 μl, 0.336 mmol) in DMF was stirred at 60° C. for 24 h. Water was added into the solution and extracted with EtOAc for twice. The combined organic extracts were washed with water, brine and dried over Na2SO4. After concentration (R)-1-(3-(ethoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (130 mg, 0.224 mmol, 100% yield) was yielded without purification.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[C:23]([O:26][CH2:27][CH2:28][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (3.5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on a rotary evaporator to give an oil. The oily product was purified on a flash chromatography column (60 g of SiO2 ; eluted with MeOH 2%-4% in DCM). The pure product thus obtained weighed 4.43 g. This oil was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. The salt crystallized out at room temperature to yield 3.44 g (57%), m.p.=154°-155° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:29][CH2:30][CH2:31][NH2:32].N1C(C)=CC=CC=1C>C(O)(C)C>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([C:12]3[NH:32][CH2:31][CH2:30][CH2:29][C:13]=3[C:14](=[O:23])[N:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCBr
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Agent: Br
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: O=C1C2=C(NCCC2)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Temperature: 80 °C

Procedure:
To a solution of 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione (Intermediate 1A.4-1, 300 mg, 0.85 mmol) in isopropanol (4.3 ml) were added 3-bromopropylamine hydrobromide (205 mg, 0.94 mmol) and 2,6-lutidine (0.22 ml, 1.87 mmol). The reaction vessel was sealed and heated at 80° C. for 3 days. The reaction was concentrated in vacuo and partitioned between dichloromethane and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-5% methanol (10% NH4OH)/dichloromethane) to yield 1-benzyl-6′-(3-fluorophenyl)-1′,2′,3′,4′-tetrahydrospiro[piperidine-4,7′-pyrrolo[3,4-b]pyridin]-5′(6′H)-one. LCMS (M+H) 392.1. 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 6H), 7.03 (td, J=8.2, 2.0 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.92 (dt, J=9.9, 2.1 Hz, 1H), 3.46 (s, 2H), 3.33 (m, 2H), 2.52 (t, J=6.1 Hz, 41H), 2.33 (t, J=6.2 Hz, 2H), 2.06 (quint, J=6.9 Hz, 2H), 1.84 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH:10]([CH3:14])[C:11](Cl)=[O:12]>ClCCl.O>[Br:9][CH:10]([CH3:14])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(Br)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloroaniline (400 mg, 3.13 mmol) in anhydrous dichloromethane at room temperature under N2 was added slowly 2-bromopropanoyl chloride (474 μL, 4.7 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give 2-bromo-N-(4-chlorophenyl)propanamide, which was used without further purifications.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:21][CH:22]3[CH2:26][CH2:25][N:24]([C:36](=[O:39])[CH:37]=[CH2:38])[CH2:23]3)[CH:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(Nc3cc(NC4CCNC4)ncn3)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N4-(4-phenoxyphenyl)-N6-(pyrrolidin-3-yl)pyrimidine-4,6-diamine (0.13 g, 0.3 mmol) in THF (1.5 mL) at −60° C. were added DIPEA (0.07 g, 0.5 mmol) and acryloyl chloride (1 M solution in THF, 0.3 mL, 0.3 mmol), and the reaction mixture was stirred at −60° C. for 5 min. The reaction mixture was quenched by adding water and it was extracted with EtOAc (2×5 mL). The combined EtOAc extract was washed with brine (3 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol:98/2) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyrrolidin-1-yl)prop-2-en-1-one (I-85) as a light green solid. 1H NMR (DMSO-d6) δ ppm: 1.83-1.86 & 1.90-1.94 (m, 1H), 2.07-3.0 & 2.16-2.20 (m, 1H), 3.38-3.86 (m, 4H), 4.2-4.75 & 4.35-4.5 (bs, 1H), 5.65 (dt, J=2 & 10 Hz, 1H), 5.78 (d, J=3.6 Hz, 1H), 6.11 & 6.15 (dd, J=2.4 & 7.0 Hz & dd, J=2.4 & 7.2 Hz, 1H), 6.51-6.64 (m, together 1H), 6.93-7.00 (m, 4H), 7.07-7.18 (m, 2H), 7.36 (t, J=8 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 8.12 (s, 1H), 8.93 (s, 1H); LCMS: m/e 401.8 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:10][CH2:11][OH:12])[C:6]([CH3:9])=[CH:7][CH:8]=1.Cl[CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>O1CCCC1.O>[CH3:3][C:4]1[N:5]([CH2:10][CH2:11][O:12][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C)n1CCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)COCCn1c(C)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
32 g of sodiumhydride (60% oil dispersion) was added to 500 ml of tetrahydrofuran, and 56 g (0.4 mol) of 2-(2,5-dimethylpyrrole-1-yl)ethanol obtained in Preparation Example 1 was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and a solution obtained by dissolving 65.84 g (0.4 mol) of ethyl 4-chloroacetoacetate in 200 ml of tetrahydrofuran was added thereto dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours and then adjusted to pH 6 to 7 with 3N hydrochloric acid. A sufficient amount of water was added to dissolve solid precipitates formed, and the reaction mixture was extracted two times with 600 ml and 100 ml of ethyl acetate, respectively. Combined ethyl acetate extract was dried over anhydrous magnesium sulfate, treated with decolorizing carbon, and then, the solvent was distilled off under a reduced pressure, to obtain 96.2 g of the titled compound as a pale yellow oil (yield: 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([PH:10](=O)[C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]([CH3:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=2)=[CH:5][C:4]=1[CH3:23].[BH3:25].O1CCCC1>C1(C)C=CC=CC=1>[CH3:24][N:2]([CH3:1])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([PH:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]([CH3:19])[CH3:20])=[C:13]([CH3:21])[CH:12]=2)=[CH:5][C:4]=1[CH3:23].[BH3:25]
Reactant: Cc1cc([PH](=O)c2cc(C)c(N(C)C)c(C)c2)cc(C)c1N(C)C
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(Pc2cc(C)c(N(C)C)c(C)c2)cc(C)c1N(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Under an argon atmosphere, to a solution of bis(4-dimethylamino-3,5-dimethylphenyl)phosphine oxide (4.6 g, 14 mmoL) synthesized in Example 1 in toluene (30 mL) was added borane-tetrahydrofuran solution (71 mL, 5.4 equivalents) at room temperature over 2 hr. Then, silica gel (8.7 g, 10.8 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 1.5 hr. The silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 20 g, toluene) and the residue was recrystallized from n-hexane to give the title compound (3.0 g, white crystals). yield 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17]Cl)=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[I-:25].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][I:25])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)OCI
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Chloromethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate 1 (3.0 g, 8.2 mmol) was dissolved in acetone (50 mL) at room temperature. Sodium iodide (2.4 g, 16.3 mmol, 2 eq) was added and the clear solution was stirred 10 min at room temperature, then heated to 50° C. for 6 hr. The mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and filtered. The filtrate was washed with water (3×10 mL) and brine then dried over sodium sulfate. The drying agent was filtered off and the solution was concentrated by rotary evaporation to leave iodomethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate 2 as a thick, yellow oil (3.7 g, 99% yield) that was used directly in the next reaction without further purification. 1H-NMR (CDCl3) δ 7.74 (d, 2 H), 7.71 (d, 2 H), 7.45 (d, 2 H), 6.85 (d, 2 H), 5.97, (s, 2 H), 1.67 (s, 6 H) ppm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:16][C:9]1([CH3:17])[C:10]2[C:15](=[CH:14][C:13]([C:19](=[O:21])[CH3:20])=[CH:12][CH:11]=2)[C:6]([CH3:18])([CH3:5])[CH2:7][CH2:8]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3.45 g (25.9 mmol) aluminum chloride in 15 ml methylene chloride was cooled under argon in an ice/salt bath and treated while stirring with a mixture of 4 g (21.2 mmol) 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro naphthalene (from Example 2) and 1.94 g (24.7 mmol) acetylchloride via a dropping funnel over a period of 0.5 hours. Then the cooling bath was removed, the mixture stirred for 2 hours at room temperature and the reaction quenched with ice. The organic layer was recovered and the aqueous layer extracted with 2×50 ml methylene chloride.
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:3][CH2:4]/[CH:5]=[N:6]/[S@:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].[C-:23]#[N:24].C([Al+]CC)C.C(O)(C)C.[Cl-].[NH4+]>O1CCCC1>[C:23]([C@@H:5]([NH:6][S@:7]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:8])[CH2:4][CH2:3][C:2]([CH3:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])#[N:24]
Reactant: [C-]#N
Reactant: Cc1ccc([S@](=O)/N=C/CCC(C)(C)c2ccccc2)cc1
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc([S@](=O)N[C@H](C#N)CCC(C)(C)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
(S)-4-methyl-benzenesulfinic acid [4-methyl-4-phenyl-pent-(E)-ylidene]-amide (1.29 g) was dissolved in tetrahydrofuran (35 ml) and cooled to −78° C. In a second flask diethylaluminium cyanide solution (1N in toluene, 9.5 ml) was diluted with tetrahydrofuran (35 ml). After cooling down to −78° C. isopropanol (0.31 ml) was added and the mixture was stirred additional 30 min at room temperature. This mixture was added slowly to the imine solution in the first flask at −78° C. and stirred overnight while warming up to room temperature. After cooling down to −78° C. saturated ammonium chloride solution (18 ml) was added. The suspension was filtered through Celite. Ethyl acetate was added and the solution was washed with sodium chloride solution, dried (MgSO4) and concentrated. The crude product was purified by column chromatography (SiO2; heptane/EtOAc 4:1) to give (S)-4-methyl-benzenesulfinic acid ((S)-1-cyano-4-methyl-4-phenyl-pentyl)-amide (0.6 g, 43%) as a light yellow oil.