Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:36]=[CH:35][CH:34]=[CH:33][C:8]=2[CH2:9][CH:10]([CH2:14][CH2:15][CH:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](O)=[O:18])[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:39].[ClH:41]>>[C:1]1([C:7]2[CH:36]=[CH:35][CH:34]=[CH:33][C:8]=2[CH2:9][CH:10]([CH2:14][CH2:15][CH:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]([Cl:39])=[O:18])[C:11]([Cl:41])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(CCC(Cc1ccccc1-c1ccccc1)C(=O)O)Cc1ccccc1-c1ccccc1
Product: O=C(Cl)C(CCC(Cc1ccccc1-c1ccccc1)C(=O)Cl)Cc1ccccc1-c1ccccc1
Temperature: 50 °C
Yield: 100 %

Procedure:
In a 1 L flask equipped with a reflux condenser, containing 77.0 g (0.16 mol) of 2,5-bis(2-phenyl-benzyl) adipic acid, obtained as described above, were added 150 mL (2.06 mol) of SOCl2). A white suspension was obtained, which was warmed to 50° C. and became a yellow solution, with concomitant evolution of HCl and SO2. After gas evolution had finished, the excess SOCl2 was removed under vacuum. To the obtained mixture were then added 100 mL of toluene, which was subsequently removed under vacuum to ensure complete removal of SOCl2. 2,5-bis(2-phenyl-benzyl) adipic acid dichloride (82.9 g, yield of 100%) was isolated, in the form of a viscous beige oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[C:33]([F:42])=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[C:33]([F:42])=[C:34]([S:38]([N:19]2[CH2:18][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]2=[O:28])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-chloro-2-fluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 570.8 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(O)[CH2:39]C[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:37][CH2:36][CH2:35][CH2:39]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCC4)cc3)c2cc1OC
Yield: 90 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclopentanol (22 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 76%).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:17])[CH2:12][CH2:13][C:14](Cl)=[O:15]>>[C@H:2]1([NH:1][C:11](=[O:17])[CH2:12][CH2:13][C:14]([NH:1][C@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: N[C@@H]1CCc2ccccc21
Product: O=C(CCC(=O)N[C@@H]1CCc2ccccc21)N[C@@H]1CCc2ccccc21

Procedure:
This was prepared by the same procedure as in Example 73 starting from (R)-1-aminoindan (8.02 g, 60 mmole) and succinoyl chloride (2.32 g, 14 mmole), to give the white product, (1.30 g, 26.7%). Melting point: 266°-9° C.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.[CH:16]1([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=O)[CH2:18][CH2:17]1>O1CCOCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:22]3[CH2:23][CH2:24][N:19]([CH:16]4[CH2:18][CH2:17]4)[CH2:20][C:21]=3[C:10]=2[CH:9]=1
Reactant: O=C1CCCCN1C1CC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Clc1ccc2[nH]c3c(c2c1)CN(C1CC1)CC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-Chloro phenyl hydrazine hydrochloride (1 equiv.) in dioxane and stirred for 5 min. at RT. N-cyclopropyl piperidone (1 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction product is extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.CCN(CC)CC.[CH3:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38].[O-]CC.[Na+]>C(Cl)Cl.CO>[CH3:35][N:36]([CH3:41])[S:37]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[O:16])[N:14]=[C:3]21)(=[O:39])=[O:38]
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: CN(C)S(=O)(=O)Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
To a solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.067 mmol) in CH2Cl2 (2 mL) was added Et3N (0.047 mL, 0.336 mmol) followed by dimethylsulfamoyl chloride (0.036 mL, 0.336 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with sodium ethoxide (0.2 ml, 21 wt % in ethanol) and the heated at 70° C. overnight. The mixture was then cooled, concentrated and purified by preparative HPLC to afford the title compound as a white solid (3.5 mg, 11% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (s, 1H), 8.90 (s, 1H), 7.34 (dd, 2H, J=8.39 & 5.34 Hz), 7.01 (t, 2H, J=8.55 Hz), 4.53 (d, 2H, J=6.41 Hz), 4.15 (d, 2H, J=3.97 Hz), 2.77 (s, 6H), 2.50 (s, 1H), 2.12 (t, 4H, J=7.63 Hz), 1.85-1.97 (m, 2H), 1.64-1.73 (m, 2H). LCMS (M+H)=480.21. HPLC purity: >95%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cccnc3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1cncc(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of the product from step 3 (100 mg, 0.22 mmol) in dioxane (1 mL) was added 4M HCl in dioxane (5 mL) at rt and the resulting mixture was stirred for 2 h at that temperature. Solvent was removed in vacuo, residue was triturated with ether and dried under vacuum to obtain the title product (79 mg, 95%): MS; m/z 347.7 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.72-1.77 (m, 1H), 1.90-2.00 (m, 2H), 2.11-2.15 (m, 1H), 3.21-3.24 (m, 2H), 3.89-3.91 (m, 1H), 4.15-4.19 (m, 2H), 7.05-7.13 (m, 6H), 7.83-7.86 (m, 2H), 7.94 (dd, 2H, J1=5.2 Hz, J2=8 Hz), 8.63 (d, 1H, J=7.6 Hz), 8.77 (dd, 1H, J1=5.2 Hz, J2=1.2 Hz), 9.13 (d, 2H, J=2 Hz), 9.67 (br, 3H); HPLC (UV); 97%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[CH:43]1([C:40]2[CH:41]=[CH:42][C:37]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]4[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=4[C:22]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]4)=[O:23])=[CH:4][CH:3]=3)=[CH:38][CH:39]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: ClCc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(C4CCCCC4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-(3-{4-[(4-cyclohexylbenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-cyclohexylbenzene.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[O-]CC.[Mg+2:14].[O-]CC.C(#N)C>C(O)C>[OH2:9].[C:1]([O-:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[Mg+2:14].[C:1]([O-:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)O
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CC#N
Product: CCCC(CCC)C(=O)[O-]
Product: O
Reaction time: 0.5 h

Procedure:
Unless magnesium ethoxide is freshly generated in situ by reaction of magnesium metal with ethanol, the magnesium ethoxide solids that are obtained commercially frequently contain colored by-products that are potential contaminants of the desired product, magnesium valproate hydrate. To demonstrate the purification of an alcohol solution containing magnesium valproate and colored contaminants, a solution of magnesium valproate in absolute ethanol was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (15.12 g; 0.105 mol; Sigma Aldrich Chemical Co.) in 90 mL of absolute ethanol was added 5.7 g (0.05 mol) of magnesium ethoxide solid (Sigma Aldrich Chemical Co.). Within 30 minutes, a clear, pale yellow solution was obtained; no increase in reaction temperature was observed. The pale yellow solution was treated with decolorizing carbon. After filtration with the aid of Celite to facilitate carbon removal, a nearly colorless filtrate solution was obtained. Acetonitrile (45 mL) was added to the ethanol solution in portions, and when the addition was complete, a white precipitate formed. The reaction mixture was cold to the touch. The slurry was stirred for 15 minutes. The product, magnesium valproate hydrate, was isolated by filtration, washed with fresh acetonitrile, and dried to constant weight. The product, magnesium valproate hydrate, was obtained in 77% yield as a white solid, which exhibited an elemental composition identical to that calculated for magnesium valproate hydrate (Table 4). The product did not melt at temperatures as high as 300° C. The product was not hygroscopic or deliquescent and was stable during storage under ambient conditions. X-ray diffraction analysis showed that magnesium valproate hydrate of the present invention is a polymorph having both crystalline and amorphous structural features. The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 88.5%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH3:21][C:22]([CH3:24])=O>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:21][CH2:22][CH:24]2[CH2:15][O:18]2)[CH2:11][CH2:10]1
Reactant: CC(C)=O
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Clc1cccc(N2CCN(CCC3CO3)CC2)c1Cl
Yield: 95 %

Procedure:
2.31 g (10.0 mmol) 1-(2,3-dichlorophenyl)piperazine was added to a suspension of 2.27 g (15.0 mmol) 24, 4.15 g (30.0 mmol) potassium carbonate in 150 mL acetone and the reaction mixture was refluxed for 24 h. The reaction mixture was filtered and the volatiles were removed in vacuo to give an oil (2.86 g, 95%), which was used without further purification. 1H NMR (CDCl3): δ 1.72 (m, 1H), 1.83 (m, 1H), 2.53 (dd, J 5.0, 2.7, 1H), 2.61 (ddd, J 8.3, 6.5, 3.0, 2H), 2.66 (s, 4H), 2.79 (dd, J 4.9, 4.0, 1H), 3.01 (m, 1H), 3.07 (s, 4H), 6.96 (dd, J 6.5, 3.1, 1H), 7.11-7.19 (m, 2H). 13C NMR (CDCl3): δ 30.2, 47.1, 51.0, 51.4, 53.3, 55.0, 118.6, 124.6, 127.5, 134.0, 151.3.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([CH2:20][CH3:21])[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16]C=2NC1=O)[CH3:4].[CH3:22]I.O.[CH3:25][N:26]([CH:28]=[O:29])[CH3:27]>C(OCC)(=O)C>[CH2:20]([C:5]1([CH2:3][CH3:4])[C:11](=[O:12])[N:10]([CH3:22])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:25]=2[N:26]([CH3:27])[C:28]1=[O:29])[CH3:21]
Reactant: CCC1(CC)C(=O)Nc2ccc(OC)cc2NC1=O
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(CC)C(=O)N(C)c2ccc(OC)cc2N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Sodium hydride (60% in oil, 170 mg, 4.3 mmol) was suspended in DMF (15 ml). 3,3-Diethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (452 mg, 1.7 mmol) was added thereto at 0° C., and stirring was conducted at the same temperature for 1 hour. Methyl iodide (0.42 ml, 6.8 mmol) was added to the mixture, and stirred at room temperature for 3 days. Water was added to the reaction mixture and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 373 mg (yield: 76%) of 3,3-diethyl-7-methoxy-1,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a white powder.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].[CH3:19][NH2:20].[BH4-].[Na+].CC(C)=O>CO.O>[CH3:19][NH:20][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([CH:2]([OH:1])[CH3:3])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: CN
Reactant: CC(O)c1ccc(Cc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CNCc1ccc(Cc2ccc(C(C)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.8 g of the 4-[4-(1-hydroxyethyl)benzyl]benzaldehyde prepared in the step (c) and 3.7 ml of methylamine (40% methanolic solution) were stirred together in 20 ml of methanol at room temperature. After one hour, the resulting mixture was cooled with ice, followed by the addition of 0.93 g of sodium borohydride. The obtained mixture was stirred at room temperature for 30 minutes. 5 ml of acetone was dropwise added to the resulting mixture under cooling with ice to treat excess sodium borohydride therewith. The reaction mixture was poured into water and the resulting mixture was extracted with dichloromethane. The organic phase was washed with water and a saturated aqueous solution of common salt, dried and distilled to dryness. The residue was recrystallized from ether/isopropyl ether to give 10.2 g of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:29][N:30]([CH2:32][CH2:33][NH2:34])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:49]>C(Cl)Cl.CO.CCOC(C)=O>[ClH:49].[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH2:4][NH:34][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29]
Reactant: CN(C)CCN
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(CNCCN(C)C)c3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [275 mg, 072 mmol, Example 35(j)], unsym-dimethylethylenediamine (217 μL, 1.97 mmol), sodium triacetoxyborohydride (500 mg, 2.36 mmol) and 3 Å sieves (500 mg) in DCM (7 mL) is stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture is filtered and the filter cake is washed with DCM (50 mL). The combined filtrate and washings are extracted water with (50 mL) and the aqueous is extracted with DCM (50 mL). The new organic extract is washed with water (30 mL), with brine (30 mL), dried over sodium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica (4.5 g) eluting with 0 to 7% MeOH in DCM gradient to afford a solid that is dissolved in methanol. This solution is treated with hydrogen chloride in EtOAc and concentrated to afford N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N′,N′-dimethyl-ethane-1,2-diamine hydrochloride [300 mg, 92%, Example 13(d)]. LCMS: RT=2.04 minutes, MS: 454 (M+H). IC50=56 nM
Reaction SMILES: [CH:1]([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[O:5]1)([CH3:3])[CH3:2].[CH:14]([Mg]Cl)([CH3:16])[CH3:15]>C1COCC1.CCOCC>[OH:5][C@H:4]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:6]([OH:13])[CH:14]([CH3:16])[CH3:15])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)[C@@H]1OC(O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@H](O)c1ccccc1[C@@H](O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3S)-3-isopropyl-1,3-dihydro-isobenzofuran-1-ol (2.0 g, 11.2 mmol) in THF (20 mL) was heated under an atmosphere of nitrogen at reflux. To this solution was added slowly a solution of isopropyl magnesium chloride (39.3 mmol) in THF (ca. 20 ml). This solution had been prepared from the commercial solution (19.6 ml 2N solution in ether), from which the solvent had been removed in vacuum, and where the residue was made up with THF to a volume of 20 ml). After the addition of the Grignard reagent was completed, the mixture was stirred for another 30 minutes, and then allowed to cool to ambient temperature. To the mixture was then added a 10% solution of ammonium chloride (ca. 30 ml). The aqueous layer was removed, and re-extracted with TBME (ca. 20 ml). From the combined organic layers the solvent was removed, and the residue was redissolved in TBME (ca. 50 ml). After washing with water and brine, the organic layer was dried (Na2SO4). Removal of the solvent left the product as an oil, 2.2 g (88%). There was only one isomer present by 13C-NMR, which turned out to be the (S,S)-diol. 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 0.783 (d, J=6.7 Hz)/20.02 (CH3); 1.065 (d, J=6.5 Hz)/18.99 (CH3); 2.02 (m)/35.29 (CHMe2); 4.60 (d, J=7.6 Hz)/76.51 (CH(OH)); 2.38 br s (OH); 7.20-7.26 (m)/126.75 (Ar ortho-CH); 7.33-7.39 (m)/127.55 (Ar meta-CH); 141.41 (Ar ipso-C).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1)#[N:2].CS(C)=[O:35].[OH-].[Na+].OO>O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1)(=[O:35])[NH2:2]
Reactant: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)c1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)c1
Reaction time: 0.33 h

Procedure:
To a flask were added tert-butyl [(1S,2R)-2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate (18.9 g, 43.3 mmol) and DMSO (380 mL). The resulting mixture was cooled in an ice bath. To the reaction mixture was added sodium hydroxide (6.0 M in water, 21.7 mL, 130 mmol) followed by the slow addition of hydrogen peroxide (35% solution in water, 7.96 mL, 91 mmol). The addition was performed at such a rate to maintain the internal reaction temperature between 25° C. and 30° C. After 20 minutes, the reaction mixture was slowly diluted with water (500 mL). After 30 minutes, the mixture was filtered, and the collected solids were washed with water and then dried overnight under a nitrogen bag. The collected solids were suspended in ethyl acetate (500 mL) and the resulting slurry was seeded with a previously processed batch of tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate. After 1 hour, the mixture was diluted with hexanes (150 mL), filtered, washed with hexanes, and dried in a nitrogen bag to afford tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate. MS ESI calc'd. for C24H35N6O3 [M+H]+ 455. found 455. 1H NMR (600 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 7.81 (d, J=3.0 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.21 (s, 1H), 6.54-6.50 (m, 2H), 6.40 (s, 1H), 6.05 (d, J=6.0 Hz, 1H), 3.81 (s, 1H), 3.54 (s, 1H), 2.34 (s, 3H), 2.17 (s, 3H), 1.82-1.76 (m, 1H), 1.72-1.64 (m, 1H), 1.60-1.42 (m, 4H), 1.36-1.28 (m, 1H), 1.27 (s, 9), 1.10-1.06 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.C(O)(=O)C.[N:20](OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:20][N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(Nc2ccccn2)c(N)cn1
Reactant: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)nnn2-c1ccccn1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 6-methyl-N4-(pyridin-2-yl)pyridine-3,4-diamine (550 mg, 2.7 mmol) in THF (30 mL) was added acetic acid (0.17 mL, 6.49 mmol) and tert-butyl nitrite (0.54 mL, 4.12 mmol). The reaction was then heated to reflux and stirred overnight. The reaction was concentrated and the residue was purified by chromatography on silica gel (0-10% [2M NH3 in MeOH]CH2Cl2) to give the desired product as a yellow gum (408 mg, 70%). MS (ESI) mass calcd. C11H9N5, 211.09. m/z found, 212.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.44 (d, J=0.9, 1H), 8.67-8.62 (m, 1H), 8.37 (s, 1H), 8.31-8.23 m, 1H), 8.01-7.96 (m, 1H), 7.41-7.35 (m, 1H), 2.80 (s, 3H).