Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:8][CH:9]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1C(=O)O)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(COCc1ccccc1C(=O)O)Cc1ccccc1
Yield: 98 %

Procedure:
Compound 1b (34.7 g, 90 mmol) was treated with HCl (g) in dioxane (700 mL) at rt overnight. Concentrated in vacuo gave the hydrochloride salt of compound 1c which was used for next step without any further purification (28.3 g, 98% yield). MS (ESI+): 286 [M+1]+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][Si:16]([CH3:25])([CH3:24])[C:17]1[O:18][CH:19]=[CH:20][C:21]=1[CH:22]=[O:23]>O1CCCC1>[OH:23][CH:22]([C:21]1[CH:20]=[CH:19][O:18][C:17]=1[Si:16]([CH3:25])([CH3:24])[CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C[Si](C)(C)c1occc1C=O
Reactant: CCCCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1ccoc1[Si](C)(C)C

Procedure:
A solution of dodecylmagnesium bromide (a 1M solution in tetrahydrofuran; 14.3 ml; 14.3 mmol) was added to a solution of 2-trimethylsilyl-3-furaldehyde (1.20 g, 7.1 mmol) in tetrahydrofuran (30 ml) at 0°. After all the aldehyde has reacted, as shown by tlc, the mixture was quenched with dilute hydrochloric acid and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by a silica column using 5% ethyl ether/hexane to give the title furan.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=C.[O:25]=[O+][O-]>CO>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]2=[C:5]3[C:4]=1[CH2:1][CH:2]([OH:25])[N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]3=[N:7][CH:8]=[N:9]2
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccccc3)c12
Reactant: O=[O+][O-]
Solvent: CO
Product: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-phenyl-amine (0.35 g, 1.09 mmol) (from Example 15, Step E ,supra) in methanol (50 mL) at −78° C. was passed a continuous stream of O3 until the color of the solution became blue. The reaction solution was then purged with argon, and methyl sulfide (5 mL) (Aldrich) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The solution was concentrated, the residue was dried in vacuo to give the desired 7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol as a crude yellow solid. (Yield 0.17 g, 48%).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>>[C:18]1(=[O:23])[N:10]([CH2:9][CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Product: CC(CCN1C(=O)c2ccccc2C1=O)c1ccccc1-c1ccccc1

Procedure:
2.25 g of 3-p-biphenylyl-butylamine and 5 g of phthalic anhydride are heated at 120°for 90 minutes, cooled and worked up in the customary manner to give 1-phthalimido-3-p-biphenylyl-butane, m.p. 120°- 123°.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]([C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=O)=[N:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O.C[O-].[Na+].O>CO>[N:9]([C:10]([CH3:15])([CH3:16])[C:11]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])=[N:8][C:17]([CH3:23])([CH3:22])[C:18]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: NC1CCCCC1
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(N=NC(C)(C)C(=O)NC1CCCCC1)C(=O)NC1CCCCC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
47.3 Grams of cyclohexylamine is mixed with 50 g of dimethyl 2,2'-azobis (2-methylpropionate) and 20 g of 28% sodium methoxide solution in methanol is dropwise added thereto under stirring, following by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 59.4 g (yield 81 %) of 2,2'-azobis (N-cyclohexyl-2-methylpropionamide) as yellow crystals. The solubility is shown in Table 1.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N[C@H:11]([C:16](O)=O)[C@H:12](CC)C.N[C@H](C(O)=O)CCSC>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]1[CH:6]=[CH:16][CH:11]=[CH:12][CH:5]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
F Leu: L Ile: I Met: M
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ncc(Br)cc12
Temperature: 0 °C
Yield: 92.7 %

Procedure:
To a stirring solution of aluminum chloride (6.77 g, 50.75 mmol) suspended in anhydrous CH2Cl2 (100 mL) under N2 was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 10.15 mmol). The reaction solution was stirred for 1 hour at ambient temperature whereupon acetyl chloride (3.61 mL, 50.75 mmol) was added dropwise and the resulting solution was stirred for 5 more hours. The reaction was cooled to 0° C. in an ice bath and quenched carefully by addition of MeOH until the solution became clear. The reaction was concentrated under vacuum. H2O was added and 1 N NaOH was added dropwise until the pH=4. The product was extracted into ethyl acetate and the organic layer was washed with a saturated solution of sodium potassium tartrate to remove any remaining aluminum salts. The organic layer was dried over Na2SO4 and concentrated under vacuum. The material was redissolved in ethyl, acetate and filtered through a bed of silica gel. The filtrate was concentrated to afford the title compound as an orange solid (2.25 g, 93% yield). 1H NMR (500 MHz, d6-DMSO) δ 12.70 (br s, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.55 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 2.46 (s, 3H). MS: m/z 238.9/240.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:20][S:21](O)(=[O:23])=[O:22].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 1 mmol of 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) was introduced into 1 ml of chlorosulfonic acid and stirred at room temperature for 3 hours. For workup, the reaction mixture was poured onto ice, adjusted to pH 7 to 8 with 1 N NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases were dried with Na2SO4 and concentrated in a rotary evaporator. The crude product obtained in this way was reacted further without further purification.
Reaction SMILES: [CH2:1]([O:17][C:18]1[O:22][C:21]([C:23]([OH:25])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH2:16].[CH2:26](OC1OC(C(O)=O)=CC=1)CCCCCCCCCCCCC>>[CH2:1]([O:17][C:18]1[O:22][C:21]([C:23]([CH3:26])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH2:16]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: C=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Product: C=CCC=CCC=CCCCCCCCCOc1ccc(C(C)=O)o1

Procedure:
When in the procedure of Example 1(B) an appropriate amount of 5-(9,12,15-hexadecatrienyloxy)-2-furoic acid is substutited for 5-tetradecyloxy-2-furoic acid, methyl 5-(9,12,15-hexadecatrienyloxy)-2-furyl ketone is obtained.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.[SH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[Cl:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:17])[N:3]=[C:2]([S:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Br
Reactant: Sc1nccs1
Product: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nccs1

Procedure:
The title compound was prepared from 2-bromo-6,7-dichloro-3-trifluoromethylquinoxaline and 2-mercaptothiazole in analogy with the method outlined in example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.CN(C)C=O.[C:45]([OH:54])(=[O:53])[C@@H:46]([C@H:48]([C:50]([OH:52])=[O:51])[OH:49])[OH:47]>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:50]([C@@H:48]([C@H:46]([C:45]([O-:54])=[O:53])[OH:47])[OH:49])([O-:52])=[O:51]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 250 mL reactor equipped with a reflux condenser and a mechanical stirrer was charged with Nilotinib base Form A (8.00 g, 15.11 mmol) and absolute EtOH (80 mL, 10V). The suspension was heated to 80° C. and stirred for 0.5 h. To the resulting mixture was added a solution of L-tartaric acid (2.49 g, 16.7 mmol, 1.1 eq) in absolute EtOH (20 mL) in one portion, followed by an additional 120 mL of absolute EtOH. The resulting mixture was stirred at 80° C. during 20 min and then cooled to room temperature over 0.5 h with continuous stirring at room temperature for another 16 h. The mixture was then transferred to a refrigerator at 5° C. and kept there for 16 h (in a closed vessel). The solid was isolated by vacuum filtration and dried in a vacuum oven at 70° C. for 24 h to give Nilotinib L-tartrate form IV as a yellow solid (9.10 g, 89%). Mono L-tartrate salt was obtained according to assay determination.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([N:10]1[C:18]2[C:13](=[C:14](I)[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH2:6]([N:10]1[C:18]2[C:13](=[C:14]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCn1ccc2c(I)cc(C(=O)OC)cc21
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCCCn1ccc2c(-c3ncco3)cc(C(=O)O)cc21
Temperature: 85 °C
Yield: 70.4 %

Procedure:
To a −72° C. solution of oxazole (0.069 g) in dry THF (20 mL) was added dropwise 1.6 M N-butyl lithium (0.68 mL). The mixture was stirred at −72° C. for 30 minutes at which time 1.0 M zinc chloride (3.3 mL) was added. The mixture was allowed to warm to 0° C. at which time methyl 1-butyl-4-iodo-1H-indole-6-carboxylate (0.37 g) and tetrakis triphenylphosphine palladium (0) (0.07 g) were added and the mixture heated to 85° C. The mixture was heated at 85° C. for 20 h then cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography was performed on silica gel (100 mL) using 20% ethyl acetate in hexanes as eluent. The residue was dissolved in methanol (10 mL) and 1N NaOH (3 mL) and heated at 60° C. for 2 h. The mixture was acidified to pH 4 with 1N HCl and extracted with ethyl acetate. The ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 0.2 g of the title compound: MS (ESI+) for C16H16N2O3 m/z 283.16 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[C:18]1[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[C:12]([C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:29]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC1CCCCN1CCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCCN1CCOc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A mixture of 4-[2-(2-Methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.031 g, 0.1 mmol), 3,4-difluorobenzoyl chloride (0.015 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol)) in methylene chloride (1.5 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 459 as a white solid in 88.2% yield. LCMS m/z (%)=455.5 (M+H, 100).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:31](=[O:33])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CN(C)CCNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 80.9 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 46 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:18]([CH3:17])[CH2:19][CH2:20][OH:21])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CNCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(Nc2cc(N(C)CCO)ncn2)cc1
Temperature: 200 °C
Yield: 89 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 23 mg of 2-(methylamino)ethanol and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 30 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. 2-((6-(4-Methoxyphenylamino)pyrimidin-4-yl)(methyl)amino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(N(CC)CC)C.Cl[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>O1CCCC1>[C:25]1([C:23]([O:1][C:2]2[CH:7]=[C:6]([Si:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=2[C:12](=[O:14])[CH3:13])=[O:24])[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccc([Si](C)(C)C)cc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Oc2cc([Si](C)(C)C)ccc2C(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Under ice-cooling, to a solution of 832 mg (4 mmol) of 2'-hydroxy-4'-trimethylsilylacetophenone in 20 ml of tetrahydrofuran were added dropwise successively, 0.61 ml (4.4 mmol) of triethylamine and 874 mg (4.4 mmol) of methyl p-chloroformylbenzoate with stirring. The mixture was stirred at room temperature for 1 day and filtered. The filtrate was evaporated and the residue was dissolved in AcOEt. The organic solution was washed with H2O, aqueous sodium bicarbonate solution and brine, dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel [eluent: n-hexane-AcOEt (5:1)] to give 1.40 g of pale yellow viscous liquid (yield 95%).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)[CH:2]=[CH2:3].C([Br:18])C=C>CCOCC>[BrH:18].[CH2:1]([O:4][CH:5]1[CH2:6][C:7]([CH3:14])([CH3:13])[NH:8][C:9]([CH3:12])([CH3:11])[CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Agent: C=CCOC1CC(C)(C)NC(C)(C)C1
Solvent: CCOCC
Product: Br
Temperature: 90 °C

Procedure:
A mixture of 9.87 parts of 4-allyloxy-2,2,6,6-tetramethylpiperidine and 3.03 parts of allyl bromide was heated at 90° C. for 96 hours. Ether was added to the cooled reaction mixture and the 4-allyloxy-2,2,6,6-tetramethylpiperidine hydrobromide formed during the reaction was filtered off. The ether solvent was removed by distillation under reduced pressure and the residue purified by chromatography to give 4-allyloxy-1-allyl-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.CO.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][N:16]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(NCCCN2CCOCC2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnc(NCCCN2CCOCC2)nc1
Reaction time: 8 h

Procedure:
The crude N-(3-morpholinopropyl)-5-nitropyrimidin-2-amine was combined with 10% Pd/C (500 mg) in EtOAc (20 mL) and MeOH (10 mL) was added. The mixture was purged with H2 and allowed to stir under 1 atm H2 overnight. Filtration through a pad of celite and concentration afforded N2-(1-methylpiperidin-4-yl)pyrimidine-2,5-diamine 16 as a thick rust colored oil, which may be used without further purification. MS: m/z found 270 [MH+].
Reaction SMILES: [CH2:1]([C:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]2[CH2:13][CH:12]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:30]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[OH:30][CH2:3][CH2:2][CH2:1][C:4]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]2[CH2:13][CH:12]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][CH2:5]1
Reactant: C1CCOC1
Reactant: C=CCC1(c2ccccc2)CCN(C2CC2c2ccccc2)C(=O)O1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: O=C1OC(CCCO)(c2ccccc2)CCN1C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one (200 mg, 0.60 mmol) in dry THF (5 mL) was added dropwise 1 M of BH3/THF (1.8 mL, 1.8 mmol) at 0° C. under N2. After stirring at rt for 2 h, the reaction mixture was cooled to 0° C. again, and water (0.1 mL), 3 M of aqueous NaOH solution (0.1 mL), and 30% H2O2 (0.3 mL) were added sequentially. After the mixture was stirred at rt for another 2 h, 1 N aqueous HCl (0.5 mL) was added. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC followed by preparative HPLC to afford two isomers.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([CH:30]=[O:31])[O:19][CH2:18]2)([CH3:16])[CH3:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[Cl-].[NH4+].[C:35](OCC)(=O)C>CCOCC.O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:20]([CH:30]([OH:31])[CH3:35])[O:19][CH2:18]2)([CH3:16])[CH3:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)N1COC(C=O)=C(c2ccccc2)C1=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)C1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(Cl)cc(Cl)c2)CO1

Procedure:
Methylmagnesium bromide (1.7 ml of a 3M solution in ether) was added dropwise to a stirred solution of N-(3,5-dichlorophenyl)-2-(6-formyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.0 g) in dry tetrahydrofuran under an inert atmosphere at -5° C. After 1 hour at that temperature, ammonium chloride solution (saturated) and ethyl acetate were added. The organic phase was washed (brine), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with dichloromethane/ethyl acetate to give N-(3,5-dichlorophenyl)-2[2,3-dihydro-6-(1-hydroxyethyl)-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 123, 0.27 g) as a cream solid, m.p. 85-88° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:12]2[C:13]([CH3:30])=[N:14][N:15]([C:20]3[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16]=2[C:17](O)=[O:18])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:12]3[C:13]([CH3:30])=[N:14][N:15]([C:20]4[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[C:16]=3[C:17]2=[O:18])[CH:3]=1
Reactant: COc1ncc(-n2nc(C)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C(=O)O)c(OC)n1
Solvent: ClCCl
Solvent: CO
Product: COc1ncc(-n2nc(C)c3c2C(=O)N(c2cc(Cl)c(=O)n(C)c2)C3c2ccc(Cl)cc2)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (Step 52.4). tR: 4.45 min (HPLC 1); tR: 1.02 min (LC-MS 2); ESI-MS: 527/529 [M+H]+ (LC-MS 2); Rf=0.41 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99 (s, 3H) 3.41 (s, 3H) 3.93 (s, 3H) 3.96 (s, 3H) 6.21 (s, 1H) 7.30-7.36 (m, 2H) 7.38-7.44 (m, 2H) 7.87 (d, J=2.7 Hz, 1H) 7.92 (d, J=2.7 Hz, 1H) 8.56 (s, 1H).