Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:22])[C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH2:15][C:14](=[O:21])[CH2:13][C:12]=1[CH2:11][CH2:10]3.C1C=C[NH+]=CC=1.Br[Br-]Br.O>N1C=CC=CC=1>[F:1][CH:2]([F:22])[C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:4]12[CH3:5])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2C(F)F)CC(=O)CC4
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@H]2C(F)F

Procedure:
The 17β-difluoromethylestr-5(10)-en-3-one is dissolved in pyridine under nitrogen with stirring. Pyridinium bromide perbromide is added over a 5-minute period. The reaction is stirred at 20°-25° under nitrogen for about 2.5 hr. Water is then added and the product extracted with diethyl ether. The diethyl ether extract is washed with water, dilute hydrochloric acid, water, dilute bicarbonate, water, and chromatographed over a silica gel column. The column is eluted with a gradient between 10% ethyl acetate-SSB and 60% ethyl acetate-SSB. The appropriate fractions are pooled and concentrated. The concentrate is rechromatographed and recrystallized from acetone to give the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+]>C1COCC1.C(OCC)C>[OH:24][CH2:3][CH2:2][CH2:1][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: C=CCn1ccc2cc(C=O)ccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(ccn2CCCO)c1

Procedure:
In a 10 mL round-bottom flask, 1-Allyl-1H-indole-5-carbaldehyde (169 mg, 0.91 mmol) is dissolved in 0.5 mL of anhydrous THF. To this solution is added 0.5 M of 9-BBN in THF (2 mL, 1.0 mmol). The reaction is allowed to stir at room temperature for 1 hr, whereupon a 1 M solution of NaOH (2.5 mL) is added. The organic layer is diluted with 10 mL of diethyl ether and the aqueous layer is removed. The organic layer is washed 3×10 mL with 1 M NaOH, followed by 2×10 mL water and 2×10 mL saturated NaCl solutions. The organic layer is then dried over Na2SO4 and the solvent is removed under reduced pressure to afford 1-(3-hydroxypropyl)-1H-indole-5-carbaldehyde.
Reaction SMILES: [N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25]>>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:25][C@H:24]([C:23]([O:22][CH3:21])=[O:28])[CH2:26][OH:27])=[O:16])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)[C@@H](N)CO
Reactant: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Agent: Cl
Product: COC(=O)[C@H](CO)NC(=O)c1ccc(-n2cnc3ccccc32)cc1

Procedure:
Using essentially the same procedures described in Example 1, step 2, and Example 2, and employing methyl 4-(1H-benzimidazol-1-yl)benzoate and serine methyl ester HCl as reactants, the title compound was obtained and identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.12 (s, 1H), 8.05 (d, J=7.2 Hz, 2H), 7.88-7.90 (m, 1H), 7.69-7.71 (m, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.51-7.57 (m, 2H) 7.36-7.38 (m, 2H), 7.22-7.24 (m, 1H), 4.92-4.94 (m, 1H), 4.10-4.23 (m, 4H), 3.86 (s, 3H), 3.6 (s, 3H). LCMS (ESI+) 340 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH2:10][OH:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br>CN(C=O)C.CCOC(C)=O>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([N:1]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:3]([F:12])[C:4]=1[CH2:10][OH:11]
Reactant: BrCCOCCBr
Reactant: Nc1cc(F)c(F)c(CO)c1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCc1c(F)c(F)cc(N2CCOCC2)c1F
Temperature: 80 °C
Yield: 48 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)methanol (200 mg, 1.1 mmol) in DMF (3 mL) was added DIEA (1.6 mL) and 2-bromoethylether (5 eq) and the reaction heated to 80° C. for 18 h. The reaction was allowed to cool to rt, diluted with EtOAc and washed with H2O then saturated NH4Cl (aq). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give (2,3,6-trifluoro-5-morpholinophenyl)methanol (110 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH:41]=[N:40][CH:39]=[N:38]3)[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26](=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3cncn3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 2,2-dimethyl-6-(3-[1,2,4]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example J13) according to the general procedure K. Obtained as an orange foam (233 mg).
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:6][CH2:5]1.[Br:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[C:11](N(OC)C)=[O:12]>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([C:11](=[O:12])[CH2:6][CH2:5][CH:4]=[CH2:3])[CH:17]=[CH:18][CH:19]=1
Reactant: BrCC1CC1
Reactant: CON(C)C(=O)c1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)c1cccc(Br)c1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A mixture of magnesium (0.48 g, 20.29 mmol) in THF was treated dropwise with (bromomethyl)cyclopropane (2.49 g, 18.45 mmol) in THF, heated at reflux temperature for 1 hour, poured into a cold (0° C.) mixture of 3-bromo-N-methoxy-N-methylbenzamide (2.5 g, 10.24 mmol) and THF, allowed to come to room temperature, stirred for 10 min, quenched with aqueous NH4Cl and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (ISCO) using hexanes/EtOAc 10/1 as the eluting solvents gave a clear oil (2.4 g, 54% yield), MS m/e (M−H)+ 239; 1H NMR (400 MHz, DMSO-d6) 2.3 (m, 2H), 3.1 (t, J=7.19 Hz, 2H), 5.02 (m, 2H), 5.8 (m, 1H), 7.47 (t, J=7.93 Hz, 2H), 7.77 (dd, J=7.08, 2.2 Hz), 7.94 (dd, J=7.81, 1.58 Hz), 8.04 (t, J=1.83 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](=[S:41])[NH2:40])[CH2:35][CH2:34]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:41][C:39]([CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[N:40][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: NC(=S)C1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (85 g, 243 mmol) in DMA (700 mL), NBS (43.2 g, 243 mmol) was added at 0° C. The reaction mixture was stirred at rt for 1 h. Then tetrahydro-2H-pyran-4-carbothioamide (42.3 g, 291.6 mmol) was added at rt. The mixture was stirred at 60° C. for 1.5 h. The mixture was poured into water and extracted with EtOAc (400 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound. (40 g, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48-9.54 (br, 1H), 8.58 (d, J=5.3 Hz, 1H), 7.76-7.83 (m, 1H), 7.23-7.32 (m, 2H), 7.02 (d, J=5.3 Hz, 1H), 5.87-5.98 (m, 1H), 5.27-5.36 (m, 1H), 5.16-5.21 (m, 1H), 4.54-4.60 (m, 2H), 3.87-3.94 (m, 2H), 3.41-3.50 (m, 2H), 3.27-3.37 (m, 1H), 1.97-2.04 (m, 2H), 1.69-1.82 (m, 2H).
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1([CH3:30])[CH2:29][CH2:28][NH:27][CH2:26]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[CH:16]=[C:15]([N:27]2[CH2:28][CH2:29][C:25]([CH3:30])([CH3:24])[CH2:26]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: CC1(C)CCNC1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCC(C)(C)C2)ncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
Into 4 ml of N,N-dimethylformamide was resolved 0.37 g of 4-(2-butynyloxy)-6-chloropyrimidine, 0.56 g of potassium carbonate and 0.2 g of 3,3-dimethylpyrrolidine was added therein, and the mixture was stirred for 6 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.11 g of 4-(2-butynyloxy)-6-(3,3-dimethylpyrrolidin-1-yl)pyrimidine (hereinafter, referred to as Compound (27)).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH:8]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[C:2]1([CH3:1])[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[NH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)C2C(=O)c3ccccc3C2=O)cc1
Reactant: NN
Solvent: O
Product: Cc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 0 °C

Procedure:
A mixture of 2-(4-methylbenzoyl)indan-1,3-dione (1.32 g, prepared in a similar manner to the starting material in Example 6) and hydrazine hydrate (15 ml) was boiled under reflux for 24 hours. The mixture was cooled, poured into ice-water and the solid was collected by filtration, washed with absolute ethanol and dried to give 3-(p-tolyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 267-269° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl.Cl[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)CC1
Temperature: 70 °C
Yield: 40 %

Procedure:
A mixture of 57.5 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate, 33 parts of 2-(chloromethyl)pyridine hydrochloride, 43 parts of sodium carbonate, 0.1 parts of potassium iodide and 630 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was cooled and poured onto water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 30 parts (40%) of ethyl 4-[[1-[(2-pyridinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 161.5° C. (intermediate 60).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from {4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-acetic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=389.4 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[NH:4][CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[N:7]=1.Cl.C[OH:20]>>[CH3:1][N:2]([CH3:17])[C:3]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5](=[O:20])[N:4]=1
Reactant: CN(C)c1nc(-c2c[nH]c3ccccc23)c[nH]1
Reactant: CO
Agent: Cl
Product: CN(C)C1=NC(=O)C(c2c[nH]c3ccccc23)=N1

Procedure:
The instability of 2-dimethylamino-4-(3-indolyl)imidazole 5 normally would not be judged very significant on its own. Referring to FIG. 5, unexpectedly, upon exposure of 2-dimethylamino-4-(3-indolyl)imidazole 5.HCl to a methanol solution saturated with ammonia, α-carboline 8 was produced. Autooxidation of 2-dimethylamino-4-(3-indolyl)imidazole 5.HCl took place upon standing in a MeOH solution in air to yield 2-dimethylamino-5-(3-indolyl)imidazol-4-one 4 as a yellow solid which was identical, by spectral comparison of 1H and 13C NMR data, to natural and synthetic material reported in references 6 and 9, respectively. During the course of the reaction, dimer 7 partially precipitated from solution after 1 day as a dark violet solid. Collection and resubjection of dimer 7 to the reaction conditions afforded α-carboline 8. One mechanistic pathway that might account for the above involves the initial oxidative dimerization of 2-dimethylamino-4-(3-indolyl)imidazole 5 to yield dimer 7. Upon standing in a methanol-saturated ammonia solution in air, dimer 7 undergoes an electrocyclization-aromatization event via tautomer 7a. Oxidation of the resulting intermediate 7b to 7c followed by facile aminolysis results in loss of dimethylguanidine and the formation of α-carboline 8. The sequence is remarkably efficient, delivering 8 directly in one pot and good overall yield from 2-dimethylamino-4-(3-indolyl)imidazole 5. Aromatic α-carboline imine 8 was found to be quite stable and required fairly rigorous hydrolysis conditions to yield grossularine-1 1 as a yellow solid. All spectral data of synthetic grossularine-1 1 were in excellent agreement with data reported for the natural product.[1]
Reaction SMILES: [CH:1]1([N:4]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23](OC)=[O:24])[CH2:18][CH2:17]2)[C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[BH4-].[Li+].CO>C1COCC1>[CH:1]1([N:4]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][OH:24])[CH2:20][CH2:21]2)[C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(C(C)C)cc2)C2CC2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)N(C2CC2)[C@H]2CC[C@H](CCO)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(trans-4-(N-cyclopropyl-4-isopropylbenzamido)cyclohexyl)acetate (0.100 g, 0.28 mmol) in THF (3 mL) was added lithium borohydride (2 M solution in THF, 0.14 mL, 0.28 mmol) at 0° C. The reaction mixture was checked after being stirred overnight. HPLC-MS showed product and starting material. More lithium borohydride (0.14 mL) (2 M solution in THF) and MeOH (0.1 mL) were added to the mixture. After being stirred overnight, the reaction mixture was quenched with saturated NH4Cl (10 mL) and then extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 55% EtOAc-hexane. The alcohol product was obtained as a sticky white solid (80 mg). MS: 330 (M+1), C2131NO2.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.O.CCOCC>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[C:1]#[N:2])[CH:20]1[O:22][CH2:21]1
Reactant: BrCC1CO1
Reactant: COc1cccc(O)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: COc1cccc(OCC2CO2)c1C#N
Reaction time: 72 h
Yield: 32 %

Procedure:
2-Cyano-3-methoxyphenol (1 g, 6.7 mmol) and powdered potassium carbonate (2.78 g, 20.1 mmol) were stirred in 15 mL of acetone for 5 minutes, followed by addition of epibromohydrin (1.38 g, 10.1 mmol). The mixture was stirred for 72 hours then poured into water/ether. The ether layer was separated, washed with sodium carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude solid was triturated with ether/hexane, filtered, and dried under vacuum to give 0.44 g of 2-cyano-3-methoxyphenyl glycidyl ether.
Reaction SMILES: C([S:5][C:6]1[C:11]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:10][C:9]([CH2:24][CH3:25])=[C:8]([CH3:26])[N:7]=1)(C)(C)C.Cl.N1C=CC=CC=1>O>[CH2:24]([C:9]1[CH:10]=[C:11]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:6](=[S:5])[NH:7][C:8]=1[CH3:26])[CH3:25]
Reactant: CCc1cc(NCc2ccc3ccccc3c2)c(SC(C)(C)C)nc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(NCc2ccc3ccccc3c2)c(=S)[nH]c1C
Temperature: 140 °C
Yield: 38.4 %

Procedure:
A mixture of 2-tert-butylthio-5-ethyl-6-methyl-3-(2-napthylmethylamino)pyridine (98 mg, 0.27 mmol) and pyridine hydrochloride (0.45 g, 3.8 mmol) was heated under an atmosphere of nitrogen at 140° C. until evolution of gas ceased (about 45 minutes). Water was added and the resultant mixture was extracted three times with chloroform. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (15 torr). The residue was then subjected to column chromatography on silica gel (eluted with 2% methanol in ethyl acetate). Collection and concentration of appropriate fraction yielded 32 mg (36%) of the pyridinethione. Anal. Calcd for C19H20N2S·0.25 EtOAc: C, 72.68; H, 6.71; N, 8.48. Found: C, 72.41; H, 6.59; N, 8.86.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20].ClC[CH:23]([O:26]C(CCl)CCl)CCl>C(Cl)Cl>[CH3:9][N:10]1[C:15]2[CH:16]=[C:17]([CH:23]=[O:26])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20]
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: CN1C(=O)COc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CN1C(=O)COc2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
1 g of AlCl3 were suspended in 10 ml DCM, 0.5 ml of nitromethane were added to dissolve AlCl3, and the solution was cooled to 0° C. 4-Methyl-4H-benzo[1,4]oxazin-3-one (0.5 g, 3.06 mmol) dissolved in DCM was added to the above solution and stirred for 15 minutes at 0° C. To this solution was further added 0.36 ml of bis-chloromethyl-methylether in DCM. The reaction was stirred at 0° C. for 15 minutes and at room temperature for 3 h. The crude reaction mixture was then poured onto ice, the layers were separated and the organic phase was washed with NaHCO3 and brine. After drying over MgSO4 and filtration the solvent was evaporated, which afforded 0.43 g of crude product. The dark oil was purified by flash chromatography using EtOAc and cyclohexane as eluents, affording 0.2 g (37%) of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde as colourless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)(=O)OCC)C.CN(C)C=O.C(O)C>O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Under argon, to a stirred mixture of N-benzyl-4-piperidone (Aldrich) (26.0 g, 0.137 mol) and (4-cyano-benzyl)-phosphonic acid diethyl ester (36.6 g, 0.1445 mol) in dimethylformamide (260 mL) sodium hydride (60%, 7.8 g, 0.195 mol) was added at 0° C. The reaction mixture was stirred at room temperature overnight, then ethanol (10 mL) was added dropwise, the so obtained mixture was poured into water (300 mL), and extracted with diethyl ether (3×300 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and n-hexane:ethyl acetate=2:1 as eluent to yield 34.65 g (87%) of the title compound as an oil.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:32][N:33]4[CH2:38][CH2:37][N:36]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:35][CH2:34]4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.CS(O)(=O)=O>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:35][CH2:34]3)[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)N(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN(C(=O)N(C)C)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 85 °C
Yield: 36.7 %

Procedure:
A stirred mixture of 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide (0.3555 g, 0.482 mmol) in TFA (1.859 mL, 24.12 mmol) was treated with methanesulfonic acid (0.031 mL, 0.482 mmol) and the solution was heated at 85° C. overnight. After cooling, the residue was carefully concentrated and diluted with 5% MeOH/DCM w/NH3. The solution was concentrated with SiO2 and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM to 10% MeOH in DCM) to give 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide (88 mg, 0.177 mmol, 36.7% yield). 1H NMR (400 MHz, d6-DMSO) δ 12.04 (s, 1H); 8.92 (br. s., 1H); 8.45 (s, 1H); 8.40 (br. s., 1H); 8.33 (d, J=11.35 Hz, 1H); 7.96 (br. s., 1H); 7.87 (br. s., 1H); 4.40 (br. s., 2H); 3.95 (s, 3H); 3.64 (d, J=14.87 Hz, 2H); 3.25-3.35 (m, 2H); 2.88-3.15 (m, 4H); 2.78 (s, 6H); 2.44 (s, 3H). m/z (ESI, +ve ion) 497.1 (M+H)+.