Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:3]=1[NH:4][N+:5]([O-:7])=[O:6].[OH-].[Na+].CO.Br[CH2:19][C:20]#[CH:21]>O>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:3]=1[N:4]([N+:5]([O-:7])=[O:6])[CH2:21][C:20]#[CH:19]
Reactant: C#CCBr
Reactant: O=[N+]([O-])Nc1c(Br)cc(Br)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCN(c1c(Br)cc(Br)cc1Br)[N+](=O)[O-]
Reaction time: 16 h

Procedure:
2,4,6-tribromo-N-nitroaniline (5.0 g; 0.01334 mol) is reacted with a methanolic solution of sodium hydroxide (0.53 g; 0.01324 mol) in the presence of methanol (60 ml). The solvent is then removed, and the residue dried. The thus obtained sodium salt is dissolved in dimethyl sulfoxide (DMSO) and reacted with 3-bromopropyne (1.52 g; 0.0147 mol) at 25° C. The reaction mixture is stirred 16 hours and then poured into water. The title product is extracted with ether (3×125 ml), the combined extract washed with water, dilute sodium hydroxide, water and brine. The ethereal solution is then dried over magnesium sulfate and the solution concentrated to afford the product, mp. 58°-58.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:22])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:5]([N:44]2[CH2:45][CH2:46][CH:41]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:42][CH2:43]2)=[O:6])=[C:8]([CH3:22])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:11]=1
Reactant: COc1nc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A suspension of 0.200 g (0.64 mmol) 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid in 5 ml of CH2Cl2 was treated at RT with one drop of DMF; then, 0.06 ml=0.09 g (0.71 mmol) of oxalyl chloride was added to this solution drop by drop below 25° C. and the reaction mixture was stirred for 0.5 hour. After removal of the solvents by evaporation in a high vacuum, the residue was dissolved again in 10 ml of CH2Cl2 and 0.36 ml=0.26 g (2.57 mmol) of Et3N was added while stirring, followed by 0.099 g (0.64 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was stirred at RT. After 16 hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.278 g (97%) of the title compound as yellow amorphous solid. MS: 448.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][OH:18]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:18][CH2:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCC1CCCCO1
Reactant: N#Cc1cnc(N)cc1Cl
Product: N#Cc1cnc(N)cc1OCC1CCCCO1

Procedure:
From intermediate 16 and (tetrahydro-2H-pyran-2-yl)methanol, reacted in an analogous manner to the preparation of intermediate 34. (UPLC-MS 3) tR 0.69 min; ESI-MS 234.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[CH:23][S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:24]([CH3:25])=[CH:23][S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Reactant: NCCc1ccccc1
Product: Cc1csc2nc(-c3ccno3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:18]1[CH:22]=[CH:21][C:20]([C:2]2[N:7]=[C:6]([O:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)=[CH:19]1
Reactant: OB(O)c1ccoc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OC1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2ccoc2)nc1OC1CCOCC1
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A solution of 6-chloro-3-nitro-2-(tetrahydro-2H-pyran-4-yloxy)pyridine (0.259 g, 1.00 mmol), furan-3-boronic acid (0.123 g, 1.10 mmol), tetrakis(triphenylphosphine)palladium (0) (0.058 g, 0.05 mmol) and potassium carbonate (0.276 g, 2.00 mmol) in 1,4-dioxane/water (5 mL, 4:1) was de-gassed with nitrogen and then heated at 80° C. for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with n-hexane to afford the title compound as an off-white solid (0.197 g, 66%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[C:30]([C:34]1[C:39](Cl)=[N:38][N:37]2[N:41]=[CH:42][N:43]=[C:36]2[CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>O1CCCC1>[C:30]([C:34]1[C:39]([O:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:11]2)=[N:38][N:37]2[N:41]=[CH:42][N:43]=[C:36]2[CH:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc2ncnn2nc1Cl
Reactant: OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ncnn2nc1OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 32.9 %

Procedure:
4-(Diphenylmethoxy)-1-piperidineethanol (740 mg) was dissolved in dried tetrahydrofurane (18 ml), followed by addition of sodium t-butoxide (251 mg). The mixture was refluxed under heating for 25 minutes. After the mixture was cooled, 7-tert-butyl-6-chloro[1,2,4]triazolo[1,5-b]pyridazine (501 mg) was added thereto. The mixture was refluxed under heating for 2 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. Fractions containing the objective compound were collected and recrystallized from ethyl acetate to yield the title compound (380 mg).
Reaction SMILES: I[CH2:2][CH:3]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1(=O)[NH:26]C(=O)C2=CC=CC=C12.[K].O.NN>CN(C=O)C.CCCCC.C(O)C>[CH2:14]([CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCCCCCCC(CI)CCCCCCCC
Agent: NN
Agent: [K]
Solvent: CCO
Solvent: CCCCC
Solvent: O
Product: CCCCCCCCCCC(CN)CCCCCCCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.4 %

Procedure:
Iodoalkane 5 (5.90 g, 14.5 mmol) and potassium phthalimide (2.94 g, 15.9 mmol) were taken up in 25 mL of DMF and vigorously stirred for 72 hours at 25° C. The reaction mixture was then taken up in 200 mL of pentane, washed four times with 100 mL of water, passed through a 3 cm silica gel plug, and concentrated to give a colorless oil. The oil was next taken up in 150 mL of ethanol, 4 mL of hydrazine hydrate was added, and the mixture was heated at reflux overnight. The resulting precipitate was collected by filtration, dissolved in 100 mL of water, and the solution was made alkaline by the addition of 6 M NaOH (aq). The resulting mixture was then taken up in 200 mL of pentane, washed four times with 100 mL of water, once with 70 mL of brine, and concentrated to give a colorless oil (3.08 g, 72% yield). Anal. Calcd. for C20H43N: C, 80.73; H, 14.57. Found: C, 80.78; H, 14.52; 1H NMR (CDCl3): 2.60 (d, J=5.0 Hz, 2H), 2.00 (t, J=5.0 Hz, 1H), 1.30-1.20 (b, 32H), 0.89 (t, J=7.5 Hz, 6H); MS (EI): m/z (%) 297.34 (100) [M+].
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH2:23]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1
Reactant: CCOCCOCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in 1-methyl-2-pyrrolidone (1.1 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg), and the reaction mixture was stirred at 120° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=100/0→95/5). The object fraction was concentrated under reduced pressure and dried to give the title compound (146 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:26])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CNc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: COC(=O)CN(C(=O)NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Three grams (15 mmol) of methyl 4-chlorophenylaminoacetate were dissolved in 40 ml of benzene, and 2.2 ml (15 mmol) of 4-chlorobenzenesulfonyl isocyanate were added to the resultant solution, followed by stirring for 1 hour. Crystals formed were collected by filtration to obtain N-(4-chlorobenzenesulfonyl)-N'-(4-chlorophenyl)-N'-methoxycarbonylmethylurea (6.1 g) as white crystals.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]>N1C=CC=CC=1>[C:1]([NH:15][C:14]1[CH:16]=[CH:17][NH:10][C:11](=[O:12])[N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Benzoyl chloride (2.3 mL, 20 mmol) was added dropwise over 30 min to a stirred suspension of cytosine (1.1 g, 10 mmol) in dry pyridine, and stirring was continued at room temperature for a further 4 h at room temperature. The reaction was quenched by adding a small amount of methanol. The solid was filtered, washed with EtOH and dried in vacuo to give 1.92 g of the desired product 6 (90%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:11]=[C:10]([CH:9]=[CH:8][C:6]=1[OH:7])[O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(O)c(C(C)(C)C)c1

Procedure:
33.2 g of tert.-butyl hydroquinone, 41.35 g of methyl bromoacetate and 37.3 g of potassium carbonate (anhydrous) are refluxed in 300 ml of acetone under nitrogen for 3 days. The solvent is removed under reduced pressure and 500 ml of ether are added. This ether solution is washed with water, dried with magnesium sulfate and evaporated. The residue is distilled in vacuo. The brown distillate obtained at 138°-140° under 10-3 mm Hg is purified by means of column chromatography. The methyl 2-(3-tert.-butyl-4-hydroxyphenoxy)-acetate thus obtained can be crystallised from hexane. Melting point: 87°-89°.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:8]([CH:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]([CH3:37])=[CH:6]2.[Br:38]C1C=CC=CC=1CC(=O)C.COC1C=C(CC(=O)C)C=CC=1>>[Br:38][C:4]1[CH:3]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:37])[C:8]([CH:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:9]2[O:13][S:14]([C:17]([F:18])([F:20])[F:19])(=[O:15])=[O:16]
Reactant: CC(=O)Cc1ccccc1Br
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2cc(OC)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: COc1cccc(CC(C)=O)c1
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(Br)cccc2c1OS(=O)(=O)C(F)(F)F

Procedure:
Ethyl 2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyl oxy)acetate (35) was prepared similarly to ethyl 2-(6-methoxy-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate of Example 32, using 1-(2-bromophenyl)propan-2-one as the starting material instead of 1-(3-methoxyphenyl)propan-2-one. 1H-NMR: 400 MHz, (CDCl3) δ: 8.11 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.81 (d, J=7.6 Hz, 2H), 5.61 (s, 1H), 4.62 (q, J=11.2 Hz, 2H), 4.26-4.15 (m, 2H), 3.75 (s, 3H), 2.62 (s, 3H), 1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:11][CH2:10][CH:9]([CH:12]3[CH2:14][CH2:13]3)[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:12]1([CH:9]2[O:8][C:6]3[N:7]=[C:2]([C:29]4[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]=3[O:11][CH2:10]2)[CH2:14][CH2:13]1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)OCC(C1CC1)O2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCC(C2CC2)O3)cn1
Temperature: 120 °C

Procedure:
A microwave vial was charged with 2-chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (205 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (324 mg, 1.47 mmol), Pd(PPh3)2Cl2 (51 mg, 0.07 mmol), sodium carbonate (2.41 mL, 2.41 mmol, 1M aqueous solution) and acetonitrile (2.5 mL). The vessel was sealed then evacuated and back filled with argon (×3) before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was filtered and the filtrate concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-4% methanol in DCM), then triturated in diethyl ether/pentane. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient methanol 10-98%) affording 118 as an off white solid (4.5 mg, 3%). LCMS: RT=3.52 min, [M+H]+=357. 1H NMR (400 MHz, DMSO-d6): δ 8.91 (2H, s), 7.01 (2H, s), 4.40 (1H, dd, J=11.38, 2.41 Hz), 4.01 (1H, dd, J=11.41, 7.52 Hz), 3.80-3.60 (9H, m), 1.11-0.98 (1H, m), 0.69-0.41 (4H, m).
Reaction SMILES: [OH:1][CH:2](P(=O)(OC)OC)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.O>C1(C)C=CC=CC=1>[C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][CH:7]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COP(=O)(OC)C(O)c1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C=O)cc1
Yield: 85.1 %

Procedure:
27.2 g (0.1 mol) of dimethyl α-hydroxy-4-tert.-butylbenzylphosphonate were dissolved in 25 ml of toluene and were added dropwise, from a dropping funnel, into a distillation apparatus which had been preheated to 180° C. and had a small Vigreux column to which a water pump vacuum was applied. The distillate was fractionally distilled in a high vacuum. 13.8 g (81.5% of theory) of 4-tert.-butylbenzaldehyde of boiling point 72° C./0.15 mbars were obtained.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1.Cl>C1COCC1>[F:18][C:16]([F:17])([F:19])[C:14]1[O:13][N:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:20])=[O:2])=[CH:10][CH:9]=2)[N:15]=1
Reactant: COC(=O)Cc1ccc(-c2noc(C(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2noc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[4-(5-Trifluoromethyl-[1,2,4]oxadiazol-3-yl)-phenyl]-acetic acid methyl ester (1.333 g, 4.66 mmol) was dissolved in THF (8.28 mL) and 4 M HCl (12.42 mL) added. The mixture was stirred at RT for 24 h. The reaction mixture was then stirred for 29 h at 60° C. The solvent was removed by rotary evaporation. To ensure complete removal of the HCl, the product was dissolved in Toluene and evaporated again 3 times. The substance was then dissolved in water:acetonitrile 1:1 and lyophilised over the weekend. For analytical purposes, a small sample was subjected to purification by reverse phase prep-HPLC (gradient elution, water/ACN both containing 0.1% TFA). Fractions containing the desired compound were combined and freeze-dried to yield the product as white salt.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:23][CH2:22][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[C:20]([F:21])=[C:12]3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)[C:27]1=[O:58].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]2[CH2:22][CH2:23][N:10]([C:6]3[N:5]=[CH:4][CH:3]=[C:2]([C:30]4[CH:29]=[C:28]([NH:41][C:42]5[CH:47]=[CH:46][C:45]([N:48]6[CH2:53][CH2:52][N:51]([CH:54]7[CH2:55][O:56][CH2:57]7)[CH2:50][CH2:49]6)=[CH:44][N:43]=5)[C:27](=[O:58])[N:26]([CH3:25])[CH:31]=4)[C:7]=3[CH:8]=[O:9])[C:11](=[O:24])[C:12]=12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 55.6 %

Procedure:
A mixture of 134c (300 mg, 0.86 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (403 mg, 0.86 mmol), CH3COONa (142 mg, 1.72 mmol), K3PO4 (460 mg, 1.72 mmol), PdCl2(dppf) (71 mg, 0.086 mmol) in CH3CN (25 mL) and H2O (1 mL) was heated at 100° C. for 3 hours. After reaction it was evaporated the residue was purified by silical-gel column eluting with methylene chloride/methanol (30:1) to afford 134d (312 mg, yield 55%) as a brown solid. MS: (M+H)+ 653.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccnc2)c(O)c1

Procedure:
Following a procedure similar to that described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, and nicotinoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(nicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(nicotinoyloxy)-alpha-(isopropylaminomethyl) benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8](=[CH:14]N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.Cl.[C:24]([NH2:27])(=[NH:26])[CH3:25].C(N(CC)CC)C>C(O)C>[CH3:25][C:24]1[N:27]=[C:6]([C:5]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:26]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C)nc1-c1ccc(OC)c(OC)c1
Yield: 45.9 %

Procedure:
A solution of ethyl 2-(3,4-dimethoxybenzoyl)-2-(dimethylaminomethylene)acetate (31 g), acetoamidine hydrochloride (13.3 g) and triethylamine (16.2 g) in ethanol (200 ml) was refluxed for 10 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The separatedorganic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl ether to give ethyl 2-methyl-4-(3,4-dimethoxyphenyl)-5-pyrimidinecarboxylate (14 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:15][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([CH2:23][OH:24])[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:15][N:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([CH2:23][OH:24])[CH2:12][N:11]1[C:26]([O:28][CH3:29])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CN[C@H](COCc2ccccc2)CN1Cc1ccccc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)N1C[C@@H](CO)N(Cc2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 5 (1.67 g, 5.11 mmol) in acetonitrile (20 mL) was treated with a solution of methyl chloroformate (0.532 g, 5.63 mmol) in acetonitrile (10 mL) at 0° C. The mixture was stirred at ambient temperature for 30 min and then aqueous sodium carbonate solution (15 mL) was added. The organic solvent was removed, and the aqueous residue was extracted with chloroform (3×10 mL). The combined organic extracts were washed with aqueous sodium carbonate solution (10 mL), dried, and evaporated to give 6 (1.52 g. 77.3% yield) as an oil. 1H NMR (CDCl3) δ2.54 (dd, 2H, CH2), 2.45 (t, 1H, OH), 2.72 (dd, 2H, CH2), 3.51 (dd, 2H, CH2), 3.67 (dd, 2H, CH2), 3.69 (s, 3H, OMe), 3.81 (dd, 2H, CH2), 4.44 (dd, 2H, CH2 benzylic), 7.17-7.31 (10H, ArH).