Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:8][C:9](=[O:28])[CH:10]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[CH:5]([CH3:7])[CH3:6].O.CCN(C(C)C)C(C)C.ClC(OC1C=CC=CC=1)=O>C(O)(C(F)(F)F)=O.O1CCOCC1.CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]([N:8]1[C:9](=[O:28])[CH:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[NH:20][C:21]1=[O:22])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: O=C(Cl)Oc1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C(C)C)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Reaction time: 1.5 h

Procedure:
The compound obtained in step f above (22f) (900 mg, 1.907 mmol) was stirred in TFA (8 mL) at 0° C. for 5 h, and then concentrated under vacuum. The residue was diluted with CH2Cl2, washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, concentrated to give the crude product. The obtained crude product was stirred in dioxane (9 mL) and water (1 mL) at 0° C., DIEA (737 mg, 5.72 mmol) and phenyl chloroformate (446 mg, 2.861 mmol) were added, and the mixture was stirred for 1.5 h. The solvent was removed under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated to give a yellow oil. The obtained oil was then stirred with DIEA (737 mg, 5.72 mmol) in DMF (10 mL) for 24 h. After general workup, the crude product was purified by silica gel column chromatography to give the title compound as colorless oil (245 mg, 32% from step f.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32]C)=[O:31])[CH:18]=[N:19][CH:20]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([OH:32])=[O:31])[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1ccccc1OCc1cncc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(COc2ccccc2CC(=O)O)c1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To a mixture of methyl 2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate (1.05 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at 50-60° C. for 1.5 hrs. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (1.00 g, 97%) of 2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 207-208° C.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][N:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[C:10](=[O:13])[C:11]=2[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.CN(C)C=O.[ClH:43]>CCOC(C)=O>[ClH:43].[O:13]=[C:10]1[N:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:8]=[CH:7][C:6]2[N:5]=[CH:4][C:3]([O:2][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:12][C:11]1=2
Reactant: CC(C(=O)O)n1ccc2ncc(O)cc2c1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C(=O)O)n1ccc2ncc(OCC(F)(F)F)cc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A resealable pressurized vial was charged with 2-(3-hydroxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrobromide (0.54 g, 2 mmol), cesium carbonate (2 g, 7 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2 g, 7 mmol), and N,N-dimethylformamide (6 mL, 0.3M). The vessel was sealed and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure to afford brown oil. This was purified via MPLC (10-50% EtOAC/Hexanes) to afford tan solid of bis alkylated material. This was suspended and refluxed in 5 mL of 6N HCl for 2 hours. Reaction mixture concentrated and dried under reduced pressure to afford 2-(5-oxo-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (0.3 g, 50% yield). This was concentrated under reduced pressure to dryness to afford 2-(5-oxo-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (0.3 g, 50% yield) as yellow solid. Free base material MS m/z=317.0 [M+1]+. Calc'd for C13H12ClF3N2O4: 352.7.
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)CC>[Cu].C(OCC)(=O)C>[Cl:11][C:10]1[CH:2]=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CCC(=O)O
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with 2,3-dichlorobenzoic acid (4.55 g, 23.8 mmol) and copper powder (3.02 g, 47.6 mmol). Propionic acid (30 mL) was added, and the resulting mixture was heated to 130°-135° C. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (1 hour). Ethyl acetate (30 mL) was added as the reaction mixture was cooled to room temperature. The resulting mixture was filtered, and the solids were washed with ethyl acetate. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting yellow organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum to afford 3.55 g of 3-chlorobenzoic acid as a pale yellow solid, mp 153°-153.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:6][CH:7]=1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]1([C:2]2[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:6][CH:7]=2)[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)NCc1cncc(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cncc(C2CC2)c1
Temperature: 100 °C
Yield: 60 %

Procedure:
To a solution of tert-butyl (5-bromopyridin-3-yl)methylcarbamate (496 mg, 2 mmol), cyclopropyl boronic acid (223 mg, 2.6 mmol), potassium phosphate (1.49 g, 7.0 mmol) and tricyclohexyl phosphine (56 mg, 0.2 mmol) in toluene (9 mL) and water (0.45 mL) under a nitrogen atmosphere was added palladium acetate (22 mg, 0.1 mmol). The mixture was heated at 100° C. for 3 h and then cooled to rt. Water (20 mL) was added and the mixture extracted with EtOAc (2×30 mL), the combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. Crude product was purified by column chromatography (50% EtOAc in hexanes) afforded tert-butyl (5-cyclopropylpyridin-3-yl)methylcarbamate in 60% yield. (5-cyclopropylpyridin-3-yl)methanamine was then generated by removal of the Boc protecting group by treatment with HCl (in methanol or dioxane) or trifluoroacetic acid in dichloromethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH:12]([NH2:15])([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:15][CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=C(NC(C)C)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with isopropylamine (1.135 g, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-isopropylamino-cyclopent-1-enecarboxylic acid ethyl ester (2.44 g, 12.38 mmol, 64.5%), as a light yellow oil. LC-MS (ESI) calcd for C11H19NO2 197.14, found 198.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[Br:8][C:4]1[CH:5]=[CH:6][C:7]([C:13](=[O:16])[CH2:14][CH3:15])=[C:2]([F:1])[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Fc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1ccc(Br)cc1F
Temperature: 90 °C
Yield: 17.9 %

Procedure:
A mixture of 3-fluorobromobenzene (5.0 g, 29 mmol) and aluminium (III) chloride (11.6 g, 87 mmol) was heated under argon until a slurry formed. Propionyl chloride (3.2 g, 35 mmol) was added over 15 min and the mixture was heated at 90° C. for 1 h. The reaction was poured onto ice-water (100 mL) and the resultant mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography (SiO2; heptane) to give the product (1.2 g, 18%) as a colourless oil: NMR δH (400 MHz, CDCl3) 1.18 (3H, t, J 7.5), 2.95 (2H, m), 7.29-7.38 (2H, m) and 7.75 (1H, t, J 8 Hz).
Reaction SMILES: [CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[CH:20][CH:19]=1)[C:6](=[O:16])[CH2:7][CH2:8][C:9]([C:12]([O:14]C)=[O:13])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH3:4].C([Sn]([N:45]=[N+:46]=[N-:47])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:31][N:47]=[N:46][N:45]=2)=[CH:20][CH:19]=1)[C:6](=[O:16])[CH2:7][CH2:8][C:9]([C:12]([OH:14])=[O:13])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(C)(C)C(=O)OC
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CCC(C)(C)C(=O)O

Procedure:
A solution of 5.5 g (11.3 mmol) of 4-methoxycarbonyl-4-methyl-pentanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 4.9 g (14.2 mmol) of tributyltin azide in 50 ml of o-xylene is reacted and worked up analogously to Example 2 to yield 4-carboxy-4-methyl-pentanoic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)biphenyl4-ylmethyl]-amide in the form of a beige-coloured foam that has an Rf value of 0.34 [toluene/isopropanol/glacial acetic acid (170:30:2)].
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.[Na].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1)[CH3:22]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Reactant: CCO
Agent: [Na]
Product: CCOc1nc2ncnn2c2c1cnc1c2cnn1CC

Procedure:
2.7 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine of Example 1 (b) (0.01 mol.) are added with stirring to a solution of 2.3 g. of sodium in 50 ml. of dry ethanol. The mixture is stirred at room temperature for 6 hours. The precipitate is filtered off, washed with water and recrystallized from ethanol to obtain 5-ethoxy-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine, yield 2.1 g. (74%); m.p. 196°-197°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=[O:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:13][C:11](=[O:12])[C:3]=12)=[O:7])(=[O:16])[CH3:15]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)OC2=O
Temperature: 2.5 °C
Yield: 61 %

Procedure:
A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to about 25° C. and further to 0-5° C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61% yield) of 3-acetamidophthalic anhydride as a white product. 1H-NMR (CDCl3) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:14]1[S:15][C:16]([Br:19])=[CH:17][N:18]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO>[NH2:1][CH:2]([C:14]1[S:15][C:16]([Br:19])=[CH:17][N:18]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(N)c2ncc(Br)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 50 °C

Procedure:
The crude mixture from Step 1 was dissolved in methanol (3 mL), and sodium hydroxide (1.0 M in water, 0.950 mL, 0.950 mmol) was added to the resulting solution. The reaction mixture was then heated to a temperature of 50° C. for 30 minutes. The reaction was subsequently cooled, acidified with TFA (0.1 mL) and concentrated to afford racemic trans-4-[amino(5-bromo-1,3-thiazol-2-yl)methyl]cyclohexanecarboxylic acid, which was used in subsequent synthetic transformations without purification. MS ESI calc'd. for C11H15BrN2O2S [M+H]+ 319, 321. found 319, 321.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)=[CH:18]\[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:33][C:23]1[CH:22]=[C:21]([O:20][CH2:19]/[CH:18]=[C:17](\[C:14]2[CH:15]=[CH:16][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:12][CH:13]=2)/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[CH:32]=[CH:31][C:24]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Propargylmorpholine (171 mg, 1.37 mmol) was added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.68 mmol; prepared as described in example 34) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (20 mg, 0.108 mmol) and tetrakis(triphenylphosphine)-palladium (62 mg, 0.054 mmol) were added. The reaction mixture was degassed once more and then stirred at ambient temperature for 2 days under argon. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (50 mL) and the solution was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and its evaporation gave oil that was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyl-oxy]phenoxy]acetate as oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O)[CH3:11].C([BH3-])#N.[Na+]>C(O)C>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=1)[CH3:3]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCNCc1ccc(OC)c(OCC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.1 %

Procedure:
A mixture of β-alanine ethyl ester hydrochloride (1.6 g), 3-ethoxy-4-methoxybenzaldehyde (1.8 g), sodium cyanoborohydride (0.42 g) and powdered 3Å molecular seives (2.5 g) in ethanol (25 ml) was stirred at ambient temperature for 24 hours. A further aliquot of sodium cyanoborohydride (0.42 g) was added and stirring was continued for a further 24 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was treated with ethyl acetate (100 ml) and the solution was washed with 10% aqueous potassium carbonate (50 ml), then twice with water (25 ml), then with brine (25 ml), then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5, v/v) to give the title compound as a colourless oil (1.1 g).
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:16][CH2:17][CH2:18][CH3:19])[CH2:6][NH:7][CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][CH2:11][O:10]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][CH2:33][C:34](Cl)=[O:35]>O>[CH2:17]([O:16][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][N:7]([CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][CH2:11][O:10]1)[C:34](=[O:35])[CH2:33][Cl:32])[CH2:18][CH3:19]
Reactant: O=C(Cl)CCl
Reactant: CCCOC(CNCC1OCCC(C)O1)OCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(CN(CC1OCCC(C)O1)C(=O)CCl)OCCC

Procedure:
N-(2,2-Dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-yl-methyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [C:1]([CH:3]([CH:12]([CH3:14])[CH3:13])[C:4]([NH:6][C:7]([NH:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].C[Si](N[Si](C)(C)C)(C)C.C[Si](Cl)(C)C>>[CH2:10]([N:9]1[C:1]([NH2:2])=[C:3]([CH:12]([CH3:13])[CH3:14])[C:4](=[O:5])[NH:6][C:7]1=[O:8])[CH3:11]
Reactant: CCNC(=O)NC(=O)C(C#N)C(C)C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CCn1c(N)c(C(C)C)c(=O)[nH]c1=O
Temperature: 125 °C
Reaction time: 20 h
Yield: 42.3 %

Procedure:
A flask was charged with 1-(2-cyano-3-methylbutanoyl)-3-ethylurea (1, 17.1 g, 87 mmol), HMDS (86 mL), and TMSCl (1.21 mL, 9 mmol). The reaction mixture is heated to reflux (125° C.) and left stirring for 16-24 h until solution became clear. Reaction is monitored by TLC and upon completion was cooled to room temperature then concentrated. To the resulting residue was added 1 vol. sat. NaHCO3 solution in dropwise. The mixture was added 4-5 vol. of water along with 4-5 vol. of EtOAc. An emulsion forms as the two layers are combined and the slurry is filtered, and the solid is filtered and washed with water (2×0.25 vol) to afford an off-white solid. These solids were dried in a vacuum oven overnight at 40 to 50° C. to yield 7.25 g (42.4%) of 1-ethyl-5-isopropyl-6-amino uracil 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C(Br)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: Clc1ccc(CCCCBr)cc1
Solvent: O
Solvent: CCBr
Product: CCOP(=O)(CCCCc1ccc(Cl)cc1)OCC
Yield: 78 %

Procedure:
A mixture of 12.38 g of 4(p-chlorophenyl)butyl bromide and 20 g of triethyl phosphite was refluxed at 160° for seven hours. During this period the circulating water in the condenser was maintained at 50° to allow the ethyl bromide to distill off. After removal of the excess of triethyl phosphite, distillation under reduced pressure gave 11.9 g (39 mmol) of a white viscuous oil.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C.CCOCC>[Br:20][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Reaction time: 3 h

Procedure:
2-Fluoro-3-trifluoromethylaniline (28.8 g, 161 mmol) is dissolved in DMF (100 mL). A solution of NBS (28.6 g, 161 mmol) in DMF (100 mL) is added dropwise at room temperature. After 3 hours, the reaction is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give 4-bromo-2-fluoro-3-trifluoromethylaniline as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[CH:10]=[N:9]2)[C:5]([NH:18][C:19]([C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)=[O:20])=[CH:4][N:3]=1.N1CCCCC1.[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:40]#[C:39][C:37]([OH:41])([C:33]4[S:32][CH:36]=[CH:35][N:34]=4)[CH3:38])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([NH:18][C:19]([C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)=[O:20])=[CH:4][N:3]=1
Reactant: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(I)cc32)COC1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(C#CC(C)(O)c4nccs4)cc32)COC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-[2-amino-4-(6-iodo-1H-indazol-1-yl)pyrimidin-5-yl]-3-methyloxetane-3-carboxamide (76% purity, 20 mg, 0.034 mmol) and piperidine (0.1 mL) was added tetrakis(triphenylphosphine)palladium (7.8 mg, 0.007 mmol), copper(I) iodide (1.2 mg, 0.007 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (10.3 mg, 0.068 mmol). The reaction was purged with N2 and stirred at RT for 2 hr. Reaction mixture was concentrated in vacuo. Purification by flash chromatography (Isolute column, 100% DCM to 2% MeOH-DCM) followed by recrystallization (1:1 MeOH-EtOAc mixture) gave the title compound: 1H NMR (500 MHz, MeOD) δ 1.73 (3H, s), 1.98 (3H, s), 4.47 (2H, d, J=5.99 Hz), 5.01 (2H, d, J=6.15 Hz), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.57 (1H, d, J=3.31 Hz), 7.79 (1H, d, J=3.31 Hz), 7.83 (1H, d, J=8.35 Hz), 8.39 (1H, s), 8.82 (1H, s), 8.92 (1H, s); m/z=+476.1 (M+H)+.