Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH:14]#[C:15][CH2:16][CH2:17][CH3:18]>COCCOC.[Cu]I.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:14]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)#[C:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCC
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCC#Cc1nccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (183 mg, 0.96 mmol) were combined in DME (30 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8 mL, 60 mmol) and PdCl2(PPh3)2 (337 mg, 0.48 mmol) were added and 1-pentyne (979 mg, 14.4 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 6 h at which time GC/MS analysis indicated that the reaction was not complete. Additional 1-pentyne (3.0 mL, 29 mmol) was added and the reaction was heated to 35° C. under a condenser. After heating for 16 h, GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite.™., and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, 99:1, then 97:3 hexane:ethyl acetate to 2-(1-pentynyl)-1,3-thiazole (820 mg, 44% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) Δ7.76 (d, J=3.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 2.47-2.42 (m, 2H), 1.68-1.60 (m, 2H), 1.08-0.99 (m, 3H). MS (ESI) 151.6 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N12CCCNC1CCCC=C2.O>CN(C)C=O>[N:17]1[CH:16]=[CH:15][N:14]2[C:9]([S:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]3[C:21](=[O:23])[CH2:22][S:18][C:19]3=[O:24])(=[O:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:13]=12
Reactant: O=C1CSC(=O)N1
Reactant: O=S(=O)(CCCCCl)c1cccc2nccn12
Agent: C1=CN2CCCNC2CCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSC(=O)N1CCCCS(=O)(=O)c1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 0.27 g (1.0 mmol) of 5-(4-chlorobutylsulfonyl)imidazo[1,2-a]pyridine and 0.177 g (1.0 mmol) of thiazolidine-2,4-dione in 7 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=50/1) to yield 0.22 g (62.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:13]([CH:9]1[CH2:8][C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: COc1cccc2c1C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cccc(OC)c2C1=O
Yield: 28 %

Procedure:
A solution of 26.4 g of 7-methoxy-1-indanone, 33.6 ml of 3-buten-2-ol and 265 mg of p-toluenesulfonic acid in 33.6 ml of 2,2-dimethoxypropane and 265 ml of anhydrous toluene was boiled under reflux for 17 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 9.9 g (28%) of (RS)-2-(2-buten-1-yl)-7-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:65]1[CH2:71][CH2:70][CH2:69][CH:68]([NH2:72])[CH2:67][CH2:66]1)(OC(C)(C)C)=O>>[NH:65]1[CH2:71][CH2:70][CH2:69][CH:68]([NH:72][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:15])([F:14])[CH2:13][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:67][CH2:66]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc-hexahydro azepine 4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-2.05 (m, 16H) 2.88 (d, J=3.28 Hz, 1H) 3.01 (br. s., 2H) 3.31 (s, 3H) 3.34 (br. s., 1H) 3.94 (s, 3H) 4.06 (t, J=13.26 Hz, 3H) 4.46 (m, 1H) 7.47 (d, J=8.1 Hz, 1H) 7.50 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.23-8.30 (m, 2H). [M+H] calculated for C28H37F2N7O3, 558. found 558.
Reaction SMILES: F[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([F:16])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[F:16][C:9]1[C:3]([CH2:4][O:5][C:6](=[O:8])[CH3:7])=[C:2]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CC(=O)OCc1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Yield: 81.5 %

Procedure:
A solution of acetic acid 2,6-difluoro-3-nitrobenzyl ester (3 g, 12.9 mmol) and aniline (1.5 mL, 16.9 mmol) in DMSO (10 mL) was heated at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×15 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a brown oil (3.2 g, 81%). 1H NMR 400 MHz 6 (CDCl3): 8.21 (1H, dd, J=9.4, 5.9 Hz), 7.30-7.24 (2H, m), 7.10-7.04 (1H, m), 6.97-6.92 (2H, m), 6.83 (1H, dd, J=9.3, 8.4), 4.93 (2H, d, J=2.0 Hz), 1.94 (3H, s)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11]4[N:12]([CH:14]=[CH:15][CH:16]=4)[CH:13]=3)=[CH:4][CH:3]=2)[CH:29]=[N:28]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cn2cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(-c2ccc(-c3cnn(CCOC4CCCCO4)c3)cc2)cn2cccc12
Temperature: 40 °C
Reaction time: 20 h

Procedure:
Under nitrogen, a suspension of 145 mg (0.50 mmol) 3-(4-bromo-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one, 177 mg (0.55 mmol) 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 50 mg (0.60 mmol) sodium hydrogen carbonate in 1 ml DMF and 0.5 ml water is heated to 40° C. Then 7.0 mg (0.010 mmol) bis(triphenylphosphine)palladium(II)-chloride is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 20 hours. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to give 3-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.39 min (B), [M+H] 405;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].C(N(CC)CC)C.[O:29]=[C:30]1[NH:35][C:34](=[O:36])[C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:32][NH:31]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][S:37]([C:33]2[C:34](=[O:36])[NH:35][C:30](=[O:29])[NH:31][CH:32]=2)(=[O:38])=[O:39])[C:10]=1[CH2:11][CH3:12]
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c(=O)[nH]1
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(CCNS(=O)(=O)c2c[nH]c(=O)[nH]c2=O)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 18 h

Procedure:
A solution of the amine of Example 43 (6.5 mg, 20 μmol) and triethylamine (6 μl, 40 μmol) in dimethylformamide (250 μL) was treated with 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfonyl chloride (J. Am. Chem. Soc., 1956, 78, 401) (0.8 mg, 4.0 μmol) and the mixture was shaken for 18 hours. The reaction mixture was filtered and the filtrate was purified by HPLC (Hypersil Thermoquest Luna C8 150×10 mm column; a gradient mobile phase was used, 10:90 (by volume)→95:5 (by volume) acetonitrile:(water, 95% by volume/trifluoroacetic acid, 0.1% by volume/acetonitrile 5%, by volume)).
Reaction SMILES: ClC1C=C(C=CC=1)C[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:7]1.[N-:35]=[N+:36]=[N-:37].[Na+]>CS(C)=O.O>[N:35]([CH2:17][CH2:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][N:7]=[C:8]2[S:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[N+:36]=[N-:37]
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1cccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.25 g, 0.49 mmoles) and sodium azide (0.04 g, 0.58 mmoles) in DMSO (3 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.23 g, 0.44 mmoles).
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][CH:12]\2[OH:13])[CH:3]=[N:2]1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:38][O:37][C:35]([CH2:34][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][CH:12]\2[OH:13])[CH:3]=[N:2]1)=[O:36]
Reactant: COC(=O)CBr
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)cn1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (10.31 g) and methyl bromoacetate (7.0 ml) in N,N-dimethylformamide (150 ml) were added potassium carbonate (10.20 g) and potassium iodide (12.30 g) with stirring at room temperature, and the resulting mixture was refluxed for 1 hour. After water was added, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane, and dichloromethane (2:1:1) as the eluent to afford the title compound (4.74 g, yield: 39%) as a pale yellow amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.ON1C2C=CC=CC=2N=N1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:34]([NH:41][C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)NCc4ccccc4)c3)cc2)S1
Reaction time: 24 h
Yield: 60.3 %

Procedure:
600 mg (1.84 mmol) of 4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-carboxylic acid (prepared in Example 23(c)), 5 ml of dimethylformamide, 340 mg (2.5 mmol) of 1-hydroxybenzotriazole and 250 μl (2.3 mmol) of benzylamine are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 480 mg (2.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride are added portionwise. The mixture is stirred for 24 hours while allowing the temperature to rise. The reaction medium is immersed in water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue obtained is washed with dichloromethane and filtered. 460 mg (60%) of the desired product are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[OH:33].Cl.[C:35](=N)(OC)[CH3:36]>C(Cl)Cl>[CH2:9]([O:8][CH:7]1[CH:2]2[N:1]=[C:35]([CH3:36])[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: COC(C)=N
Agent: Cl
Solvent: ClCCl
Product: CC1=NC2C(CC(COCc3ccccc3)C(OCc3ccccc3)C2OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
To a solution of Intermediate B (224 mg, 0.50 mmol) in dry DCM (2 mL) was added methyl acetimidate hydrochloride (110 mg, 1.00 mmol) followed by a solution of TEA (51 mg, 0.50 mmol) in dry DCM (2 mL). The mixture was stirred under nitrogen at room temperature for 3 h. The mixture was diluted with satd. aqueous NaHCO3 (10 mL), extracted with DCM (3×10 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 40% EtOAc in hexanes to give the product rac-(3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-methyl-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole (105 mg, 45%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.39-7.25 (m, 15H), 4.86 (d, J=11.6 Hz, 1H), 4.77 (d, J=11.3 Hz, 1H), 4.71 (m, 1H), 4.68 (d, J=11.3 Hz, 1H), 4.47-4.41 (m, 3H), 4.17-4.12 (m, 1H), 3.64 (t, J=5.8 Hz, 1H), 3.56 (dd, J=9.0, 4.4 Hz, 1H), 3.51 (dd, J=8.6, 6.3 Hz, 1H), 3.47 (dd, J=9.1, 2.8 Hz, 1H), 2.14-2.08 (m, 1H), 1.98 (s, 3H), 1.93-1.85 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]([F:29])[F:28])[N:20]=1>>[F:29][CH:27]([F:28])[O:26][CH2:25][C:21]1[N:20]=[C:19]([CH2:18][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:24]=[CH:23][CH:22]=1
Reactant: FC(F)OCc1cccc(CBr)n1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COC(F)F)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2-bromomethyl-6-difluoromethoxymethylpyridine by the alkylation method described in Example 36.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[N:23](C3CCCCO3)[N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:66][N:67]([CH3:71])[CH2:68][CH2:69][NH2:70].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:12]([C:13]([NH:70][CH2:69][CH2:68][N:67]([CH3:71])[CH3:66])=[O:15])=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: Cc1cc(C(=O)O)c(C)cc1Nc1ncc(Cl)c(Nc2cc(C)n(C3CCCCO3)n2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C(=O)NCCN(C)C)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylbenzoic acid (35.0 mg, 0.077 mmol) in DMF (0.5 mL) was added HATU (29.1 mg, 0.077 mmol), DIEA (26.7 μL, 0.153 mmol) and N1,N1-dimethylethane-1,2-diamine (25.2 μL, 0.230 mmol). The reaction mixture was stirred at room temperature overnight. 1N HCl aqueous solution (0.5 mL) was then added and the reaction mixture was heated at 100° C. for 1.5 hours to remove the tetrahydro-2H-pyran-2-yl protecting group. The mixture was purified by preparative RP-HPLC to provide 4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-N-(2-(dimethylamino)ethyl)-2,5-dimethylbenzamide; ESMS m/z 443.2 (M+H+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.O[CH2:34][C:35]1[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=1)[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=2)[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.41 ml (15.4 mmol) of diethyl azodicarboxylate (DEAD) are added dropwise to a mixture, cooled with water, of 3.37 g (11 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide, 3.26 g (13.8 mmol) of tert-butyl 3-(hydroxymethyl)benzylcarbamate and 4.04 g (15.4 mmol) of triphenylphosphine in 60 ml of absolute THF. The reaction mixture is stirred vigorously at room temperature for 90 min and then concentrated to a volume of about 30 ml. 300 ml of ether are added to the solid and the mixture is filtered. Another crystallization of the mother liquor yields a second batch. The product is dried under high vacuum. Alternatively, the product can be purified by column chromatography on silica gel (dichloromethane/methanol mixture or cyclohexane/ethyl acetate mixture). Yield: 4.79 g (82.8% of theory);
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)(=O)C>CCOCC>[CH3:24][O:20][C:19](=[O:21])[C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
(O-benzyl) Boc Serine 2.00 g (6.8 mmoles) was dissolved in 50 ml of ether. To this solution was added an ether solution containing freshly prepared diazomethane prepared from 5 g of Diazald using the procedure from Aldrich Technical Bulletin number AL-180. After stirring the solution for 30 minutes, glacial acetic acid was added dropwise until the solution became clear. The resulting solution was concentrated in vacuo to yield 2.00 g, 95% as a clear oil. 1H: (CDCl3); 7.3 (d, 5H), 5.5 (bs, 1H), 4.5 (s, 2H), 3.8 (m, 2H), 3.7 (s, 3H), 1.4 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[N:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1)[CH2:6][CH2:5]2.[NH2:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH2:25])=[O:24].C(N(C(C)C)C(C)C)C.CC(O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[N:13]=[CH:14][N:15]=[C:16]([NH:19][C:20]3[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:25])=[O:24])[N:17]=1)[CH2:6][CH2:5]2
Reactant: Cc1c(N)cccc1C(N)=O
Reactant: Clc1ncnc(N2CCc3cc(Br)ccc3C2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Nc2ncnc(N3CCc4cc(Br)ccc4C3)n2)cccc1C(N)=O
Temperature: 95 °C
Yield: 25.1 %

Procedure:
To a vial charged with 6-bromo-2-(4-chloro-1,3,5-triazin-2-yl)-1,2,3,4-tetrahydroisoquinoline (163 mg, 499 μmol) and 3-amino-2-methylbenzamide (75 mg, 499 μmol) was added N-ethyl-N-isopropylpropan-2-amine (174 μl, 999 μmol) and propan-2-ol (1665 μl, 499 μmol). The vial was sealed and heated to 95° C. overnight. The product was purified by reverse phase liquid chromatography using TFA as a modifier. Fractions containing the product were combined and neutralized with saturated NaHCO3 (35 mL). The product was extracted with DCM (3×30 mL). The organics were separated, dried over Na2SO4, and filtered to afford 3-(4-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-1,3,5-triazin-2-ylamino)-2-methylbenzamide (55 mg, 25%) as a white solid upon drying.