Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:31])([F:20])[F:32])=[CH:27][N:26]=1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
To a mixture of 0.96 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.53 g of 5-(trifluoromethyl)-2-pyridinecarboxylic acid, 0.37 g of triethylamine and 10 ml of chloroform was added 0.64 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-(trifluoromethyl)picolinamido)propoxy)benzene (10% yield), m.p., 55.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (190 mg, 0.607 mmol) and 2-chloro-5-propylpyrimidine (114 mg, 0.728 mmol) in DMF (4 mL) was added K2CO3 (252 mg, 1.820 mmol). Upon completion of addition, the reaction mixture was heated to 100° C., where it stirred overnight. At the conclusion of this period, the reaction mixture was cooled to rt, diluted with water (10 mL) and then extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and then concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 30% EtOAc) to afford Compound 1C as a white solid (131 mg, 0.302 mmol, 50% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.17 (s, 2H), 7.77 (d, J=1.9 Hz, 1H), 7.51-7.56 (m, 1H), 7.44-7.49 (m, 1H), 5.40-5.49 (m, J=7.9, 7.9, 4.0, 3.9 Hz, 1H), 4.23 (ddd, J=13.4, 6.8, 4.0 Hz, 2H), 3.63-3.73 (m, 2H), 2.42 (t, J=7.6 Hz, 2H), 2.14-2.22 (m, 2H), 1.89-1.99 (m, 2H), 1.56-1.64 (m, 2H), 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.C=O.[OH-].[CH3:20][N+](C)(C)CC1C=CC=CC=1>O1CCCC1.CO>[CH2:20]=[C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH:10]=[CH:11][N:12]2[C:3]([S:2][CH3:1])=[N:4][N:5]=[C:6]12
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Agent: C=O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C1c2ccccc2C=Cn2c(SC)nnc21

Procedure:
To 4.6 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 60 ml of tetrahydrofuran was added 2.4 g of paraformaldehyde together with 4.0 ml of a 40% solution of trimethylbenzylammonium hydroxide in methanol. After refluxing the mixture for 30 minutes, the solvent was evaporated off. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residual crystals were collected by filtration, washed with isopropyl alcohol and dried. The above procedure provided 11-methylene-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethyl acetate yielded colorless needles melting at 121°-122° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:9].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>COCCOC.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>[CH3:7][CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)Oc1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of sodium carbonate (906 mg), tetrakis(triphenylphosphine)palladium(0) (247 mg), 4-(1-methylethoxy)phenylboronic acid (1000 mg) and 3-bromopyridin-2-amine (0.739 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (883 mg) as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[C:29]2[CH:30]=[C:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH:33][C:28]=2[O:27][CH2:26]1>O1CCCC1>[O:27]1[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:36])=[CH:30][C:29]=2[CH2:25][CH2:26]1
Reactant: O=C=Nc1ccc2c(c1)CCO2
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2,3-dihydrobenzo[b]furan-5-isocyanate (197 mg, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 268 mg (81.0%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:8]1[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=1.C(N(C(C)C)CC)(C)C>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH2:3]1
Reactant: N[C@@H]1CCNC1
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](N)C2)nc1C
Yield: 86.5 %

Procedure:
The same operation as in Example (237a) was performed using (3R)-3-aminopyrrolidine (0.16 mL, 1.80 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (300 mg, 1.20 mmol) and diisopropylethylamine (0.42 mL, 2.40 mmol), to obtain 265 mg of the title compound as a pale yellow solid (87%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CCCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccccc1OCC(=O)OCC
Temperature: 0 °C
Yield: 103.9 %

Procedure:
2-Propylphenol (15.0 g, 110 mmol) was dissolved in DMF (70 mL), and stirred at 0° C. To the solution was added K2CO3 (30.43 g, 220.2 mmol) and ethyl 2-bromoacetate (13.43 mL, 121.1 mmol), and the reaction was stirred at room temperature for 3.5 h. The reaction was diluted with water, and the product was extracted with EtOAc twice. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give residue. The residue was purified using silica gel column chromatography (hexane/EtOAc=30/1) to give 4.2 (25.4 g). 1H NMR (400 MHz) (CDCl3) δ 7.18-7.08 (2H, m); 6.91 (1H, t, J=7.4 Hz); 6.71 (1H, d, J=8.1 Hz); 4.62 (2H, s); 4.25 (2H, q, J=7.1 Hz); 2.68-2.57 (2H, m); 1.70-1.60 (2H, m); 1.29 (3H, t, J=7.1 Hz); 0.95 (3H, t, J=7.4 Hz).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([C:27](=[O:28])/[C:9](/[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:8]\[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(CS(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1
Product: O=C(/C(=C\c1ccc(I)cc1)S(=O)(=O)Cc1ccc(I)cc1)c1ccc(Br)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-iodophenyl)-2-(4-iodobenzylsulfonyl)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].Cl>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Temperature: 120 °C
Yield: 85.6 %

Procedure:
To a suspension of 27 (0.400 g, 2.60 mmol) [G. B. Evans, R. H. Furneaux, et. al J. Org. Chem., 2001, 66, 17, 5723-5730] in diphenylether (25 ml) was added 2-fluoro-4-nitrophenol (614 mg, 3.90 mmol) and HCl (2N in Et2O) (0.19 ml, 3.90 mmol). The reaction mixture was heated at 120° C. for 4 hours, cooled to room temperature and concentrated under reduced pressure, to afford title compound 243 (610 mg, 86% yield) as a black solid. MS (m/z): 274.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17]([O:25][CH3:26])=[N:18][C:19]([NH:22][CH2:23][CH3:24])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:23]([NH:22][C:19]1[N:18]=[C:17]([O:25][CH3:26])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=1)[CH3:24]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(OC)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Temperature: 90 °C
Yield: 70.9 %

Procedure:
A solution of Example C1 (0.12 g, 0.26 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.070 g, 0.35 mmol) in dioxane (4 mL) was sparged with Ar, treated with a solution of K2CO3 (0.07 g, 0.51 mmol) in water (1 mL), Pd(PPh3)4 (0.03 g, 0.026 mmol) and heated at 90° C. for 2 h. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by column chromatography (MeOH/DCM) to afford N-ethyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine as a white solid (77 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.36 (br s, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.40-3.30 (m, 2H), 2.37 (s, 3H), 1.14 (br m, 3H); MS (ESI) m/z: 418.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCCCCN
Solvent: CCN(CC)CC
Product: CCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(pentylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, pentylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)(C)(C)C.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.[F-].[Cs+]>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>[CH2:27]([S:24]([C:20]1[CH:19]=[C:18]([C:17]#[C:16][C:10]2[CH:11]=[C:12]([C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:30])[CH:23]=[CH:22][CH:21]=1)(=[O:25])=[O:26])[CH2:28][CH3:29]
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3ccsc3)ccc2OCC(=O)O)c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl (4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191, 200 mg; 0.41 mmol), 3-thienylboronic acid (78 mg; 0.61 mmol), caesium fluoride (185 mg; 1.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (28 mg; 0.04 mmol) was placed in a microwave tube. The tube was sealed and degased with nitrogen before adding dioxane (4 ml) and water (2 ml). The reaction mixture was heated at 150° C. for 15 minutes in a microwave reaction system. The reaction mixture was taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM (1.00 ml), treated with a 4 N solution of HCl in dioxane (2.0 ml) and stirred for 1 day. The solvents were removed under reduced pressure and the residue purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:23][C:10]3[N:11]=[CH:12][N:13]=[C:14]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(#N)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]3[C:9]4[CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[NH:23][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][CH:18]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reaction time: 1 h

Procedure:
After dissolving 40 mg of 4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine in 4.5 ml of toluene and 4.5 ml of acetonitrile at 110° C., 4-fluorophenylisocyanate (16.6 μl) was added and the mixture was stirred for 1 hour. After returning the mixture to room temperature, the precipitated crystals were filtered out and dried to obtain 37 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:26]([OH:28])=[O:27])=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Yield: 10.7 %

Procedure:
6-(4-tert-Butyl-phenyl)-1-methyl-1H-indole-3-carboxylic acid was prepared from 6-(4-tert-butyl-phenyl)-1-methyl-1H-indole (0.541 g, 2.05 mmol), n-butyllithium (0.98 mL, 2.5 mmol), crushed dry ice (3 g, 70 mmol) in dry THF (10 mL) according to the procedure described in Example 60. Purification by flash chromatography using 10-50% ethyl acetate in hexane and 100% ethyl acetate as eluants afforded the title compound as a light yellow solid (0.0675 g, 10.7%), mp: 236-238° C. (dec.). Mass spectrum (−APCI, [M−H]−) m/z 306. 1HNMR (400 MHz, DMSO-d6): δ 12.8-13.0 (br s, 1H), 7.8 (s, 1H), 7.65-7.7 (m, 3H), 7.45-7.5 (m, 2H), 7.4 (dd, 1H, J=8.3 Hz and 1.6 Hz), 7.2 (d, 1H, J=0.75 Hz), 4.05 (s, 3H) and 1.35 ppm (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[N+:11]([O-])([O-:13])=[O:12].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:11]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[OH:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)c1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 27.3 %

Procedure:
3-isopropylphenol (3.00 g, 22 mmol) was dissolved in methylene chloride(40 ml) followed by the addition of sodium nitrate (2.06 g, 24 mmol). The addition of sulfuric acid (25 mL/3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 h, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.09 g, 27%). 1H NMR (CD3COCD3): δ 7.95 (d, 1H), 7.62 (d, 1H), 7.11 (d, 1H), 2.95 (m, 1H), 1.24 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:24])=[C:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.N1C=CN=C1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[CH3:1][C:2]1([CH:8]([O:24][C:30](=[O:32])[CH3:31])[C:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C(O)=C(Cc2ccc(Cl)c(Cl)c2)n2cncn2)COCOC1
Agent: c1c[nH]cn1
Product: CC(=O)OC(C(=Cc1ccc(Cl)c(Cl)c1)n1cncn1)C1(C)COCOC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A mixture of 14 g (0.0378 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(3,4-dichlorophenyl)-propen-1-ol (Example 25), 1 g of imidazole and 80 g of acetic anhydride is stirred for 8 hours at 70° C. and then concentrated under reduced pressure. The residue is taken up in 300 ml of ether and stirred for half an hour with 100 ml of 6% strength sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated under reduced pressure, finally at 50° C. under 0.1 mbar. 10.8 g (69.3% of theory) of 1-(5-methyl-1,3-dioxan-5-yl)-1-acetoxy-2-(1,2,4-triazol-1-yl)-3-(3,4-dichlorophenyl)-prop-2-ene are obtained as a pale yellow resin.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC1=CC(=O)C(O)(CCC(C)C)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=CC(=O)C(CCC(C)C)(OCc2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of Example 11A (25 mg, 0.094 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added 60% wt sodium hydride (15.4 mg, 0.384 mmol). The reaction solution was stirred for 0.5 h and benzylbromide (0.046 mL, 0.384 mmol) was added. The solution was stirred 16 h at room temperature, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic extract was concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) afforded the title compound as an oil (29 mg, 86%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71 (dd, 6H), 0.80-1.03 (m, 2H), 1.19-1.38 (m, 1H), 1.69-2.04 (m, 2H), 3.85 (d, J=10.66 Hz, 1H), 3.98 (s, 3H), 4.04 (d, J=11.03 Hz, 1H), 5.84 (s, 1H) 7.19-7.39 (m, 5H), 7.40-7.57 (m, 1H), 7.58-7.71 (m, 2H), 7.85 (d, J=7.72 Hz, 1H); MS m/z 351.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][P:24]([C:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][C:35]=1[Br:42])([F:33])[F:32])(=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])([CH3:21])[CH3:20]>>[Br:42][C:35]1[CH:36]=[C:37]([CH2:40][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][N:9]=2)[CH:38]=[CH:39][C:34]=1[C:31]([P:24](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[O:23][C:19]([CH3:22])([CH3:20])[CH3:21])([F:32])[F:33]
Reactant: c1ccc(Cc2noc(-c3ccccc3)n2)cc1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1Br
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(c2ccccc2)c2noc(-c3ccccc3)n2)cc1Br

Procedure:
Starting with 3-benzyl-5-phenyl-1,2,4-oxadiazole and di(tert-butyl)[[2-bromo-4-(bromomethyl)phenyl](difluoro)methyl]phosphonate, the title compound was prepared as an oil by using the same procedure described in Step 3 of Example 4.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1)[CH3:2].Cl.CC(OC)(C)C>CC(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 49 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (limiting reagent) (step a) in iPrOH (3 volumes) was added hydrogen chloride (2 molar equivalents of a 5-6N solution in iPrOH). The reaction mixture was heated and stirred at 49° C. (internal) for 18 hr before being cooled to 22° C. TBME (4.3 volumes) was added and the suspension was stirred at 22° C. for 3 days. The solid was collected by filtration, washed with TBME (3.5 volumes) and air dried for 2 days to give an off white solid. Yield 95% of theoretical.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11]>>[CH2:9]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CN
Reactant: CCOC(=O)CC#N
Product: CC(C)CNC(=O)CC#N
Reaction time: 2 h

Procedure:
Ethyl cyanoacetate (113 g., 1.0 mole) and isobutylamine (73 g., 1.0 mole) were refluxed with stirring for 2 hours to give N-isobutyl cyanoacetamide.