Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([OH:16])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:46][C:47]([F:54])([F:53])[CH:48]([CH3:52])[CH2:49][CH2:50]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:50][CH2:49][CH:48]([C:47]([F:54])([F:53])[F:46])[CH3:52])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2O)cc1
Reactant: CC(CCO)C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (189mg, 0.5 mmol), Ph3P (262 mg, 1 mmol) and 3-trifluoromethyl-1-butanol (66 mg, 0.5 mmol) in THF (25 mL) was added dropwise a solution of DIAD (0.2 mL, 1 mmol) in THF (5 mL) and the resulting mixture was stirred at room temperature for 8 hours. The mixture was concentrated in vacuo and the residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product, (yield: 180 mg 71%). mp 126–128° C. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=7 Hz, 3H), 1.55 (m, 1H), 1.97 (m, 1H), 2.30 (m, 1H), 3.29 (s, 3H), 4.46 (m, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 503 (M+H)+; (APCI−) m/z 537 (M+Cl)−. Anal. calc. for C22H19F5N2O4S: C, 52.59; H, 3.81; N, 5.57. Found: C, 52.70; H, 3.73; N, 5.63.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Br-].[CH2:33]([Zn+])[CH:34]([CH3:36])[CH3:35].[Li+].[OH-].Cl>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[CH2:33]([C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30])[CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Reactant: CC(C)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)Cc1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
Ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (200 mg, 0.443 mmol) was dissolved in THF (7 mL) and isobutylzinc(II) bromide (2.66 mL, 1.328 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.011 g, 0.022 mmol) were added. The reaction was stirred at room temperature for 16 h and warmed to 50° C. After stirring for 24 h, isobutylzinc(II) bromide (4 mL) was added and the mixture was heated to 90° C. The reaction was cooled to room temperature, and 1.0 M LiOH (5 mL) and dioxane (5 mL) were added. The reaction was stirred at room temperature for 24 h and then acidified to pH 3 with 1 M HCl. The aqueous mixture was extracted three times with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the title compound (33 mg). LCMS m/z=446.7 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.6 Hz, 6H), 1.87-1.98 (m, 1H), 2.03-2.13 (m, 1H), 2.35 (dd, J=15.9, 9.0 Hz, 1H), 2.60-2.76 (m, 6H), 3.42-3.50 (m, 1H), 5.12 (s, 2H), 6.71 (dd, J=8.6, 2.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.75 (d, J=1.4 Hz, 1H), 10.47 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]1[C:37](=[C:52]([C:55]#[N:56])[C:53]#[N:54])[O:38][C:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:42]([F:45])([F:44])[F:43])[C:40]=1[CH3:41])#[N:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=[CH:41][C:40]2[C:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:42]([F:45])([F:43])[F:44])[O:38][C:37](=[C:52]([C:55]#[N:56])[C:53]#[N:54])[C:36]=2[C:34]#[N:35])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 65 °C
Yield: 60.9 %

Procedure:
In 8 ml of ethanol were dissolved 155 mg (0.33 mmol) of 5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-carboaldehyde and 116 mg (0.37 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene]propanedinitrile. The mixture was stirred with heating at 65° C. for 1 hour. The tar-like matter was separated by decantation, purified by silica gel column chromatography, crystallized in methanol, and separated by filtration to give 153 mg of a dark brown crystal having amp of 181-183° C. (yield: 60.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.C(O)(=O)C.[C:20]1(=O)[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>[OH-].[Na+].[Pd].O1CCOCC1>[C:20]1(=[O:25])[N:1]([C:4]2[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=[O:10])[C:23](=[O:24])[CH:22]=[CH:21]1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)c1cc(C(=O)O)cc(N2C(=O)C=CC2=O)c1

Procedure:
211.2 g (1.0 mol) of 5-nitroisophthalic acid are dissolved in 1,590 g of aqueous sodium hydroxide (90.0 g of sodium hydroxide in 1,500 ml of water) and the solution is rendered neutral with 15 ml of anhydrous acetic acid and hydrogenated in the presence of 10 g of a palladium-on-charcoal catalyst (5% by weight of Pd). The catalyst is filtered off and a solution of 118.0 g (1.2 mols) of maleic anhydride in 150 ml of dioxane is added to the filtrate in the course of 2 hours, whilst stirring vigorously. A white suspension is formed and is stirred overnight at 20°-25° C., 250 ml of acetic acid are then added and the mixture is stirred for a further 2 hours. The amide-acid which has precipitated is filtered off, washed with water and methanol and dried at 30° C. in vacuo for 24 hours. The reaction product (315 g) is then heated, in 2,500 ml of acetic anhydride, whilst stirring, to 80°-85° C. for 30 minutes. About 1.8 liters of liquid (acetic acid+acetic anhydride) are distilled off under a waterpump vacuum. The residual suspension is poured onto 2,000 g of ice and the mixture is stirred overnight. The reaction product which has precipitated is filtered off, washed with water and the methanol and dried at 60° C. in vacuo for 12 hours. 210 g of white, crystalline 5-maleimidylisophthalic acid are obtained; melting point>300° C. (=80% of theory, based on the nitroisophthalic acid).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)O1.Br[C:24]1[C:25]([C:30]([NH:32][CH3:33])=[O:31])=[N:26][CH:27]=[N:28][CH:29]=1.O>O1CCOCC1.C([O-])(O)=O.[Na+].C(#N)C.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]>[CH3:33][NH:32][C:30]([C:25]1[C:24]([C:9]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[CH:29][N:28]=[CH:27][N:26]=1)=[O:31]
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3[nH]ncc23)OC1(C)C
Reactant: CNC(=O)c1ncncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1ncncc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 140 °C
Yield: 12.1 %

Procedure:
A vial was charged with a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (0.144 g, 0.463 mmol), 5-bromo-N-methylpyrimidine-4-carboxamide (0.1 g, 0.463 mmol) and PdCl2(dppf) (0.017 g, 0.023 mmol) in dioxane (8 mL) and aqueous saturated NaHCO3 (2 mL). The resulting light brown suspension was heated at 140° C. for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated and the crude residue was purified by preparative HPLC, eluting with a gradient of 25-30% ACN in H2O (containing 10 mMol NH4HCO3) over a period of 8 minutes. The product-containing fractions were combined and the solvent was removed via rotary evaporation. The crude product was extracted into DCM and was washed with water. The volatiles were removed in vacuo to give the title compound as a white solid (0.018 g, 0.056 mmol, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (d, J=4.80 Hz, 3H), 7.43 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 8.89 (d, J=4.29 Hz, 1H), 9.09 (s, 1H), 9.38 (s, 1H), 13.72 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C14H10F3N5O, 322.1. found 322.2.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([CH3:15])[N:4]=1)[NH2:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][CH3:24])=[CH:18][CH:17]=1>C(O)C>[CH3:15][C:5]1[N:4]=[C:3]([NH:1][N:2]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)[CH2:23][CH3:24])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: CCC(=O)c1ccc(C)cc1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Solvent: CCO
Product: CCC(=NNc1cc(-c2ccccc2)nc(C)n1)c1ccc(C)cc1

Procedure:
The title compound was prepared from 4-hydrazino-2-methyl-6-phenylpyrimidine (300 mg, 1.5 mmol) and 1-p-Tolyl-propan-1-one (174 μL, 1.05 mmol) in 3.0 mL of ethanol by a procedure similar to example 1, step 4 yielding 110 mg (22%) of a white solid. HPLC Purity: 96%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C.C(=O)([O-])O.[Na+].C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:22][CH:20]1[CH2:21][CH2:19]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 953 ml of DMF, 9.2 g of HOBT, 11.5 g of EDC, 3.4 g of cyclopropylamine and 13.8 g of DIPEA was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over MgSO4. The solvents were removed under reduced pressure and the crude product was pure enough for the next reaction step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]([O:38]CC)=[O:37])[CH:32]=2)[O:27]1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[CH3:24])=[CH:16][CH:17]=1)[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]([OH:38])=[O:37])[CH:32]=2)[O:27]1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[CH3:24])=[CH:16][CH:17]=1)[OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2c(c1)CC[C@H](CN(C[C@H](O)c1ccc(-n3c(C)ccc3C)nc1)C(=O)OC(C)(C)C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)n1-c1ccc([C@@H](O)CN(C[C@H]2CCc3cc(C(=O)O)ccc3O2)C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of ethyl (2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromene-6-carboxylate (Example 359, 0.21 mmol, 1.0 eq.) and 1N NaOH (0.63 mmol, 3.0 eq.) in EtOH (2 mL) was heated to reflux for 1.5 hours. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo to afford a residue that was purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, 100:5 CH2Cl2:MeOH). The product was obtained as a white foam in 72% yield. MH+=522.3, RT=3.11 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 4-(methanesulfonyl)phenyl acetic acid (43.63 g, 0.204 mol) in methanol (509 mL) was treated slowly with concentrated sulfuric acid (2 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (800 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×200 mL), washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.42 g, 98%) as a yellow oil which solidified to a cream colored solid upon sitting over time at 25° C.: mp 78-80° C.; EI-HRMS m/e calcd for C10H12O4S (M+) 228.0456, found 228.0451.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[CH:9]2.Cl>O>[N:1]([C:7]1[C:6]([OH:5])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[N:10][CH:11]=[N:12]2)=[O:3]
Reactant: Oc1ccc2ncncc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Nc1c(O)ccc2ncncc12
Reaction time: 1 h

Procedure:
During one hour and while stirring, a solution of 0.14 mole of sodium nitrite in 30 ml water is added to a cold solution (0°-5° C.) of 0.14 mole of 6-hydroxy quinazolin, 12 ml concentrated hydrochloric acid and 50 ml distilled water. Stirring is continued for one hour. The 5-nitroso 6-hydroxy quinazolin (formula IV) is thus obtained as a yellow precipitate, which is washed with water, then dried.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2([C:32](OC)=[O:33])[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)=[O:15])[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2([CH2:32][OH:33])[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)=[O:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(CO)(Cc5ccc(F)cc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flask, methyl 1-(4-fluorobenzyl)-3-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)cyclohexanecarboxylate (0.31 mmol) was dissolved in tetrahydrofuran (6 mL). Lithium aluminum hydride in THF (1M) (0.62 ml, 0.62 mmol) was added to the flask. The reaction was stirred for 3 hrs at room temperature. Upon completion, the reaction was quenched with ethyl acetate (5 ml) drop-wise. Water (5 mL) was added to the reaction. The reaction mixture then was extracted 3 times with ethyl acetate (20 mL). The organic layers were combined, were dried with sodium sulfate, concentrated and purified using HPLC to give the titled compound. LC-MS: 473.23 [M+H]. LC/MS RT=2.46 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[N+:22]([O-:40])[CH:23]=[C:24]([Cl:39])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)O.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:39][C:24]1[CH:23]=[N+:22]([O-:40])[CH:21]=[C:20]([Cl:19])[C:25]=1[CH2:26][C@H:27]([O:17][C:16](=[O:18])[CH2:15][C:13]1[S:14][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][CH:12]=1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CC(=O)O)s1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(CO[Si](C)(C)C(C)(C)C)s2)cc1OC
Yield: 46 %

Procedure:
To a solution of 2-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-thienyl]acetic acid (995 mg, 3.48 mmol) in dichloromethane (40 mL) was added (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (1.43 g, 4.17 mmol), followed by 4-(dimethylamino)-pyridine (212 mg, 1.74 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.33 g, 6.96 mmol). The resultant solution was stirred at room temperature for 72 h. The reaction solution was washed with saturated aqueous sodium bicarbonate (2×30 mL), the organic phase passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-100% ethyl acetate in iso-hexane to give the title compound as a pale yellow oil (980 mg, 46%).
Reaction SMILES: Br[C:2]1[N:3]([CH:24]([CH2:26][CH3:27])[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=2.[CH3:28][Zn]C.CO>O1CCOCC1.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]>[CH:24]([N:3]1[C:2]([CH3:28])=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[N:7][C:8]=2[C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: C[Zn]C
Reactant: CCC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CCC(C)n1c(C)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Temperature: 65 °C
Yield: 47 %

Procedure:
To a solution of 5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (20 mg, 0.046 mmol), Pd(dppf)Cl2, (3 mg, 8% mmol) in 3 ml of anhydrous dioxane, was added slowly dimethyl zinc (230 μl, 1.0M in heptane solution). The mixture was heated to about 65° C. until in the sealed tube. MeOH was added dropwise and solvents were removed in vacuo. EtOAc was added to the residue and the resulting solution washed with 1 M HCl, water, brine and then dried over Na2SO4. The solvent was removed and the crude mixture was subjected to flash chromatography to obtain 5-(9-sec-Butyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine 8 mg in a yield of 47%. 1H NMR, MeOD: 9.45 (s, 2H); 4.55 (m, 1H); 3.87 (m, 4H); 3.80 (s, 4H); 2.69 (s, 3H); 2.43 (m, 1H); 2.02 (m, 1H); 1.71 (d, 3H); 0.86 (t, 3H). m/z: 369.22 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[CH:5]=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[CH:16]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([Br:10])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)c(Br)c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(Br)c(Br)c1
Yield: 84.6 %

Procedure:
The above aldehyde (2.25 g) was dissolved in dichloromethane (25 ml) and carboethoxymethylenetriphenylphosphorane (2.96 g) was added. After 18 hours at 25° the solution was concentrated in vacuo and the residue washed with hexane. Combined hexane washings were concentrated in vacuo to give ethyl-3-(3,4-dibromophenyl)propenoate (2.4 g). NMR 1H 7.7(2H,m), 7.50(1H,d), 7.15(1H,dd), 6.32(1H,d), 4.26(2H,q), 1.33(3H,t).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[C:7]([C:20]([F:23])([F:22])[F:21])[CH:6]=1.[C:24]([O:28][C:29]([N:31]1[C:39]2[N:34]([C:35](=[O:41])[N:36]=[C:37](Cl)[CH:38]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:13]([C:12]1[CH:11]=[C:10]([CH:17]=[CH:16][CH:15]=1)[O:9][C:8]1[CH:18]=[CH:19][C:5]([CH2:4][O:3][C:37]2[CH:38]=[C:39]3[N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33][N:34]3[C:35](=[O:41])[N:36]=2)=[CH:6][C:7]=1[C:20]([F:21])([F:22])[F:23])#[N:14]
Reactant: N#Cc1cccc(Oc2ccc(CO)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cccc(C#N)c3)c(C(F)(F)F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 3-(4-(hydroxymethyl)-2-(trifluoromethyl)phenoxy)benzonitrile and tert-butyl-7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(F)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
A mixture of 1,2-difluoro-3-nitrobenzene (690 μL, 6.29 mmol), phenylamine (600 μL, 6.60 mmol) and potassium carbonate (1.74 g, 12.57 mmol) in DMSO (3 mL) was stirred at RT for 3 h and then heated to 90° C. for 4 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The organic layer was then washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% EtOAc in cyclohexane) followed by (Si—PCC, gradient 0-50% DCM in cyclohexane) affording (2-Fluoro-6-nitrophenyl)phenylamine as a orange/red oil (563 mg, 39%). 1H NMR (CDCl3, 400 MHz): δ 8.70 (1H, s), 8.00 (1H, d, J=8.66 Hz), 7.36-7.23 (3H, m), 7.09 (1H, t, J=7.41 Hz), 7.03-6.89 (3H, m).