Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(OC([N:19]1[CH2:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[CH2:21][CH2:20]1)=O)(C)(C)C>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[NH:19]1[CH2:20][CH:21]=[C:22]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:23][CH2:24]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cccc(C2=CCNCC2)c1
Yield: 103.4 %

Procedure:
3-Cyanophenyl boronic acid (3.0 g, 20.4 mmol) and 4-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.0 g, 21.1 mmol) are dissolved in acetonitrile (100 ml) and 0.4 M aqueous sodium carbonate (100 ml). The solution is degassed and treated with palladium tetrakistriphenylphosphine (1.2 g, 1.04 mmol) at 90° C. for 1 hour. The reaction is cooled, filtered and the filtrate is concentrated to an oil. The oil is extracted with methylene chloride (3×) and the solvent is removed under vacuum. The residue is chromatographed (15% ethyl acetate/hexane) to give the title compound as a white solid (6.0 g, 21.1 mmol). This material is treated with methylene chloride (100 ml) and 40% TFA/methylene chloride (100 ml) at ambient temperature for 2 h. The solvents are removed under vacuum and the residue is chromatographed (NH4OH/MeOH/CH2Cl2, 1:5:94) to give title compound as a brown solid contaminated with inorganic salts (4.6 g).1H NMR (CDCl3, 300 MHz) δ7.87 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 6,28 (m, 1H), 3.90 (m, 2H), 3.49 (t, 2H), 2.83 (m, 2H). EI MS M+ 184.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(CSc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: Cc1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-methylbenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 177°-179° C.) and piperazine.
Reaction SMILES: NCCCCCC([O:9][C:10]1[C:11](=[CH:16][CH:17]=[C:18](CN)[CH:19]=1)[C:12]([NH:14][OH:15])=[O:13])=O>C([O-])(O)=O.[Na+]>[C:12]([NH:14][OH:15])(=[O:13])[C:11]1[C:10](=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:9]
Reactant: NCCCCCC(=O)Oc1cc(CN)ccc1C(=O)NO
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NO)c1ccccc1O

Procedure:
SHA-Sepharose 4B was prepared by mixing 130 mg of (6-aminohexanoyl)-4-aminomethylsalicylhydroxamic acid (SHA-Z-NH2), dissolved in 30 mL 0.2M NaHCO3, with. 6.5 g HCl washed CNBr activated Sepharose 4B (Pharmacia) overnight at room temperature. After the coupling reaction, 2 mL of 0.5M Tris, pH 8.5 were added and the gel slurry mixed at room temperature for 1 hour, and washed with water, 0.5M NaCl, and water again. The resulting SHA-Sepharose 4B was suspended in 30 mL of 20% ethanol, and stored at 4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.[C:25]([C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)#[N:26].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CCOC(C)=O>[F:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[C:6]([NH:8][C:32]([C:30]2[O:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)=[O:33])[CH:7]=1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 82.1 %

Procedure:
The procedure of Example 4, step (c) was followed using 58.5 mg (0.174 mmol) of 1-[2-fluoro-5-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine (as prepared in the previous step), 29 mg of 10% palladium on carbon (50% by weight water), 28.6 mg (0.209 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 27.3 μL (0.314 mmol) of oxalyl chloride, and 72.8 μL (0.418 mmol) of DIEA except the isolated impure product was dissolved in 10 mL of EtOAc, washed with 1M K2CO3 (2×5 mL), dried (Na2SO4) and then concentrated in vacuo. Chromatography on a 5-g silica SPE column with 1-3% MeOH-dichloromethane afforded 60.8 mg (82%) of the title compound as a crystalline yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.76 (br s, 1H), 8.19 (d, 1H, J=14.1 Hz), 7.22, 7.26 (AB q, 2H, J=3.7 Hz), 6.80 (d, 1H, J=8.5 Hz), 3.11-3.19 (m, 4H), 2.92-2.95 (m, 2H), 2.69-2.76 (m, 2H), 2.55-2.65 (br m, 4H), 2.37 (s, 3H), 1.82-1.86 (m, 2H), 1.5-1.7 (br m, 1H) and 1.42-1.53 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C23H28FN5O2, 426.2 (M+H), found 426.3.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[OH-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[K+].[Br-]>O>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCCCCCBr
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: ClCCCCCCOc1ccc(Br)cc1
Temperature: 100 °C
Yield: 78 %

Procedure:
A 1 L flask provided with a stirrer was charged with 173.0 g (1.0 mol) of p-bromophenol (available from Tokyo Chemical Industry Co., Ltd.), 84.2 g (1.5 mols) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 399.0 g (2.0 mols) of 1-chloro-6-bromohexane (available from Wako Pure Chemical Industries Ltd.) and 200 g of water. The content was maintained at 100° C. for 6 hours. Then the reaction liquid was cooled to room temperature, and deposited KBr, produced by side reaction, was filtered off. The organic phase was separated and subjected to distillation under reduced pressure to give 236.9 g of the target p-(6-chlorohexyloxy)bromobenzene (yield: 78%, purity: 96%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].[CH2:22]([OH:26])[CH:23](O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:24][CH:23]1[CH2:22][O:26][CH:1]([C:3]2[CH:4]=[N:5][C:6]([C:12]3[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:19])[CH3:20])([CH3:17])[N:16]=3)=[C:7]([CH:11]=2)[C:8]([OH:10])=[O:9])[O:2]1
Reactant: CC(C)C1(C)N=C(c2ncc(C=O)cc2C(=O)O)NC1=O
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1COC(c2cnc(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)c2)O1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 5-formyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid, 5-(dimethyl acetal) (0.65 g, 0.00194 mol), 1,2-propanediol (0.65 g, 0.0085 mol) and a catalytic amount of p-toluenesulfonic acid in toluene is heated at reflux temperature for 2 hours. The reaction mixture is cooled to room temperature, concentrated in vacuo and the residue is dissolved in methylene chloride. The methylene chloride solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. The solid is chromatographed using silica gel and a gradient elution of 100% methylene chloride to 5% methanol in methylene chloride to yield the title compound as a yellow solid (0.5 g, 74%), mp 50°-62° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[Cl:28][C:29]1[C:30]([NH:44][CH3:45])=[CH:31][C:32]([O:42][CH3:43])=[C:33]([CH:41]=1)[C:34](N1C=CN=C1)=[O:35]>>[Cl:28][C:29]1[C:30]([NH:44][CH3:45])=[CH:31][C:32]([O:42][CH3:43])=[C:33]([CH:41]=1)[C:34]([O:14][CH:13]1[CH:12]2[CH2:11][CH2:10][N:9]([CH2:16][CH2:15]2)[CH:8]1[CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:35]
Reactant: CNc1cc(OC)c(C(=O)n2ccnc2)cc1Cl
Reactant: OC1C2CCN(CC2)C1CN1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CNc1cc(OC)c(C(=O)OC2C3CCN(CC3)C2CN2CCCCC2)cc1Cl

Procedure:
2-(1-Piperidinylmethyl)-1-azabicyclo[2.2.2]octan-3-ol cis isomer (2.47 g, 11 mmoles) was treated with n-butyllithium/hexane, and then with 1-[5-chloro-2-methoxy-4-(methylamino)benzoyl]-1H-imidazole, following the procedures described above for the corresponding trans isomer.
Reaction SMILES: C([NH:8][C:9]([CH3:22])([CH:11]=[CH:12][CH:13]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:10])(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][C:9]([CH3:22])([CH:11]=[CH:12][CH:13]1[C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][C:17]1([CH3:19])[CH3:18])[CH3:10]
Reactant: CC(C)(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(N)C=CC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture made basic with 20% KOH. The mixture is extracted with ether, the organic layer dried over NaSO4 and evaporated to yield 2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[C-]#N.[Na+].[CH3:28][OH:29]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([C:23]([O:29][CH3:28])=[O:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: CO
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a 100 mL flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.6 g, 0.0017 mol) in MeOH (60 mL) was added and cooled to 0° C. To the reaction flask, manganese (IV) oxide (0.74 g, 0.0085 mol) and sodium cyanide (0.429 g, 0.0085 mol) were added at 0° C. The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with chloroform and filtered through a pad of Celite® reagent. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound as a solid [0.52 g, 79%]. 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.87-7.86 (m, 2H), 7.29 (d, J=3.6 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 8H). LC-MS (ESI): Calculated mass: 373.1; Observed mass: 374.1 (RT: 1.57 min).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[S:38][CH:39]=[C:40]([Sn](CCCC)(CCCC)CCCC)[N:41]=1>CN(C=O)C.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>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:40]3[N:41]=[C:37]([O:36][CH3:35])[S:38][CH:39]=3)=[CH:3][C:4]([C:17]3[CH:22]=[N:21][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(-c3csc(OC)n3)c2s1
Temperature: 110 °C
Yield: 65.3 %

Procedure:
A stirred mixture of ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (150 mg, 0.274 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.0138 mmol) and 2-methoxy-4-(tributylstannyl)thiazole (0.33 mL, 0.822 mmol) in anhydrous DMF (3.0 mL) was purged with N2 for 20 min. The reaction vessel was sealed and heated at 110° C. for 10 h. After cooling to rt, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×20 mL) which was washed with brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash silica chromatography eluting with 0 to 100% EtOAc in iso-hexane to give 99 mg of the desired product as an off white gummy solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=2[S:5][C:6]=1[CH3:7].[Li]CCCC.[F:19][C:20]1[C:24]([F:26])([F:25])[C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[C:21]=1F.O>C1COCC1.CCCCCC>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([C:21]3[C:22]([F:30])([F:29])[C:23]([F:27])([F:28])[C:24]([F:25])([F:26])[C:20]=3[F:19])=[C:6]([CH3:7])[S:5][C:4]=2[CH:8]=1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Reactant: COc1ccc2c(Br)c(C)sc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(C3=C(F)C(F)(F)C(F)(F)C3(F)F)c(C)sc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a stirred solution of 7.61 g (0.03 mol) of 3-Bromo-6-methoxy-2-methylbenzo[b]thiophene (compound obtained in Step 2 of the synthesis of the compound 9) in 120 mL of anhydrous THF is added dropwise 11.90 mL (0.034 mol) of a 2.5M solution of nBuLi in hexane at −78° C. under nitrogen atmosphere. The resulting mixture is stirred for 30 min at −78° C., then 20 g (0.09 mol) of perfluorocyclopentene is added in a single portion. After the addition is completed, the mixture is allowed to return to room temperature, then hydrolysed with 120 mL of water. The mixture THF-water is extracted three times with 150 mL of Et2O. The resulting organic phase is washed several times with saturated aqueous NaCl solution, dried over magnesium sulfate and then concentrated under reduced pressure. The crude product purified by column chromatography on silica gel and eluted with mixtures consisting of pentane and CH2Cl2 of increasing polarity (100:0 to 80:20) gives an oily product (8.12 g, 72% yield), pure enough to be used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][NH2:18])=[CH:13][CH:14]=1
Reactant: NCCCc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: NCCCc1ccc(O)cc1
Yield: 91.1 %

Procedure:
100% Palladium-carbon catalyst (water content 50%, 120 mg) was added to a solution of 3-(4-benzyloxyphenyl)propylamine (620 mg, 2.57 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred for 2 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 3-(4-hydroxyphenyl)propylamine (354 mg, 91.1%).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8]([Cl:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC[C@H](C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@H](C(=O)Cl)c1ccccc1
Reaction time: 2 h

Procedure:
Combine (S)-2-phenylpent-4-enoic acid (1.53 g, 8.7 mmol), dichloromethane (10 mL), and dimethylformamide (1 drop). Add oxalyl chloride (1 mL, 11.46 mmol). After 2 hours, evaporate in vacuo to give (S)-2-phenylpent-4-enoyl chloride. Combine with toluene (10 mL) and add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (2 mL, 40%). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, dry the organic over MgSO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with hexane to give a solid. Collect the solid by filtration and dry to give (S)-2-phenylpent-4-enoic acid, N-methyl amide: mp; 97-99° C. Rf =0.53 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][CH:23]=1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36].N1C=CC=CC=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:38]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:35]([CH3:37])([CH3:36])[CH3:34])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 36 h
Yield: 62.8 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 7e (3.8 g, 7.71 mmol) was dissolved in 100 mL DMF, followed by addition of DMAP (188 mg, 1.54 mmol), TBSCl (1.39 g, 9.25 mmol) and pyridine (50 mL) in turn, and the reaction mixture was stirred for 36 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 150 mL water were added. The aqueous phase was extracted with ethyl acetate (100 mL×3) and the organic extract was washed with saturated sodium chloride solution (30 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxy-methyl]-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 7f (2.94 g, yellow grease), yield: 62.8%. 1H NMR (400 MHz, DMSO-d6): δ 7.94 (s, 2H), 7.45 (d, 1H), 7.40 (d, 1H), 7.35-7.28 (m, 1H), 7.17-7.05 (m, 2H), 7.01-6.90 (m, 2H), 5.00 (d, 1H), 4.84-4.74 (m, 2H), 4.68 (q, 2H), 4.11-3.87 (m, 3H), 3.73 (dd, 1H), 3.60-3.46 (m, 1H), 3.42 (ddd, 1H), 3.14 (td, 1H), 2.92 (s, 3H), 0.05-0.02 (m, 3H).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(O[CH:13](OCC)[N:14]([CH3:16])[CH3:15])C>>[CH3:13][N:14](/[CH:16]=[N:9]/[C:1]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:8])[CH3:15]
Reactant: NC(=O)c1ccncc1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccncc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
Isonicotinamide (2.00 g, 16.38 mmol) and N,N-dimethylformamide diethyl acetal (2.8 ml, 16.38 mmol) were combined and heated to 120° C. A short path distillation apparatus was used to collect the ethanol that was liberated during the reaction. The reaction mixture was an orange solution. After 15 minutes, additional N,N-dimethylformamide diethyl acetal (1.0 ml, 5.83 mmol) was added to the reaction mixture. After 1.5 hours, the reaction mixture was cooled to room temperature. The reaction mixture solidified upon cooling and was placed under high vacuum overnight to give the title compound (2.92 g, 16.48 mmol) as a yellow solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:11][N:10]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CC(C)=O>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:8]([F:7])([F:19])[F:20])=[N:10]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(F)(F)F
Yield: 100.1 %

Procedure:
Add K2CO3 (503 mg, 3.60 mmol) to a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 2.40 mmol) in acetone (8 mL) at ambient temperature under N2. Add 1-bromomethyl-4-methoxybenzene (0.51 mL, 3.6 mmol) dropwise to the mixture, and stir overnight under N2. Quench the reaction with H2O, and extract twice with EtOAc. Dry the combined organic layers over MgSO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 15% EtOAc in hexanes) to yield the title compound (789 mg, quantitative). ES/MS m/z 351.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32]C(=O)OC(C)(C)C)=[CH:27][CH:26]=3)=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O.C(#N)C>C(Cl)Cl>[NH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[O:24][C:20]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]4[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:18])[CH3:19])(=[O:16])=[O:15])=[CH:10][CH:9]=4)[N:4]=3)=[N:21][N:22]=2)=[CH:26][CH:27]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)o3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CN)cc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A solution of tert-butyl N-[[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]carbamate (45 mg, 0.08172 mmol) in CH2Cl2 (1 mL) was treated with TFA (1 mL, 12.98 mmol) and stirred at room temperature for 1 h. The solution was concentrated under reduced pressure then azeotroped with methanol/ CH2Cl2 (×2), dissolved in CH2Cl2/MeOH and passed through a carbonate cartridge. The eluent was concentrated then crystallised from hot acetonitrile giving a yellow crystalline solid (18 mg, 41% yield); 1H NMR (400 MHz, DMSO) d 1.20 (d, 6H), 1.97 (br s, 2H), 3.47 (m, 1H), 3.85 (s, 2H), 7.63 (d, 2H), 7.89 (br s, 2H), 7.98 (d, 2H), 8.11 (d, 2H), 8.40 (d, 2H) and 9.06 (s, 1H) ppm; MS (ES+) 451.41
Reaction SMILES: [NH4+:1].[OH-].C[O:4][C:5](=O)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1>CO>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([NH2:1])=[O:4])=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ccc(OC(F)(F)F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A 25% ammonia aqueous solution (20 ml) was added to (4-trifluoromethoxyphenoxy)acetic acid methyl ester in methanol (40 ml) and the mixture was stirred at room temperature overnight. After distilling the solvent off, the residue was washed with water and dried to afford the title compound as a white solid (12.1 g, yield 91%).